Out of the Box: Clinical Pearls for Acne and Rosacea

Linda Stein Gold, MD

  • Optimal antibiotic dosing and duration is not clear based on the literature. Data suggests that minocycline efficacy is not increased by increasing dose, only adverse effects are increased.
  • There appears to be a dose response curve for doxycycline.
  • “Short contact” benzoyl peroxide is appears to be more efficacious for decreasing p acnes on the trunk than benzoyl peroxide “wash”.
  • Diet does seem to influence acne. Low glycemic index diets and avoidance of skim milk may improve acne.
  • The current fad of coconut oil has no scientific studies in acne showing efficacy.  In-vitro and animal studies suggest an effect on inflammation and p. acnes.

Acne and Rosacea: Clinical Pearls

Guy Webster, MD, PhD

What you need to know about treating acne and rosacea…

  1. Isotretinoin absorption is very food dependent. An empty stomach causes a nearly 50% reduction in blood level.
  2. Antibiotic resistance has made macrolides useless in acne.
  3. Limiting antibiotic usage is critical for preserving antibiotic sensitivity.
  4. Use of topical retinoids early in acne therapy will allow withdrawal of antibiotics after a few months in many patients.
  5. Spironolactone and isotretinoin are two alternatives to antibiotics in severe acne.

Acne: Clinical Pearls

James Treat, MD

Dr James Treat provides us with an outline on the management of pediatric acne…

Acne Type and Age of Onset

  • Neonatal:  Birth to ≤6 wk
  • Infantile:  6 wk to ≤1 y
  • Mid-childhood:  1 y to <7 y
  • Preadolescent:  ≥7 to ≤12 y or menarche in girls
  • Adolescent:  ≥12 to ≤19 y or after menarche in girls

Neonatal Acne:

  • Benign, self-limited, asymptomatic eruption of erythematous papules and pustules; no comedones
    • Typically localized to cheeks, forehead, and scalp
      • But: can extend into scalp and onto the shoulders (Neonatal Cephalic Pustulosis)

Infantile Acne:

Clinical: Typically starts at around 3-6 months of age up (as young as 6 weeks) and usually lasts 6-12 months

  • Clinically this looks like adolescent acne:
    • Comedones, inflammatory papules and nodules
  • Scarring potential
  • Harbinger for later acne
  • Most Infantile acne is NOT associated with an endocrinopathy

BUT if on exam you see:

  • Excess Growth
  • Advancement of Tanner Stage
  • Cliteromegaly or enlarged testciles.

THEN: Hormonal workup, consider endocrine evaluation

  • FSH, LH, DHEAS, Free and Total Testosterone, 17 OH Progesteterone , androstendione, and Bone Age

Mid-Childhood Acne

Starts between 1 and 7 years of age.

Clinically this looks like adolescent acne:

  • Comedones, inflammatory papules and nodules
  • Scarring potential
  • Harbinger for later acne
  • This is not an age when there is normal androgen production so acne at this age requires a workup.
  • Clinical exam:
    • Excess Growth
    • Advancement of Tanner Stage
    • Cliteromegaly or enlarged testciles.

Hormonal workup and endocrine evaluation

  • FSH, LH, DHEAS, Free and Total Testosterone, 17 OH Progesterone, androstenedione and Bone Age

Treatment (off label): same as adolescent acne except NO tetracycline derivatives

  • Topical retinoids and Benzoyl Peroxide products often enough
  • Systemic choices: erythromycin derivatives, isotretinoin

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

Eruption! Pediatric Acne

Larry Eichenfield, MD

Dr Eichenfield provided the audience at MauiDerm 2014 with an update on the new pediatric guidelines for the management of acne. These guidelines, published in May of 2013, were developed by the American Acne and Roseacea Society and endorsed by the American Academy of Pediatrics, which is the first time that the Academy has a set of guidelines for the management of acne. One of the main reasons this was done was to address the practice gap between dermatologists and pediatricians. The group of experts was comprised of dermatologists with expertise in acne, pediatric dermatologists, and pediatricians.

As we know, acne ranges in terms of presentation and severity.  Acne can be categorized by age, i.e., neonatal (0-6wk), infantile (0-1), mid-childhood (1-7), preadolescent (7-12), and adolescent (12-19).

