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:

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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)

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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.

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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)

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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?

 

 

 

 

 

Pediatric Dermatology: What we’ve learned that has changed the way we think about and practice medicine (continued…)

Sheila Friedlander, MD and Ilona Frieden, MD

Part 4: Hemangiomas and the Use of Beta-Blockers

Propranolol

In this section, Dr Frieden discusses the use of propranolol for the treatment of infantile hemangiomas. A consensus report, published in the Journal of Pediatrics in January of 2013, discussed the initiation and use of propranolol for infantile hemangiomas. Dr Frieden was a co-author on this publication and believes that it may have an affect on the way in which we practice medicine.  The background to this report is that there was a tremendous amount of diversity among the users of this medication. When there is not a lot of data available, the idea of a consensus is to try to come to a central point with general recommendations.

Is hospitalization needed?

The consensus group, comprised by a variety of specialists, recommended inpatient hospitalization if the patient is less than eight weeks old or less than eight weeks adjusted gestational age, and if the patient has other “high-risk” medical conditions. Patients older than eight weeks should receive outpatient monitoring, using heart rate and blood pressure, with dose escalation. Monitoring should be performed one to two hours after dose escalation as great as 0.5mg/kg/day. In Dr Frieden’s practice, she finds that blood pressure monitoring can be difficult with infants; however, heart rate monitoring is easily doable and just about anyone can do this, including parents.

Is EKG needed?

A consensus was not achieved on the use of ECG for everyone.  One may; however, consider ECG in the following circumstances:

  • HR is below normal for age
    • Newborns (<1 month old), <70 beats per minute,
    • Infants (1–12 months old), <80 beats per minute, and
    • Children (>12 months old): <70 beats per minute.
  • Family history of congenital heart conditions or arrhythmias (eg, heart block, long QT syndrome, sudden death); maternal history of connective tissue disease
  • History of an arrhythmia or an arrhythmia is auscultated during examination

The consensus group developed an algorithm that you can utilize or recommend to your pediatric colleagues regarding the initiation of treatment.

Key Take Home Points

In March of 2014, propranolol was approved for the treatment of infantile hemangiomas at a dosage of 3mg/kg/day. A randomized trial demonstrated a 60 percent clearance; however, in systematic reviews, the response rate of propranolol is in the range of 90 to 97 percent, although not everyone achieved clearance. Significant uncertainty and divergence of opinion still exist regarding the safety, monitoring, and dose escalation of propranolol. If the child is at risk for PHACE, at the minimum, you should perform an echocardiogram before considering initiating propranolol. Remember that the peak effect of the medication, in terms of cardiovascular effects, occur one to three hours after administration. The dose response is most pronounced after the first dose and it is extremely important to recheck the heart rate with dose escalation greater than 0.5 percent mg/kg/day. Hypoglycemia is the most common, serious complication. You should discontinue the medication during intercurrent illness, especially with decreased oral intake.

Topical Beta-Blockers

If you are concerned about hypoglycemia and other potential side effects, topical therapy may be a viable option.

What’s the evidence with regards to timolol? There are many citations supporting the safety of  timolol with minimal to no toxicity reported. Most dermatologists have found it useful for thin facial and hand lesions; however, there are some data that support its use in focal, deep facial lesions. A randomized controlled trial demonstrated that timolol 0.5 percent gel twice a day  was a safe and effective option for small superficial infantile hemangiomas that have not ulcerated and are not on mucosal surfaces.

There have been some recent concerns regarding potential toxicity of  timolol when utilized on ulcerated lesions, mucous membranes, or when used extensively in small premature infants.  as it may be absorbed and lead to  systemic levels of drug that could be problematic. Dr Friedlander and her colleagues are currently conducting a study at UCSD investigating  this issue.

Many experts suggest utilizing the drug sparingly, not more than  one to two drops twice a day, particularly in  micropreemies.

Part 5: Vascular Birthmarks and Overgrowth

A 2013 article by Lee MS, et al published in the JAAD reconfirmed Dr Frieden’s approach to the management of vascular birthmarks and overgrowth. Vascular stain and overgrowth were previously lumped together as “Klippel-Trenaunay.” As far back as 2004, Dr Frieden and her colleagues were able to report that the geographic stains had much higher morbidity and a much poorer prognosis. Many cases that were previously diagnosed as CMTC actually reticulate port wine stain. So, how do we give accurate prognostic information to patients and families?

It is important, as clinicians, to distinguish geographic from blotchy/reticulate stains. Conduct serial leg measurements if stains involve the lower extremity and measure head circumference. It is also imperative to look for dysmorphic features, e.g, syndactyly and facila dysmorphism. If dysmorphic features are present, you should consider rare Vascular Stain/Overgrowth syndromes.

Pediatric Dermatology Summary

  • Don’t forget about Kawasaki Disease—maybe the wind blew it in??
  • Birthmarks aren’t necessarily present at birth- and we now sometimes know the associated mutation
  • Dysphagia is an early symptom in DRESS
  • Propranolol is the drug of choice for most problematic infantile hemangiomas and treatment guidelines exist
  • Timolol for children is A-OK

 

Clinical Pearls: What to do with patients on systemic steroids?

At MauiDerm NP+PA Winter, Dr Zone provided the audience with some key takeaway points regarding systemic therapy….

What Does Dr Zone do with his Patients on Systemic Steroids??

Patients on systemic corticosteroids should be tested (prior) and monitored for hyperglycemia and hypertension—many patients’ blood pressure will skyrocket on systemic corticosteroids. Gastric ulcer protection may be provided with H2 blocker or PPIs as many patients will get ulcerative changes in their stomachs. These patients should be monitored every two to three weeks.

Dr Zone also utilizes osteoporosis prophylaxis for patients on systemic corticosteroids. That should include bisphosphonates, calcium calcium carbonate plus D, calcitriol, estrogen, or testosterone.  The reason for this—if you start a patient on prednisone today, there is an excellent chance that the bones will start to demineralize immediately. When prescribing corticosteroids, start high to get control of the disease or symptoms, and then begin to minimize the dose. Give entire dose in the morning or bid early in the day. Alternate day therapy prevents adrenal suppression but NOT osteoporosis.

Taper oral corticosteroids in order to avoid rebound in cases of short-term treatment….In long-term management, slow tapers are important for dealing with adrenal suppression—the last 5mg is the crucial time for coming down slowly.