Dr Eichenfield emphasizes that mid-childhood acne (age 2 – 7) acne is the most worrisome. It can be associated with premature adrenarche, Cushings Syndrome, CAH, gonadal/adrenal tumors, and precocious puberty. Mid-childhood acne is very uncommon, and is a sign of early adrenarche, often associated with a pathologic process. The assessment for mid-childhood acne includes assessment of  testicular size (males), presence or absence of hirsutism, clitoromegaly, androgenetic alopecia, increased muscle mass, and/or deepening of the voice (males).  Tests and examinations include a growth chart, evaluation including bone age, tanner stage, Total/Free testosterone, DHEAS, androstenedione, LH, FSH, prolactin, and 17OH-progesterone. The guidelines suggest that you should refer these patients to a pediatric endocrinologist.

What do the new guidelines say?

It’s important to know that pre-adolescent (7 ≤ 12 years) acne is common and may precede other signs of pubertal maturation. Work-up beyond history and physical is generally unnecessary unless there are signs of androgen excess, polycystic ovarian syndrome, or other systemic abnormalities. According to the data, there is evidence that acne, and possibly puberty, are now occurring at an increasingly earlier age for both males and females. If you look at some of the papers that were published about a decade ago, the amount of comedones that were seen in a ten or 12 year-old then is probably different now. Twelve is no longer an age point defining “normal acne;”  if you are eight and above acne can be typical and common.

After the guidelines were published early acne in preteens was highlighted in several newspaper articles, and radio and television segments.  Articles were published in both the New York Times and USA Today. In fact, after the New York Times article was published, there were over 157 blogs that provided an interesting perspective comparing what the general public thinks regarding acne and what we do as specialists.  A recent analysis of the National Ambulatory Medical Care Survey (NAMCS) database assessed trends in the age of children seeking treatment for acne. NAMCS data from 1979 through 2007 were analyzed for all physician visits in which acne vulgaris was listed as a diagnosis in children aged 6 to 18. The analysis revealed a significant decrease in the mean age of children seeking treatment for acne over this period.

Over the past several years, clinicians have noted an earlier onset of acne—that is, the appearance of acne in patients as young as 8 or 9 years. Indeed, it has been suggested that 12 years of age should no longer be considered the low end of the “normal” range for the onset of acne.

Acne may be the first sign of the onset of puberty in children aged 7 to 11 years. The general clinical impression of earlier puberty is, in fact, supported by epidemiologic data in the US and elsewhere. In general, the trend toward earlier puberty is stronger among girls than among boys. In any event, the earlier onset of acne has mirrored the downward trend in puberty timing.

The guidelines provide an algorithm for the management of pediatric acne. If you can generally categorize the acne as mild, moderate or severe, you can access the algorithm. Keep in mind that this algorithm is slightly different than prior guidelines, in that for mild acne initial treatment benzoyl peroxide, based upon the evidence, made it as one potential, initial solo therapy.   The guidelines can be found in the Journal of the American Academy of Pediatrics, or online at: http://pediatrics.aappublications.org/content/131/Supplement_3/S163.full.pdf.

Acne Guidelines: Highlights

The guidelines emphasize appropriate use of medications based upon disease severity.  Oral antibiotics should be used concurrently with a topical retinoid because it is important to build a topical regiment to “transfer the patient to” after a limited course of antibiotics.   A variety of studies show that 70 percent of the time you can transition your patient who is on an oral antibiotic and topical retinoid to a regiment of topical retinoid alone or combinations with topical antimicrobials (like benzoyl peroxide) and/or antibiotics

Topical retinoids may be used as monotherapy or in combination products and in regimens of care for all types and severities of acne in children and adolescents of all ages. It is important to remember that topical antibiotics are not recommended as monotherapy and if a topical antibiotic treatment is to be used for more than a few weeks, topical benzoyl peroxide should be added, or used in combination products. The guidelines also suggest that fixed-dose combination topical therapies may be useful in regimens of care for all types and severities of acne.

With regards to oral antibiotics, they are a reasonable approach for moderate to severe inflammatory acne vulgaris at any age. Tetracycline derivatives should not bee utilized in children 8 years of age and below. Second generation tetracyclines are “sometimes preferred” to tetracycline because of ease of use, fewer problems with absorption with food and minerals in vitamins and other supplements, and less frequent dosing. It’s very important that patients are educated and monitored for potential adverse events when utilizing oral antibiotics for acne.

Hormonal therapy is actually interesting because there are people who are very pro-hormonal therapy and others are a bit more conservative and prefer oral antibiotics. The group ended up stating that combined oral contraceptives (OCs) may also be useful as second-line therapy in regimens of care in pubertal females with moderate to severe acne; however, tobacco use and family history of thrombotic events should be assessed. Due to concerns about growth and bone density, many recommend withholding OCs for acne until one year after onset of menstruation.

Isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents and may be utilized in younger patients. Remember that extensive counseling, particularly regarding the avoidance of pregnancy, as well as careful monitoring of potential side effects and toxicities, is recommended. As far as the specific discussion on isotretinoin in pediatric use, there are bone mineralization changes; however, the data is inconsistent and it is not associated with increased factures. Hyperostoses are very uncommon for acne and there has been one case of premature epiphyseal closure in a patient on isotretinoin for acne, but that’s not necessarily attributable to the isotretinoin. IBD is controversial, but counseling is reasonable.

Practice Gaps

Dr Eichenfield states that there is a chasm in the way that General Practitioners, Pediatricians, and Dermatologists treat acne. A 2014 paper by Tan et al showed that topical retinoids were prescribed in 41 percent of acne visits. Older age, male gender and having Medicaid insurance were associated with a lower likelihood of receiving a topical retinoid prescription. Moreover, the researchers found that in the Medicaid dataset, patients who saw a pediatrician or general practitioner had lower odds of receiving a topical retinoid prescription versus those patients who saw a dermatologist.

Another study looked at the National Ambulatory Medical Care Survey (NAMCS) data regarding the treatment of preadolescent acne in the United States. The data were stratified according to age group and physician specialty. The findings are presented below:

Screen Shot 2014-06-11 at 1.39.02 PM

 

What are Dr Eichenfield’s thoughts on the practice gaps?

  • Over-reliance on oral antibiotics
  • Use of oral antibiotics without BP
  • Use of oral antibiotics without Retinoid
  • Use of topical and oral antibiotics together, without retinoid
  • Under appreciation of early, significant acne as predictor of worse acne over time

Literature has shown that early comedonal acne may predict later severe acne. So remember that if you see a patient with a high number of comedone counts at an early age, their chances of severe inflammatory acne at a later age is much higher than someone who has low comedone counts early on.

Another issue that Dr Eichenfield is appreciating more and more in clinical practice is that you can have very early, subtle scarring. We know that there is a lot of scarring that occurs without nodular-cystic disease, so this is very common. This is an important to try to get patients evaluated early so that scarring can be prevented, and minimized. Dr Eichenfield advised  that a useful technique is to side-light the face and look for depressions in the face, displaying  scarring as opposed to post-inflammatory hyperpigmentation or persistent erythema.

A study by Patel and colleagues aimed to determine what types of acne lesions preceded the development of atrophic acne scars. Twenty-two patients with mild to moderate acne were enrolled in a split-face study in which one side was treated with non-ablative laser and the other remained untreated. A series of standardized digital facial photographs was obtained from the untreated side at 2-week intervals from baseline to week 12, and all photographs in the series were aligned with the baseline photo. When all of the atrophic scars were tracked to baseline, 53 were found to have arisen from clinically normal skin, 30 were established scars, and 21 arose from acne lesions, including closed comedones. However, no open comedones at baseline corresponded to atrophic scars.  The results of this study not only verify that inflammatory acne lesions often lead to atrophic scarring, but also demonstrate that acne scars may arise from initially comedonal lesions, as well as from clinically normal skin. Moreover, they indicate that a period of 12 weeks is sufficiently long to develop and establish atrophic scars. Thus, aggressive treatment of both inflammatory and comedonal acne is warranted to minimize acne scarring.

What about Isotretinoin?

We know that isotretinoin is the most effective treatment for acne; however, the optimal dosing regimen is still unknown.  Dr Eichenfield comments that he uses isotretinoin commonly. He also states that he tends to be biased towards lower-dose isotretinoin on a daily basis, working up to cumulative doses of 120-150 mg/kg.  He commonly will the daily doeses up to the “highest comfortable dose,”  that is, the highest dose with minimal significant side effects or laboratory abnormalities.