What about? Intramuscular triamcinolone—Dr Zone has been using this more in his practice. He finds that the patients have fewer side effects; sometimes they have trouble sleeping.

MauiDerm News Editor-Judy Seraphine

 

Hair Today Gone Tomorrow

Jerry Shapiro, MD

Dr Shapiro, an expert in hair loss treatment, provided the audience with a practical approach to treating hair loss. Dr Shapiro practices in Vancouver, Canada and New York, New York. In Canada, he sees 60-70 patients per day and 70 percent of his patients are female. 35 percent are PHL and telogen effluvium, 30 percent are alopecia areata, and 35 percent are cicatricial alopecias.

Hair Loss in Women: Part 1

It’s important to know that at least one third of women experience hair loss and the effect of hair loss on patients’ emotions is often greatly underestimated by physicians. As a clinician, you almost need to act as a detective to find out the cause of the hair loss. It is imperative that you spend a good amount of time talking to your patients about their hair loss, trying to assess an approximate duration of time since their hair loss began. Of note, the youngest cases of MPHL and FPHL that Dr Shapiro has seen is age eight and it happens suddenly versus gradually.  Ask your patients whether or not their hair loss was sudden or gradual. Another important step in evaluating hair loss is to assess the pattern. We should all be familiar with the Ludwig classification of Female Pattern Hair Loss ranging from classes I to III. Also of importance is to address whether the hair loss is thinning or shedding. The key question for shedding is to ask “is there hair on your pillow?” and “is there hair in your food? or on the stove? Is there hair in the fridge?” Keep in mind that you need to lose 50 percent of scalp hair to notice any change clinically. So, someone who has 100,000 hairs and someone who has 50,000 hairs look exactly the same, you can’t necessarily see that clinically.

The next step in the evaluation is to determine whether the hair is falling out from the roots or whether it is breaking. Hair loss from the roots can be associated with AGA, telogen effluvium, or alopecia areata; hair breaking with tinea capitis, cosmetics/trichotillomania, or hair shaft abnormalities. A thorough evaluation also includes taking a good family history. Remember that family history includes siblings, aunts, uncles, and grandparents—not just the mother and the father. Hair care practices are also very important, i.e., how often do they go to the hair dresser, how often do they shampoo, what products do they apply to their scalp? There are sorts of hair care practices that can cause hair loss.

When talking to your female patients, you need to address any systemic illnesses, recent childbirth, recent surgery and any psychosocial stressors. Psychosocial stressors such as bereavement, break-up/divorce, and bankruptcy can initiate a telogen effluvium. New medications can initiate hair loss within one to three months. (Some of these medications include acetretin, heparin, interferon alfa, isotretinoin, ramipril, and many more.)

Factors that might indicate androgen excess and thus can contribute to hair loss include seborrheic dermatitis, acne, hirsutism, and irregular menstrual cycles. Other important questions include signs of hypo or hyperthyroidism, heavy menstruation, and a vegetarian diet.

Five Stages of the Clinical Evaluation

  1. Distribution of hair loss—where is it on the scalp? We tend to think that this is just on the top, but that’s not the case.
  2. Inflammation, scale and erythema
  3. Scarring vs. non-scarring—you may have to use your dermatoscope in order to see the ostia.
  4. Quality of hair shaft—determine how much they have grown and whether or not the hairs are broken. Are there new hairs growing in? This can tell you whether or not the treatment is working…patients like to hear that there is regrowth.
  5. Pull test—tug at 60 hours in order to see how many hairs you can get. Make sure that patients have not shampooed that day because the results can give you a false negative.

Diagnostic Tools

There are several new diagnostic tools available for the scalp and these include dermascopy (10-fold magnification), videodermascopy (50-100-fold magnification), and folliscope that magnifies the scalp 50-100 times. This can count how many hairs the patient has per square centimeter and determine how wide the hairs are. It will tell you how many microns each individual hair is and give you an average at the end. Patients really appreciate this, they see you do this in front of them and they feel that you are doing something very useful. Dr Shapiro feels that because of this, he has been able to reduce the number of biopsies because he can now make a diagnosis frequently using trichoscopy or the folliscope. Usually you want your hairs more than 60 microns in hair shaft diameter on the average, if they are less than 30 then you know there is significant miniaturization.

Hair Loss: Part 2: How does Dr Shapiro treat some of these conditions?

Alopecia in women can be categorized as Female Pattern Hair Loss, alopecia areata, and cicatricial alopecia: lichen planopilaris. In patients with Female Pattern Hair Loss, this is a crucial time to utilize the Ludwig Classification for FPHL.

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Female Pattern Hair Loss

When assessing women with Female Pattern Hair Loss, it is important to test for any signs or symptoms of androgen excess. If there are no signs or symptoms, you can determine the class of hair loss based on the Ludwig stage. If there are signs or symptoms of androgen excess, an endocrine work-up should be performed in order to rule out polycystic ovarian syndrome, some kind of adrenal hyperplasia, or another form of androgen excess. You may want to consider referral to either an endocrinologist or a gynecologist. From there, you can assess the Ludwig stage.

If the patient has Ludwig stage III, a hairpiece could be considered, as that is typically their only option.  Prices on hairpieces and wigs can vary so that is an important consideration for patients. If you think that the condition will go away, you can suggest a more inexpensive wig/hairpiece from a department store.

Ludwig stages I or II can be treated with topical minoxidil solution (5%) for one year. Topical minoxidil solution is typically used twice per day; however, there are more and more studies demonstrating that a once a day treatment of minoxidil five percent may be as efficacious as minoxidil two percent bid. Women typically do not like the morning application, so Dr Shapiro will use the 5% solution or foam.

What does Dr Shapiro tell his patients?

Dr Shapiro prefers the solution to the foam because it is more precise. He instructs his patients to make five parts and put five drops in each part and spread it with their fingers afterwards. It should not take more than 90 seconds. If a patient complains that it is taking them a long time, ask them exactly what they are doing.

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Prevention is key, there is a 65 percent chance of doing so with five percent minoxidil solution.

If there is no improvement, you may want to add:

  1. antiandrogen therapy + OCA (if childbearing age)
  2. Hair transplation if donor area dense
  3. Hair prosthesis
  4. Hair cosmetics

When it comes to antiandrogen therapy for women, Dr Shapiro uses a lot of spironolactone. He starts at 50mg twice per day for one to two months and then goes to 100mg twice per day if the patient can tolerate it. He always checks their potassium at baseline, one month, and every three months after that. Dr Shapiro also checks their sodium levels. It is important to check all of their electrolytes. There are reports of dilutional hyponatremia with spironolactone and you can end up in trouble. In the elderly population, be sure to check their kidney function as that can also be affected by spironolactone. Of note, spironolactone is approved for women whereas we don’t have a track record with all of the other antiandrogens.

With regards to Propecia (finasteride), Dr Shapiro always warns female patients that he is unsure of what it could do to the breasts, ovaries or uterus 20 to 30 years down the road. We don’t have the long-term data. We do know that it works. Dr Shapiro will use the 2.5mg per day in women; however, keep in mind that this is a Class X drug and spironolactone is a Class D drug so you must warn patients about pregnancy.

What about oral contraceptives?

The oral contraceptives can be categorized as excellent, very good, good, or bad depending on the estrogen component. Products containing drospirenone and cyproterone acetate (available in Canada and other parts of the world) are excellent choices. Very good options include those with norgestimate, desogesterol, and norethindrone acetate. Don’t stop them, because once you stop and start another you can elicit a telogen effluvium or you can unmask or accelerate their androgenetic alopecia even more. If they are on levonorgesterol (a good option), it’s fine, just leave them on it. Stopping and starting birth control pills can create havoc. Norgesterol and norethindrone are bad progestogens. If a patient is on these, Dr Shapiro will get them off of it and change to something else.

Around six months, it is important to assess patient satisfaction with the current treatment. If they are satisfied, that’s great. If they are not satisfied, you may want to consider hair transplantation if the donor area is dense. One in three women have very poor donor areas and you usually cannot do a hair transplant on them.  Dr Shapiro usually does strip harvesting in women, you don’t need to do follicular unit extraction because they usually have long hair and don’t care if they have a scar in the back; if they do, you may have to go to follicular unit extraction. For men, you want to do follicular unit extraction because they usually have short hair. For women, Dr Shapiro will take a strip usually around 15-20cm long and usually 1.3cm in width. You then stitch it up and make holes in the front of the scalp and insert them in the holes.

Alopecia Areata

As dermatologists, we are all familiar with how to diagnose and treat this condition to some extent. For centuries, non-specific crude treatment has been used to treat alopecia areata. In the 1800s, they believed that treatments that irritated the scalp seemed to work. To quote Batemen from 1817 “the more caustic a substance and the application of a blister are often extremely successful” and “ointments of oil of mace, turpentine, mustard and black pepper.” Is what they used much different from what we use now? This is how Dr Shapiro treats alopecia areata…

First of all, he looks at the age of the patient. If they are less than ten years old, he will use minoxidil 5% solution with or without a topical corticosteroid or short contact anthralin. If the patient is over ten years old, then Dr Shapiro will look at the extent of scalp involvement. If there is less than 50 percent involvement, he uses intralesional corticosteroids plus or minus minoxidil 5% solution, plus or minus a topical steroid or short contact antralin. In his practice, Dr Shapiro will use 5mg/cc of triamcinolone acetonide and a maximum of 20mg triamcinolone acetonide per month. He feels that is safe and has never had any problems over the last 25 years. If a patient has a large area to be injected, he will go down to 2.5mg/cc and there didn’t seem to be much of a difference. If you have to do the whole scalp, he will use 25mg/cc for a total of 8ccs and he will do 80 injections.

What about topical corticosteroids? A study of 28 patients demonstrated that clobetasol propionate 0.05% under occlusion was effective for the treatment of alopecia totalis/universalis. Dr Shapiro began using clobetasol on his patients and there was a difference regarding hair regrowth. Anthralin one percent for one-hour daily (many times combined with five percent minoxidil) has also shown to be efficacious.

When someone has more than 50 percent of scalp involvement, Dr Shapiro uses contact immunotherapy. He usually uses DPCP and achieves a 78 percent response rate in non-totalis/universalis, but a 17 percent response rate in totalis/universalis. There is a high relapse rate of 62 percent and only half of these patients respond to therapy. Dr Shapiro has bottles in various concentrations and sensitizes not on the arm, but on the scalp. He then applies two coats on half of the scalp initially on the anteroposterior direction, then in the lateral direction, again only on half of the scalp. Make sure that you protect yourself when it is applied because this is extremely immunogenic.

Remember that there is no cure for alopecia areata. Sometimes certain areas do not respond and you may have to combine treatments, just like in psoriasis when you may use polytherapy. Dr Shapiro will inject the areas that are not responding once a month with triamcinolone acetonide and in three out of four weeks they will get the DPCP or dyphencyprone. Dr Shapiro will do the eyebrows as well if he sees that it has worked on the scalp. Problems with this include eczema, blisters, and marked edema. Make sure that your institution will cover you in the event that there are any problems as this is not FDA-approved. Patients need to sign an informed consent. Lymph node enlargement can also occur and the safety of this is unknown; however, Dr Shapiro has never had a case of lymphoma in over 20 years. The only case of lymphoma that he ever had from alopecia areata was a patient who was on cyclosporine. When you are dealing with dark-skinned individuals, be careful with hypopigmentation. NEVER give this to a patient to take home.

If people respond, then the treatment is continued. If they don’t respond, you can consider minoxidil 5 percent solution plus or minus a topical corticosteroid or short contact anthralin, and PUVA. Methotrexate has demonstrated some efficacy at a dose of 20-25mg per week. Dr Shapiro will use 25mg per week for six months and has seen some benefit in patients, especially for the eyebrows.

Lichen Planopilaris

There are different types of lichen planopilaris, i.e., classic lichen planopilaris and frontal fibrosing alopecia. Most dermatologists are only familiar with the classical type and when we look at it under trichoscopy we can see sometimes many hairs coming up out of one hole. We are starting to see more and more of frontal fibrosing alopecia, in fact, Dr Shapiro sees at least two or three new cases per day. It usually occurs in post-menopausal women; however, he has seen it in young women as well, the youngest case being in an eighteen year-old. These patients will start to lose their eyebrows, the hairline will start to recede, and it can also go around the whole scalp.

How do we treat these individuals?