A recent publication looked at 180 patients with acne resistant to other treatments who were enrolled in an observational, prospective study of istotretinoin with cumulative doses less than to 220 mg/kg versus isotretinoin greater than or equal to 220 mg/kg. Of these patients, 116 participated in the 12-month follow-up survey. At that time, 97.4 percent of the patients reported that their acne was improved. Overall, acne in 32.7 percent of the patients in the study relapsed at 12 months, and 1.72 percent of the patients required a retrial. In the lower-dose treatment group, the relapse rate was 47.4 percent compared with 26.9 percent in the high-dose group. Almost 100 percent of the patients in both treatment groups developed cheilitis and xerosis during treatment. Retinoid dermatitis was significantly more common in the high-dose treatment group and none of the other adverse effects were significantly different between the two groups.  However,  it should be noted that in the higher dose group,  nine patients had  persistent muscle aches, eight patients had persistent joint aches, and two patients  had hearing changes. (Blasiak RC et al. JAMA Dermatol 2013;149(12):1392-1398) Also of importance with regards to this study are the laboratory abnormalities based upon the dosing. (See table 1)

Screen Shot 2014-06-11 at 1.39.15 PM

 

Dr Eichenfield states that this publication has yet to “move him” to abandon his current methodology with regards to isotretinoin dosing for this patients.

Idiopathic Facial Asceptic Granuloma (IFAG) and Childhood Rosacea

We have seen a very interesting change in perspective regarding this disease. Occasionally, we see these patients who present with lumpy, cystic-type lesions, separate from acneiform lesions.   A multi-center study of four French dermatologic centers looked at patients who were diagnosed with IFAG between October 2000 and July 2007. Thirty-eight patients were included in the study. The median age at the time of diagnosis of IFAG was 43 months, with a median follow-up of 3.9 years. Sixteen patients (42.1%) had at least two criteria of childhood rosacea, 11 of 32 (34.4%) with a single lesion and 5 of 6 (83.3%) with multiple lesions. Remember that childhood rosacea presents with flushing, permanent or recurring erythema, papules and postules without comedones or microcysts, convexity predominance of lesions, ocular rosacea (chalazions, conjunctival hyperemia, keratitis). (Prey S, Ezzedine K et al. Pediatric Dermatology 2013;30:429-32)

What does this mean to us? Children with IFAG are at risk for childhood rosacea, and follow-up is advised, including periodic ophthalmologic assessment.

 

MauiDerm News Editor- Judy Seraphine

 

Hot Papers in Acne

Written by: Judy Seraphine

At MauiDerm 2014, Dr Webster lead off the discussion by reviewing some of the hot papers in acne in 2013 that help with either the understanding of acne or the treating of it. The first paper, published in JAMA Derm, discusses high dose isotretinoin and whether or not it is safe and effective. Traditionally, data demonstrated that the 120 mg/kg dose has a 20% relapse rate, this is based upon youth, severity, diet, and hormones. We have learned that if someone has really bad acne as a child, they will most likely have a relapse later and likewise, patients who had really severe acne on isotretinoin will likely relapse. A paper published in the International Journal of Dermatology in 2012 demonstrated that isotretinoin 290 mg/kg had a 12 percent relapse rate over three years; of note, adverse events were not any worse. Another retrospective paper, published in JAMA Derm in 2013, showed that isotretinoin greater than 220 mg/kg had a relapse of 27 percent versus 48 percent in doses less than 220 mg/kg—so the really high dose had a lower rate, but it was still somewhat high. Those who received the higher dose did have increased dermatitis.  Another finding from the study was that those on the higher dose of isotretinoin were aching a lot longer even when the isotretinoin was over; this is something that we don’t see with the standard dosing. As dermatologists, we have to consider that there may be a difference in how we define relapse and prospective head-to-head studies need to be done.

A paper, published by Drs Webster and Leyden in the JAAD, looked at a new form of isotretinoin that doesn’t require a dietary adjustment. We have known for years that isotretinoin requires a fatty meal, as there is decreased absorption on an empty stomach; in fact, there is a 50 percent decrease of isotretinoin if taken on an empty stomach. Dr Webster feels that the most common cause of isotretinoin resistance and relapse is due to patients taking the drug on an empty stomach. Data exist demonstrating that high-fat meals enhance the absorption of the drug, yet this new form of isotretinoin may be a viable alternative with regards to dietary change and acne outcomes. Dr Webster comments that whether or not you use this new drug or regular isotretinoin, it really should be taken with some fat in the stomach.

Figure 1 depicts the absorption rates with Accutane 40mg “fed” versus “fasted” and you can see that there is a significant difference.

Screen Shot 2014-05-26 at 8.06.28 AM

With the new product, isotretinoin-lidose, you can see that the absorption rate in Accutante (fasted) is exactly the same; however, the newer form of isotretinoin (fasted) is much higher. This drug may be helpful for compliance-challenged patients. (See Figure 2)

Screen Shot 2014-05-26 at 8.06.37 AM

What about P. acnes?

Recently, there have been a couple of papers that have been published suggesting that there may be a particularly hot strain of P. acnes that is causing acne. Years ago, one of Dr Webster’s first papers was looking at all of the strains of P. acnes with a bacteriophage typing system and they found that there were many strains of P. acnes that were reproducibly different, but there was no difference in where they showed up, i.e., the same spread of strains whether it was inflammatory or non-inflammatory acne or whether it was isolated from CNS surgery or from hip infections.

A recent paper, published in the Journal of Investigative Dermatology, reported that they found two strains of P. acnes. The type 1a strain of P. acnes predominates in inflammatory acne lesions and 1b in non-inflammatory; therefore, some strains are associated with inflammatory acne. A second paper, published in the British Journal of Dermatology, found that this association; however, is a trend and not an absolute, i.e., there were patients with bad acne who had the “non-inflammatory” strain and there were patients with no acne who had the “inflammatory” strain. Typically patients with inflammatory acne had a mixture of the two with the “bad strain” predominating.

How do you explain this and does it make sense? Does it mean that people with bad acne need to have their P. acnes replaced with a non-verulent strain so that they don’t get pimples? Or is this an ecological issue? The skin microbiome is a microecology in the same way that a swamp has its own ecology. Different selective pressures do different things to the microenvironment. For example, if you sample the forehead, it is very rich in P. acnes and malassezia. If you sample the forearm, there are usually no sebaceous glands and there is no food for P. acnes so you don’t get a lot of growth from P. acnes. This tells us that big variations in environments lead to big variations in strains.

Dr Webster suspects that this difference in P. acnes distribution between acne and non-acne is not necessarily “bad strain” versus “good strain”, it’s that inflammation is a selective pressure just like the presence or absence of food/water in an ecosystem; this adds oxidative stress on the bacteria. Remember that P. acnes defends itself against oxidation pretty well even though it is an anaerobe. Dr Webster feels that the enrichment of type 1a strains in patients with inflammatory acne is merely showing that inflammation selects through strains that can survive better in a more oxidized environment.  As dermatologists, we really need to look at how strain 1a is different from strain 1b—does it defend itself better against oxidation?

 

 

 

 

 

Acne: Part 2: Pediatric Acne

Larry Eichenfield, MD

Remember that acne can be categorized by age, i.e., neonatal (0-6wk), infantile (0-1), mid-childhood (1-7), preadolescent (7-12), and adolescent (12-19). Dr Eichenfield emphasizes that for dermatologists, mid-childhood (age 2 – 7) acne is the most worrisome. It can be associated with premature adrenarche, Cushings Syndrome, CAH, gonadal/adrenal tumors, and precocious puberty. Mid-child acne is very uncommon and dermatologists may want to consider a referral to an endocrinologist. The evaluation for mid-childhood acne includes testicular size (males), hirsutism, clitoromegaly, androgenetic alopecia, increased muscle mass, and deepening of the voice (males).  If the acne is persistent, severe, or virilizing, tests/examinations include a growth chart, evaluation including bone age, tanner stage, Total/Free testosterone, DHEAS, androstenedione, LH, FSH, prolactin, and 17OH-progesterone.

What do the new guidelines say?

These guidelines were developed by the American Acne and Roseacea Society and endorsed by the American Academy of Pediatrics, which is the first time that the Academy has a set of guidelines for the management of acne. One of the main reasons this was done was to address the gap between pediatric dermatologists and pediatricians. It’s important to know that pre-adolescent (7 ≤ 12 years) acne is common and may precede other signs of pubertal maturation. Work-up beyond history and physical is generally unnecessary unless there are signs of androgen excess, polycystic ovarian syndrome, or other systemic abnormalities. There is evidence that acne, and possibly puberty, are now occurring at an increasingly earlier age.

A recent analysis of the National Ambulatory Medical Care Survey (NAMCS) database assessed trends in the age of children seeking treatment for acne. NAMCS data from 1979 through 2007 were analyzed for all physician visits in which acne vulgaris was listed as a diagnosis in children aged 6 to 18. The analysis revealed a significant decrease in the mean age of children seeking treatment for acne over this period.

Over the past several years, clinicians have noted an earlier onset of acne—that is, the appearance of acne in patients as young as 8 or 9 years. Indeed, it has been suggested that 12 years of age should no longer be considered the low end of the “normal” range for the onset of acne.

Acne may be the first sign of the onset of puberty in children aged 7 to 11 years. The general clinical impression of earlier puberty is, in fact, supported by epidemiologic data in the US and elsewhere. In general, the trend toward earlier puberty is stronger among girls than among boys. In any event, the earlier onset of acne has mirrored the downward trend in puberty timing.