This is all based on experience, as there is no evidence. Dr Shapiro classifies the patients based upon the extent of the condition. If it is less than ten percent hair loss, then he will use clobetasol lotion plus injections with triamcinolone acetonide 10mg/cc for a total of 2ccs. If he sees improvement, he will continue with prn. If there is no improvement, he will treat the patient as if they had more than ten percent hair loss utilizing doxycycline 100mg two times per day or hydroxychloroquine 200mg two times per day, plus or minus ultra-potent topical steroids, plus or minus the injections. Dr Shapiro may also bridge things with prednisone 40mg per day over eight weeks. If there is improvement, he will taper to the lowest effective dose and if there is no improvement there are other options to consider. These options include topical tacrolimus, cyclosprorin A, griseofulvin, mychophenolate mofetil, low-dose isotretinoin, or alefacept.

It has been suggested that these individuals have low PPAR gamma in the scalp. Actos®, a PPAR gamma, did help with symptoms; however, there is an FDA black box warning for bladder carcinoma. This is worrisome for clinicians; however, many of the patients want the treatment. If the patient is aware of the warning and wants the product, Dr Shapiro will give 15-30mg per day.

Take-home Message

When it comes to cicotricial alopecia, they are trichologic emergencies. Early intervention can potentially avert scarring and secondary complications. The diagnosis must be made with a biopsy. Remember that disease-directed medical therapy is only indicated in those with active disease. Adjunctive agents, such as topical minoxidil and hair transplantation, can improve cosmesis.

Trichotillomania

There is a new medication, N-acetyl-cysteine, that has shown a decrease in obsessive compulsive behavior in patients who take 1200-2400 mgs per day. There are hardly any side effects and it can be found in any healthcare store.

In conclusion, it is important to remember that patient education is crucial. There are websites available such as www.carfintl.org, www.naaf.org and www.nahrs.org.

MauiDerm News Editor: Judy Seraphine

 

 

 

 

Contact Dermatitis 2014: Diagnosis and Management Strategies

Mathew J. Zirwas, MD

 

In this presentation, Dr Zirwas, an Associate Professor of Dermatology at Ohio State University and an expert in contact dermatitis, makes understanding contact dermatitis “easy” for the practicing dermatologist…

Dr Zirwas begins the presentation by reviewing some of the new allergens on the T.R.U.E. Test and what we need to know about them…

Steroid Allergies

Tixocortol Pivalate, budesonide, and hydrocortisone butyrate are all markers for allergy to steroid. There is a simplified way to approach the management of this allergy. We know that there are cross-reactor groups A, B, C, D1, D2…in a steroid allergic patient you can either figure out which class they are allergic to, then pick a steroid in a different class (which could still cross-react!) or you can simply use of the two topical steroids that do not cross react with other steroids. These are clocortolone and desoximetasone. These are class C steroids and do not cross-react with anything else.  Also keep in mind that about ten percent of people who react to tixocortol pivalate will have allergy to prednisone if it is given systemically. This is very similar to the way that we think about cephalosporins with penicillin. When someone is allergic to penicillin, we say that there is about a ten to 20 percent chance that they will have a reaction to cephalosporins. This is the same thing, when someone is allergic to tixocortol pivalate, there is about a ten percent chance that they will be allergic to prednisone…they will clear on 40mg, usually stay clear on 20mg and break out in a drug rash around 10mg because the pharmacologic effect of the prednisone is now being outweighed by the allergy to the prednisone.

What if someone is allergic to Diazolidinyl Urea, Imidazolidinyl Urea, 2-Bromo-2-nitropropane-1, 3-diol?

For these patients, treat them as if they are formaldehyde allergic. They may be allergic to only one or two formaldehyde-releasing preservatives, but 90 percent plus are formaldehyde allergic and need to avoid all the formaldehyde related substances. It is a little bit more of a conservative approach, but it’s the approach that experts in contact dermatitis use.

What if a patient comes in stating that she is allergic to titanium dioxide?

Remember that allergy to titanium dioxide is extremely uncommon. This patient may be allergic to gold sodium thiosulfate. How is gold related to titanium? Gold is related to titanium dioxide because gold, itself, is very inert; however, it interacts with titanium dioxide, which is in most make-ups and sunscreens. The problem is that it interacts with the gold jewelry that women wear; therefore, they may break out in a rash where they apply their make-up/sunscreen. These patients need to either stop wearing make-up and sunscreen OR replace their gold jewelry with platinum, which is the best replacement for gold. Patch test reactions to gold can persist for three to six months. If they persist, Dr Zirwas will inject 0.1-0.5ml of TAC-5.

What about a patient who comes in with a facial rash every spring?

A patch test may determine that this patient is allergic to parthenolide. Parthenolide is a marker for an allergy to the Compositae family of plants. There are around 20,000 plants in this group but as dermatologists we only need to remember a few key points about this group. The first of which is to avoid Aquaphor. Aquaphor has bisabolo in it, an extract of German Chamomile, which is in this group. In general, Dr Zirwas tells parthenolide allergic patients to avoid anything that has to do with a botanical.  This is a conservative approach; however, it is much more effective than determining to which of the 20,000 plants a patient may be allergic.  Some patients can get airborne contact dermatitis from pollens that have SQLs on the surface, especially ragweed and goldenrod. These can be difficult patients; they either need to move somewhere with less pollen, or they should be immunosuppressed during the months of the year when they tend to get this allergy.

Allergies to Dyes

There are thousands of different dyes that are used to dye clothing. Disperse Blue 106/124, while not great for ruling out textile dye allergy, is the best screening agent we’ve got.  Remember that you cannot tell what dye was used based upon the color of the clothing. If a patient is positive, then synthetic textiles of all colors become suspect. These allergic reactions tend to be acute and intermittent. Usually, specific items of clothing can be identified, such as exercise clothing and liners in dress clothing. Normally, once you tell the patient what to look for, they can tell which items of clothing are causing the reaction.

Other T.R.U.E. Test Allergens

  • Quinoline Mix
    • Rarely relevant- Bag Balm, some others
  • Mercaptobenzothiazole
    • No different than other rubber accelerators
  • Bacitracin
    • Need to avoid polysporin, etc.

 

T.R.U.E. Test Conclusions

The T.R.U.E. Test is better than it used to be; however, it is still not that good for certain things. It is good for identifying allergies to metal, rubber gloves, and topical antibacterials. It is NOT good for personal care products, make-up, topical steroids, and other interesting things such as acrylic nails, prosthetic joints, sports equipment, etc.

The T.R.U.E. Test is best for ruling IN a diagnosis of rubber glove allergy, neosporin/polysporin allergy, and metal allergy. Its WORSE uses are in ruling out contact dermatitis when you’re unsure of the etiology.

What are the chances that a patient will get better with the T.R.U.E. test?

Considering patients who aren’t allergic to metal, rubber, or polysporin, it’s actually about one percent. How does Dr Zirwas get this number? Well, when you look at a patient and think it might be contact dermatitis, but aren’t sure to what, the chances are that it is contact dermatitis in about 20 percent. The probability of an accurate diagnosis with the T.R.U.E. test is about 20 percent. The probability that a patient will remember what they are allergic to is about 50 percent, at best.  The probability that the patient will avoid the allergen, if they remember it, is 50 percent, at best. Therefore, 20% x 30% x 50% x 50% = 1% (at best).

What else can we do?

The American Contact Dermatitis Society publishes a list of allergens and a screening panel, which is an excellent resource for people who want to implement comprehensive patch testing.  But what do you need at a minimum? You need to buy ten tubes of allergen and one box of Finn® chambers. This will cost about $400.00

Supplement the T.R.U.E. Test with following 10 allergens:

  • Methylisothiazolinone 2000 ppm
  • Formaldehyde 2%
  • Propylene Glycol 100%
  • Fragrance Mix II
  • Cocamidopropyl Betaine
  • Amidoamine
  • Dimethylaminopropylamine
  • Hydroxyethyl Methacrylate
  • Ethyl Ethacrylate
  • Propolis

Additionally, The American Contact Dermatitis Society has a database, CAMP. This is very user-friendly, i.e., you check the boxes with regards to what the patient is allergic and it, in return, provides you with a list of safe products for that specific patient. This way, your patients do not have to read labels and figure out what to avoid, you can simply provide them with a list of products that they CAN use.

Mypatchlink.com is another resource containing a series of free-access videos that review all of the remotely common allergens. There are also handouts that go along with the videos and they are extremely useful.

Methylisothiazolinone 2000 is an enormous epidemic. This is probably due to a combination of reasons; firstly, there is increased exposure because of the move away from parabens and formaldehyde-based preservatives. Second, until recently, we have been patch testing with too low a concentration and as a result, for the last 10-15 years, we have probably been missing a lot of the people who are allergic to this. Remember the 3 Fs—Faces, Fannies and Fingers. Methylisothiazolinone is often found in shampoos, conditioners, facial soaps, moist toilet paper, hand soaps, and baby wipes.

Formaldehyde is still a very common allergen. One percent formaldehyde, which is the standard allergen, misses a lot of cases; therefore, we have gone to testing formaldehyde two percent.  You get a few more irritant reactions, but pick up a lot more cases of true allergy.

Propylene glycol is now tested at 100 percent. You do not get irritant reactions, but you do pick up a lot more reactions than when we used to test with 30 percent. Propylene glycol is in most topical steroids and NEEDS to be ruled out as a cause of chronic dermatitis.

Fragrance Mix 2 is no different in terms of clinical manifestations compared to the original Fragrance Mix, but these are newer fragrances that are more relevant and pertinent. If you are only testing with FM1 and Balsam of Peru, then you are probably missing 30 percent of fragrance allergy patients.

Cocamidopropyl betaine, amidoamine, and dimethylaminopropylamine are three different ways to test for allergy to modern lathering/foaming agents. Lathering agents are a very common cause of facial dermatitis from shampoos, facial cleansers, and conditioners. Keep in mind that while conditioners do not lather, there is a related ingredient called stearamidopropyl dimethylamine that is chemically related.

Hydroxyethyl methacrylate and ethyl acrylate are the best markers for acrylate allergy, a common cause of allergy from nail cosmetics. This is a much more common problem than nail polish allergy and these patients MUST avoid all types of artificial nails (acrylic, gel, solar, wraps, tips, etc..) This allergy also indicates a need to avoid bone cement in prosthetic joints.  If a patient is allergic to acrylates, this is a much bigger problem than if they were allergic to nickel and they receive a metal implant.  There is a lot of controversy around whether or not a metal implant will be problematic for patients who are allergic to nickel, but general agreement that acrylate allergic patients will have a problem if bone cement is used when putting in a prosthetic joint.

Propolis is the last of the ten allergens that Dr Zirwas would use in addition to the T.R.U.E. Test. Propolis is related to beeswax and is found in a lot more products than you would think, it is especially a problem in some lip products.

If a patient presents with widespread dermatitis, but not on the face, they may be allergic to potassium peroxymonosulfate, the active ingredient in shock treatment for hot tubs (and pools).  Dr Zirwas sees this mostly in male patients. Why? Because men are the ones who are taking care of the hot tub/pool, adding the treatment and are subsequently exposed to high concentrations while scooping it out of the container, leading to sensitization.  Then, when they get in, they break out in a widespread rash.  If a patient has widespread dermatitis, he/she should stay out of their hot tub. If they get better, they should change the shock treatment to H202 or hypercholorination.

If a patient has papules on extensor elbows, you should consider dietary nickel as a possible cause – this is a much more common cause of itching papules on the elbows than is dermatitis herpetiformis.  He/she should consider a low nickel diet consisting of oatmeal, legumes, canned goods, dark chocolate, stainless steel pots/pans, and should only drink bottled or distilled water. Patients should also take vitamin C with every meal.

Summary

Contact dermatitis can be a challenge for the practicing dermatologist. Keep in mind that the T.R.U.E. Test is best for ruling IN a diagnosis of rubber glove allergy, neosporin/polysporin allergy, and metal allergy. Its WORSE uses are in ruling out contact dermatitis when you’re unsure of the etiology.  Remember to supplement the T.R.U.E. Test with the ten allergens previously discussed.

 

MauiDerm News Editor- Judy Seraphine

 

Fillers 2014: New Fillers and New Data

Wm. Philip Werschler, MD

In this presentation at MauiDerm 2014, Dr Werschler, a pioneer in the area of toxins and fillers, provided an overview of the fillers currently available on the market along with newer fillers and new data so that we can utilize this information in clinical practice.

A Brief History of Their Time

We started off with collagen, if you wanted a filler, that’s what you got. This is no longer available. At that point in time, we were really focusing on lines and wrinkles. Collagen became products such as Zyplast and Zyderm and was mostly used on lips, crows feet lines, nasolabial folds, and vermillion borders. Then, for many, many years, we had a lull. So, you either did collagen or you didn’t do injectable fillers.Then starting in   2003, the filler market exploded, as you can see from the chart below.