Acne Guidelines: Highlights

Topical retinoids may be used as monotherapy or in combination products and in regimens of care for all types and severities of acne in children and adolescents of all ages. It is important to remember that topical antibiotics are not recommended as monotherapy and if a topical antibiotic treatment is to be used for more than a few weeks, topical benzoyl peroxide should be added, or used in combination products. The guidelines also suggest that fixed-dose combination topical therapies may be useful in regimens of care for all types and severities of acne. With regards to oral antibiotics, they are appropriate for moderate to severe inflammatory acne vulgaris at any age. Tetracycline derivatives should not be utilized in children 8 years of age and below. Second generation tetracyclines are sometimes preferred to tetracycline because of ease of use, fewer problems with absorption with food and minerals in vitamins and other supplements, and less frequent dosing. It’s very important that patients are educated and monitored for potential adverse events when utilizing oral antibiotics for acne. Combined oral contraceptives may also be useful as second-line therapy in regimens of care in pubertal females with moderate to severe acne; however, tobacco use and family history of thrombotic events should be assessed. Due to concerns about growth and bone density, many recommend withholding OCs for acne until one year after onset of menstruation. Isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents and may be utilized in younger patients. Remember that extensive counseling, particularly regarding the avoidance of pregnancy, as well as careful monitoring of potential side effects and toxicities, is recommended.

 

 

Acne: Part 1

On Day two of MauiDerm 2014, our panel of experts in the field of Acne presented new insights and new data that may help the practicing dermatologist improve the overall outcomes of patients in their practice.

Isotretinoin Issues

Written by Judy Seraphine

Dr Guy Webster lead off the discussion by discussing some of the hot papers in acne in 2013 that help with either the understanding of acne or the treating of it. The first paper, published in JAMA Derm, discusses high dose isotretinoin and whether or not it is safe and effective. Traditionally, data demonstrated that the 120 mg/kg dose has a 20% relapse rate. One thing that we have figured out is that if someone has really bad acne as a child, they will most likely have a relapse later and likewise, patients who had really severe acne on isotretinoin will likely relapse. Two recent studies showed that the more accutane than we typically use may decrease the relapse rate. Another paper, a retrospective study, looked at patients on a really, really high dose isotretinoin versus those on high dose isotretinoin and the researchers found the really high dose had a lower relapse rate, but it was still somewhat high. As dermatologists, we have to consider that there may be a difference in how we define relapse and prospective head-to-head studies need to be done.

Another paper, published by Drs Webster and Leyden in the JAAD, looked at a new form of isotretinoin that doesn’t require a dietary adjustment. We have known for years that isotretinoin requires a fatty meal as there is decreased absorption on an empty stomach. Dr Webster feels that the most common cause of isotretinoin resistance is due to patients taking the drug on an empty stomach. Data exist demonstrating that high-fat meals enhance the absorption of the drug, yet this new form of isotretinoin may be a viable alternative with regards to dietary change and acne outcomes.

What about P. Acnes? Dermatologists should remember that there are many strains of P. Acnes that have subtle differences, but there was no difference in where they developed. A recent paper reported that they found two strains of P. Acnes. The type 1a strain of P. Acnes predominates in inflammatory acne lesions and 1b in non-inflammatory. Some strains are associated with inflammatory acne; however, this association is a trend and not an absolute.  The question is whether this is due to ecology or virulence? There are two possibilities: 1a is more pathogenic and can survive better in an inflamed mileu. It’s important to look at how strain 1a is different from strain 1b.

Pediatric Acne

Lawrence Eichenfield, MD

Lots of new studies have been conducted with regards to pediatric acne along with some updates to The American Acne and Rosacea Society’s Pediatric Guidelines, which have also been recently endorsed by The American Academy of Pediatrics.

For dermatologists, mid-childhood (age 1 – 7) acne is most worrisome. It can be associated with premature adrenarche, Cushings Syndrome, CAH, gonadal/adrenal tumors, and precocious puberty. The evaluation for mid-childhood acne includes testicular size (males), hirsutism, clitoromegaly, androgenetic alopecia, increased muscle mass, and deepening of the voice (males).  If the acne is persistent, severe, or virilizing, tests/examinations include a growth chart, evaluation including bone age, tanner stage, Total/Free testosterone, DHEAS, androstenedione, LH, FSH, prolactin, and 17OH-progesterone. Dermatologists should also consider a referral to an endocrinologist.