Screen Shot 2014-01-14 at 9.47.08 AM

 

In December, 2003, the US FDA approved Restylane (Hyaluronic Acid), which revolutionized the dermal filler market . With a duration of six plus months, no pre-treatment skin testing, ease of use, room temperature storage and modest cost, there was now a viable product for the emerging, if nascent, dermal filler market.

Radiesse is a novel “next-generation” filler that was approved in 2006 by the FDA for the correction of wrinkles and folds (such as Nasolabial Folds), and for the correction of HIV-associated lipoatrophy. Radiesse is termed a “stimulatory” or “collagen-stimulator” product.  This differs from the previous generation “replacement” space occupying materials collagen and hyaluronic acid.  With the addition of collagen stimulation, the duration of effect of Radiesse was extended to 9-18 months.

On the same day that Radiesse was approved, the FDA also approved the first and only “permanent” dermal filler, Artefill (collagen + PMMA).  Artefill consists of bovine collagen in combination with polymethmethacrylate spheres.   As these spheres are non-biodegradable, they represent a permanent placement into the tissue.  Well tolerated with an excellent safety profile, Artefill does require pre-treatment skin testing because of the bovine collagen present. Special handling includes refrigeration, and collagen stimulation gradually anchors the PMMA spheres into place typically after 2-3 treatments.

In 2007/2008 Hyaluronic Acid plus lidocaine was FDA approved for the hyaluronic acids, Juvederm, Restylane and Perlane. Similarly, the FDA approved the mixing of lidocaine and Radiesse by the injector at the time of use.  These approvals resulted in greater patient comfort during injection and further expanded the dermal filler marketplace. Stabilized Porcine Collagen came onto the market briefly during this time, however due to problems with patient tolerance and complications, the manufacturer withdrew the product and it is no longer available.

In 2009, the FDA approved Sculptra, poly L lactic acid, for aesthetic use (it received FDA approval in 2004 for HIV associated facial lipoatrophy).  A pure collagen stimulator, Sculptra, is technically not actually a dermal filler, however; it is best thought of in this category.  Sculptra is routinely mixed with lidocaine and sterile water for injection, requires 3-5 injections sessions to gradually grow new collagen leading to the clinical effect developing over a period of three to six months.  Duration is a 2+ years effect based on extensive clinical trials and experience.

More recently, an advanced technology hyaluronic acid, Belotero, and  an autologous cultured dermal fibroblast  (LAVIV)  were approved. Laviv, like Sculptra, is technically not a dermal filler but rather a tissue stimulator that up-regulates native collagen production.  This process includes harvesting tissue from the patient (post-auricular) and sending it to a processing laboratory that then amplifies the cell count and returns a viable culture for re-injection. The first FDA approved tissue cell culture therapy for aesthetics, Laviv, presents a multitude of intriguing possibilities in the future.

Most recently (2013), we have hyaluronic acid with Vycross technology, known as Voluma.

In order to use fillers, it is important to understand their mechanism of action. There are two primary components of MOA:

  • Volume Replacement
  • Collagen Stimulation-either as part of its MOA or its primary MOA

If you use the above approach, collagen and hyaluronic acids have an immediate correction and they do not really have, as a primary mechanism of action, any neocollagenesis effect; therefore, collagen and hyaluronic acids are replacement fillers. PLLA (Sculptra) and LAVIV are bio-stimulatory. And notably, CaHA and PMMA are blends of both MOAs.

Screen Shot 2014-03-31 at 8.17.30 AM

 

How do fillers exert their characteristics?

Fillers are commonly compared by viscosity ,elasticity and cohesivity, the three physical properties that dictate the ability of a filler to provide volume plus lift and the ability to resist becoming separated in tissue. All three of these measurements are made in-vitro, and are surrogate measures for in-vivo activity. Viscosity is the measurement of a material’s ability to resist a force that is applied to it. It relates to the movement of the material in response to force. So, highly viscous materials require more force to move or spread compared to lower viscous materials. A filler with a high viscosity “stays where you put it”, providing a “what you see is what you get” results. Fillers with lower viscosity will have the propensity to be easily spread and splay into surrounding tissues.

Screen Shot 2014-03-31 at 8.17.45 AM

 

You’ll see on the graph above that the products with the greater viscosity are Radiesse and Restylane SubQ (not available in the US). Does this mean that they are better products? Not necessarily, it depends on the tissue characteristics for which you are looking. It means that these products have more of an ability to push back against a force that is applied to them.

Elasticity, measured as G’, is the material’s ability to push back against a force that is applied to it. Fillers with a high G’ will resist the forces placed on it, such as gravity, skin laxity, etc. and will provide greater lift to the overlying tissues. Fillers with a low G’ will not have the capacity to lift well, and; therefore, require larger volumes of material to compensate.

Screen Shot 2014-03-31 at 8.17.59 AM

 

What does this mean clinically? Well, in part it means that some activity of a filler can be predicted by laboratory measurements. It also means that only personal experience can determine which filler you use for any particular indication and patient experience and satisfaction will determine the final choice of product.

These are important concepts to think about. Some products provide soft lifting and some products provide a firm lifting.

Volume Replacement

Hyaluronic Acids (HAs)

Volume replacement is all about HAs today in the marketplace. It is when you inject a product that occupies a space and holds that space until that product is either removed or, in the case of HAs, is degraded through natural enzyme processing.

HAs have a very simple chemical structure and is identical in all species and tissues; thus it is non-immunogenic. It is found in all vertebrates and synthesized by some bacteria. The identical structure of HA from all sources makes it an ideal substance for use as a biomaterial in health and medicine.  HAs are highly hydrophilic; therefore, they absorb water, i.e., their principal method of giving a volumizing effect. They are also rapidly metabolized in vivo.

HA was first discovered in 1934 by Meyer and Palmer and was first used therapeutically in 1970. During the 1980s, Biomatrix, Inc. developed second-generation HA derivitives (hylans) through cross-linking (stabilization), and in 1986 the term “hyaluronan” was coined. The increased stabilization increases the ability of the product to do the work that you want it to do. By 1996, we had the first generation of resorbable gels based on hyaluronic acid of animal origin. In 1998, we had the second generation of resorbable gels based on hyaluronic acid of non-animal origin—these were biphasic products. In 2000, the third generation of resorbable gels came about, based on hyaluronic acid of non-animal origin—monodensified, mono-phasic products. And, in 2005, we saw more technological advances with Cohesive Polydensified Matrix technology, allowing for different tissue characteristics.