Pre-adolescent (7 ≤ 12 years) acne is common and may precede other signs of pubertal maturation. A complete work-up beyond history and physical is generally unnecessary unless there are signs of androgen excess, polycystic ovarian syndrome, or other systemic abnormalities

How should we manage preadolescent acne?

It’s important to remember that comedones are often early common on the forehead and mid-face and the truncal area is much less common. This may precede other signs of puberty. For the most part, it correlates with sebum output and sebaceous follicle numbers. P. acnes colonization is a key thing to keep in mind. **The prevalence of severity of acne of acne correlates with advanced pubertal maturation.

Acne Guidelines: Recommendations and Highlights

Acne Categorization by Age

  • Acne in neonates- 0-6 wk
  • Infantile – 0-1
  • mid-childhood 1-7
  • preadolescent 7-12
  • adolescent 12-19

 

Initial Therapy: recommendations regarding initial therapy

OTC products such as benzoyl peroxide as a single agent, topical retinoids, or combinations of topical retinoids, antibiotics, and benzoyl peroxide as individual agents or fixed-dose combinations

Topical retinoids (tretinoin, adapalene, tazarotene) may be used as monotherapy or in combination products and in regimens of care for all types and severities of acne in children and adolescents of all age

Topical Antibiotics

  • Topical antibiotics (clindamycin, erythromycin) are not recommended as monotherapy
  • If topical antibiotic treatment is to be prolonged for more than a few weeks, topical benzoyl peroxide should be added, or utilized in combination products

Oral Antibiotics

  • Oral antibiotics are appropriate for moderate to severe inflammatory acne at any age
  • Second generation tetracyclines (doxycycline, minocycline) are sometimes preferred to tetracycline because of ease of use, fewer problems with absorption, and less frequent dosing

Fixed Dose Combination Treatment

  • May be useful in regimens of care for all types and severities of acne

Hormonal Therapy

  • Second-line therapy in regimens of care in pubertal females with moderate to severe acne. Tobacco use and family history of thrombotic events should be assessed.
  • Due to concerns about growth and bone density, many experts recommend withholding OCs for acne unassociated with endocrinologic pathology until one year after onset of menstruation

Isotretinoin


  • Isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents and may be utilized in younger patients
  • Extensive counseling particularly regarding the avoidance of pregnancy, as well as careful monitoring of potential side effects and toxicities, is recommended

What about off-label treatment?

Below is a summary of some recent studies that look at off-label therapy for pediatric acne.

Tretinoin 0.04% micro-gel

  •  8-12 mild to moderate acne
  • Mean 59 lesions (9 inflammatory)
  • 12 weeks: 48% lesion count decrease
  • Tretinoin 0.04% vehicle controlled 8-11 yrs
  • Ada 0.1/BP2.5% vehicle-controlled 9-11 yrs

Retinoids

111 pt 9-11 yr olds, Retin A 0.04% micro db, vehicle controlled study, 12 wks

  • 66% prepubertal; 65 lesions (9.5 inflammatory)
  • 44% Non-inflam lesion count (vs 30%)

285 pt 9-11 yr olds, Ada .1-BP 2.5, db vc 12wks

  • 54 lesions (15 inflammatory)
  • 47% clear/almost clear (vs 15%)
  • App 50% Total lesion count decrease (vs<10%)

Oral Antibiotics

Short-term combination therapy and long-term relapse prevention in the treatment of severe acne vulgaris.

Doxycycline (DCN) and (Adapalene 0.1% – benzoyl peroxide 2.5%) = (A/BPO) or vehicle qd x 12 weeks, then A/BPO vs vehicle

  • 76% lesion count decrease

What about Isotretinoin-induced flares?

  • Appears to be a dose-related phenomenon, so start at a low dose to avoid this problem

What about prevention?

  • Systemic cyclines for anti-inflammatory effects (e.g. Mino or Doxy q day x 2 weeks)
  • Patient monitoring

 

Acne and Rosacea: Part 1

Our panel of experts in the field of Acne and Rosacea presented interesting case studies and new data that may help the practicing dermatologist improve the overall outcomes of patients in their practice.

Isotretinoin Issues

Guy Webster, MD, PhD

What are the reasons that 20% of patients do not respond to isotretinoin?

  • Inadequate dosing
  • Virilization
  • Taken on an empty stomach
  •  Young patient with bad disease

Dr Webster feels that the most common cause of isotretinoin resistance is due to patients taking the drug on an empty stomach. Data exist that demonstrate that high-fat meals enhance the absorption of the drug. A new isotretinoin, 4-oxo-isotretinoin, (brand name Absorica) demonstrated 2 times greater absorption on an empty stomach (83%) that that of the standard isotretinoin in the absence of food.

Adverse Events

Common AEs include dry skin, dry lips, high TGs, acne flare. Uncommon AEs include elevated CK, elevated AST and ALT, dry eyes, decreased night vision, depression and acne fulminans.   Acne fulminans is uncommon yet, devastating. This is most often seen early in treatment in patients with moderate to severe chest acne. To avoid this you can start with low dose, (e.g. 10mg/day or 20 mg/day) and give prednisone 20 mg/day for the first month.

Bowel disease has also been talked about in association with isotretinoin for the last thirty years. Studies found that the bowel disease was as common in the isotretinoin group as in the antibiotic group, yet both groups were higher than placebo. This could be related to the acne itself, not necessarily the medication.

Data shows that twenty-week acne therapy with isotretinoin does not affect bone. Regarding depression, there was identical risk for suicide and depression on isotretinoin as seen in that of patients on antibiotics in a very large well-powered study.

Rosacea

Hillary Baldwin, MD

We know that facial diseases cause a great deal of emotional distress. Rosacea is linked to depression and suicide and an improvement in rosacea is linked to improvement in quality of life (QOL). While teaching camouflaging/make-up techniques takes time, it does result positive effects. Many brands are available and also are accessible and affordable and in reality, minimal training is required.

Why then is it that some patients do not use makeup?

  • 53% don’t know how to use makeup
  • 29% fear it will get worse
  •  9% didn’t feel they needed it

After the use of makeup:

  •  99% made noticeable improvement
  •  99% continued to use it
  • 75% felt that it contributed to relationship with others
  • Overall improvement of QOL

Dr. Baldwin’s take home point….get familiar with a someone who knows how to do makeup and send your patients to them. It will certainly improve their QOL.

Why isotretinoin in rosacea?

It’s efficacy was first noted in 1981. There are numerous doses from 0.1-1.0 mg/kg/day. Isotretinoin improves papules, pustules, ocular disease, halts the progression of developing rhinophymas, and can lead to a reduction in erythema.

Continuous low-dose isotretinoin (10-20mg/day)

This may provide long-term control and is an alternative to antibiotics; however, appropriate monitoring necessary. Patients still have to follow iPLEDGE rules which can be difficult because they have to return monthly.

In a study with 573 patients with moderate PPR or rosacea that compared isotretinoin to doxycycline, the isotretinoin 0.3mg/kg/day dosing was found not to be inferior to doxycycline (100mg) and both were found to be superior to placebo.

Conclusions
  • In severe, refractory or recalcitrant patients, dermatologists should consider the use of isotretinoin
  • Cosmetic camouflage/makeup does work and has shown to improve patient QOL

Interesting Cases

Alan Shalita, MD

In this presentation, Dr Shalita reviewed interesting cases of acne and possible management strategies to overcome these challenging patients.

The Patient with Sandpaper Comedones

This is a rare condition that is often times difficult to treat. Dermatologists can try compounded tretinoin solution (0.05%), which can be very, very irritating but effective and possibly TCA peels, with the right concentration. Laser abrasion may be effective if you have access to a CO2 laser. Another technique that can provide some relief is what Dr Shalita refers to as “vacuum suction.”

What about chin acne?

Chin acne is typically found in young adult women and may involve the mandible and adjacent neck. Chin acne may or may not be hormonal, but frequently improves with the use of a combination of  both oral contraception and spironolactone. Oral antibiotics can also be helpful. Topical therapy is often times too irritating for patients.

Patients with Nodulopustular Acne

Many dermatologists withhold isotretinoin treatment for too long. If this is the case, you may occasionally need I&D. It is recommended to start on low isotretinoin (target: total dose 120-150 mg/kg) and you may need to culture if the patient is not responding.

Primary Irritant Reaction

This is more common in fair skin, but can occur in all skin types. In many cases, it was a common reaction to topical retinoids; however, it can also result from peels and cryotherapy. Dr Shalita finds that topical tretinoin is effective.

Summary
  • Take time with your patients
  • Topical retinoids should be used in all but he most severe forms of acne
  • Benzoyl peroxide reduces or eliminates less sensitive organisms
  • Antibiotics: Minocycline>Doxycycline>Tetracycline- (forget erythromycin)
  • Isotretinoin: Start low; consider adding steroids to avoid acne fulminans
  • Don’t be afraid to use hormonal therapy