HAs can be used virtually everywhere for anything and everything and they are the most versatile of all of the filler products. These fillers may be ideal for novice patients because they have an  “eraser” (hyaluronidase) that can be injected to make the product dissolve, if so desired for either aesthetic effect or for treatment of complications including necrosis. . This is a unique feature of this category. Remember that while some HAs seems to work better in certain areas, this is based on personal preference.

What’s New?

  • Voluma XC
  • Belotero (sort of)
  • Expressions (kind of)
  • Corporate acquisitions and news

Vycross Technology

Juvederm Voluma XC is FDA approved HA to correct age-related volume loss in the mid-face. We know that volume loss creates the aging changes. The VYCROSS technology formulation produces highly cross-linked gel, increasing lift, capacity, and duration. The duration of this product is up to two years. Duration claims  are always a slippery slope, so be sure to caution your patients.

The pivotal clinical study was a multi-center, single blind, no-treatment control study of 282 subjects (235 in the treatment group/47 control “no treatment”) in fifteen North American sites. The subjects received 20 mg/ml HA volumizing filler for cheek augmentation to correct mid-face volume deficit. There was one treatment plus one optional “touch-up” one month later.

Eligible subjects must have scored an overall Mid-Face Volume Deficit score of greater than three on a six-point scale.

  • 3 = moderate concavity of mid face, tear troughs, mild nasojugal and pre-jowl, mild prominence of bony landmarks and musculature
  • 4 = significant concavity of mid-face, tear troughs, moderate nasojugal and pre-jowl, moderate prominence of bony landmarks and musculature
  • 5 = severe concavity of mid face, tear troughs, severe nasojugal and pre-jowl, moderate prominence of bony landmarks and musculature

The study endpoint looked at the Mid-Face Volume Deficit scale at six months with the primary endpoint being greater than 70 percent responder rate versus control. The primary endpoint was met with an 85.6 percent treatment group response rate.

Subject Rated Duration

6 months = 95.1%

12 months = 80.4%

18 months = 67%

24 months = 53.7%

Physician Rated Duration

6 months = 76.8%

12 months = 64.3%

18 months = 57.9%

24 months = 46%The range of volume used in the study was rather dramatic as it went from 1.2mL to 13.9mL. The median for all three subregion treatment areas (mid-face) was 6.6mL.

VYCROSS technology has opened up the mid-face volumization category for us, as practitioners.

CPM Technology

Belotero is a “cohesive polydensified matrix” hyaluronic acid.  CPM technology allows for variable degrees of product/tissue integration. With less homogenous bulk, there is less monochromatic refraction of ambient light. The net clinical result is that the product may be injected more superficially than other HAs without risk of the Rayleigh/Tyndall effect tinting the skin blue.

Expressions

Expressions is a hyaluronic acid filler that is FDA approved for nasal splinting; however, it is not FDA approved for aesthetic use, yet it is heavily marketed to the aesthetic community. Expressions is an HA product that is made with Bacillus Subtilis Fermentation and it comes in a 1.5mL syringe.

New Approaches to Fillers

NeoCollagenesis

Poly-L-Lactic Acid

Through a variety of mechanisms of action, they stimulate fibroblasts to make collagen, making Sculptra more of a tissue stimulator as opposed to a filler, per se.

It is the only approved pure collagen stimulator currently available in the US; therefore, it is considered “stimulatory” and “biodegradable” in classification. PLLA is indicated for the correction of nasolabial folds. Of note, Dermik aesthetics, a division of sanofi-aventis, recently sold the product to Valeant Pharmaceuticals Intl. based in Canada. It takes time and a number of treatments; however, the duration is about two to three years. It is important to remember that it is difficult to establish exact duration of the product because of one’s natural course of aging.

What is the composition of PLLA?

  • Poly-L-lactic acid
  • Sodium  carboxymethylcellulose (CMC)
  • Non-pyrogenic mannitol
  • Sterile water (added) for injection (USP)
  • Lidocaine (optional—most dermatologists and plastic surgeons add lidocaine for patient comfort)

Sculptra™ is composed of microparticles of PLLA, a biocompatible, biodegradable, synthetic polymer from the alpha-hydroxy-acid family.  It is derived from natural components, it is a crystalline, amorphous mixture with microparticles averaging 40 to 63 μm in size. The slow resorption of PLLA after implantation is due to the high molecular weight (140,000 Daltons) of the polymer and the irregular crystalline shape of the microparticles.

Lactic acid can be converted through polymerization to a variety of polymers, including poly-L-lactic acid. Many of these polymers, including polylactic acid, have been used for many years in medical devices and sutures, including absorbable sealants, flow restrictors, fixation systems, suture anchors/absorbable sutures, fixation screws, and tissue regeneration.

Investigator evaluations throughout the study confirmed that improvements in facial appearance with Sculptra®Aesthetic were achieved in WAS. As this graph shows, improvements from baseline at 25 months proved to be consistent, progressive, and statistically significant at each time point (P<0.001): 100% of patients improved at week 3; 88.7% at month 13; and 86.3% at month 25.

Screen Shot 2014-03-31 at 8.18.19 AM

Where is it used?

Poly-L-lactic acid treatment primarily to add volume, and as such is used to thicken dermis and to stimulate collagen growth in the pre-periosteal plane.  Placement may include the temporal hollows, across the zygomata, in the mid face, nasolabial folds, labiomental sulcus, prejowl sulcus, mandibular sweep and angle and for genioplasty.  Sculptra is not recommended for use in areas of concentric movement such as the lips and eyelids.  In terms of adding volume, this is a great way to go. As you become skilled with PLLA, there are a lot of great things that you can do with it over time.

Personalized Dermal Technology

Azficel-T (LaViv) is an interesting, innovative technology to isolate, purify, and regenerate a patient’s own fibroblast cells for re-injection.

Fibroblast cells produce collagen and play key role in the continued health of skin. Collagen provides firmness and structure to the skin and is essential in supporting the dermis. As skin ages, fibroblast cells decrease and the collagen matrix that provide the skin its structure breaks down.

This is a way to restore the equilibrium.  LaViv is the first autologous cell therapy for use in aesthetics filed with the FDA. There is strict release testing on each clinical lot to ensure performance and safety including:

  • Collagen content testing results must achieve specification for each prepped injection, indicating cells are biologically active and produce collagen
  • Cell suspension must consist of at least 98% fibroblasts prior to release
  • Cells in suspension must achieve a viability level of at least 85%
Treatment Process

A small cell sample is removed from behind the ear from a small skin punch biopsy with the use of a local anesthetic. A proprietary manufacturing process multiplies the fibroblasts from the sample into tens of millions of new cells in approximately three months. The fibroblasts are tested by quality control and released by quality assurance prior to the shipment. The cells are then frozen for use in potentially multiple treatment sessions. The recommended regimen is three treatment sessions at three to six week intervals. In clinical trials, Azficel-T and placebo was seen by the time of the third treatment. Dr Werschler feels that if you have a patient who doesn’t want a “foreign” substance used for aesthetic purposes, this is a nice alternative to be able to offer as it’s personalized dermal cell technology. Of note, the side effects are minimal, mostly pruritis.

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Volume Replacement + NeoCollagenesis

Calcium Hydroxylapatite (CaHa)-Radiesse

CaHA has a biphasic MOA, it is 30 percent calcium particles and 70 percent CMC gel. CaHa is best used for regional facial contouring. Dr Werschler uses this product for structural augmentation, i.e., helping to define the face. Its mechanism of action is to serve as a filler material initially (particles + gel) then provide long-term benefit through natural collagen integration in and around the particles. The result is a long lasting, but not permanent correction augmentation that feels like the patient’s own tissue. Remember with Sculptra, the volume effect comes from neocollagenesis; however, with Radiesse, because it is a biphasic product, you get an immediate corrective effect which then stimulates neocollagenesis at a rate which prolongs the effect clinically that you see; therefore lasting longer.

The advantages of Radiesse include immediate site-specific correction in one to two sessions and strong structural tissue support with no Rayleigh/Tyndall effect. CaHa is malleable up to two weeks and has a long duration of nine to 18 months. No pretreatment testing is required, it is also cost-effective and does not migrate or obscure radiographic studies and it doesn’t ossify in the skin. Radiesse received approval in the United Sates in 2006 for both HIV and aesthetic use and is the only approved biodegradable dual collagen stimulator and replacement filler currently available in the US. When utilizing Radiesse, no skin or allergy testing is needed and there is no special handling. The product is available in 0.3, 0.8 and 1.5 mL and recently approved 3.0 mL syringes through Merz Aesthetics.

Where is it used?

CaHA is used most everywhere; however, it is not recommended to be used in the lips or around the eyes.

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PMMA Dermal Filler-ArteFill

ArteFill was approved in the United Sates in 2006 and is the only approved PMMA-enhanced dermal filler currently available in the US. It is indicated for the correction of nasolabial folds. Suneva Medical acquired (ARTES) Artefill in 2009 and is currently manufacturing, selling, and distributing Artefill in the US. Of note, it is currently awaiting FDA approval for acne scars.

ArteFill is a combination of purified bovine collagen plus polymethyl-methacrylate beads. Essentially, you drop the beads into the tissue that are then carried by the bovine collagen that is then rapidly reabsorbed. You see a neocollagenesis effect from the fibroblasts around the PMMA particles that are locked into place so that they do not migrate providing a long-standing correction. You can see from the graph below that the five-year follow-up study demonstrates long-lasting effects.

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Conclusions

Injectables are: Facial Shaping Agents

  • They can enhance natural features
  • They can rejuvenate fading youth
  • They can restore aged, facial features
  • They can even improve natural beauty
  • Each product has features that result in certain benefits in clinical use
  • They are not all alike!

What’s new?

  • Not that much…but quite a bit
  • CPM technology is “back” on market
  • Valeant owns Medicis, Dermik
  • FDA approval for Allergan’s Vycross technology mid-face volumizer
  • Expressions is in the neighborhood
  • Merz has acquired Neocutis
  • Allergan has acquired SkinMedica
  • Valeant (Medicis/Dermik) has Obaji
  • Merz acquired Anteis (Beletero family-Soft, Basic, Intense)

Additionally, Allergan has clinical trials underway in the United States for Volbella and Volift. A new player, Alphaeon, has products at different states of pre-approval; they have licensed Teoxane (filler and skincare line), they have also licensed a neurotoxin which is not yet on the market and the company plans to expand on lifestyle medicine, focused on wellness, beauty and performance.

Clinical Pearls

  • Use filling agents appropriate to the requirements of the job
    • Lifting tissue requires robust strength, longevity, durability, and safety
    • For surface “crinkles” use “thin” or “dilute” products
  • Not all products are created equal – understand the differences!
    • Some products create “soft” volume, others “firm” volume
  • Some areas are more difficult to correct than others  (e.g. lips and tear troughs)
    • Create facial filling improvement by starting with low-risk/high-satisfaction areas—utilize a STEP approach
  • Evaluate and approach filling from a multi-step progression:
    • Integrate filling with development of structure and support, progress to volume replacement and refine with contour
  • Product duration claims are a slippery slope—be careful with those and be conservative with your ranges

 

MauiDerm News Editor- Judy Seraphine

 

 

 

Psoriatic Arthritis Update

Arthur Kavanaugh, MD

Dr Arthur Kavanaugh is a Rheumatologist and a Professor of Medicine at the University of California, San Diego. At MauiDerm 2014, he provides the practicing dermatologist with an update on PsA and the latest treatment advances…

The reported estimates of the prevalence of PsA among psoriasis patients have been highly variable, i.e., six percent to 42 percent. It is currently estimated that between 20 and 30 percent of psoriasis patients also have PsA. In addition, psoriasis precedes PsA in over 85-90 percent of the cases, though we’re not sure why. Dr Kavanaugh believes that in 20 to 30 years, we may have that answer. In 2012, there were an estimated 1,600,000 PsA patients in the United States. Of those patients, about 485,000 were diagnosed and only about 345,000 received treatment. Now that we have treatment available, Dr Kavanaugh feels that healthcare providers will be seeing more of these patients. As dermatologists, it is important to remember that PsA is a serious condition; approximately 20 percent of patients with PsA will develop destructive, disabling arthritis. PsA results in radiological damage in up to 47 percent of patients at a median interval of two years. Remember that other comorbididites often exist among PsA patients; these include, metabolic syndrome, CAD, uveitis, IBD, impaired function and quality of life, and economic implications.

Recent data presented at the 2013 American College of Rheumatology, suggest that a delay in the diagnosis of PsA correlates with poor patient outcomes. A study of 283 PsA patients, fulfilling the CASPAR criteria, demonstrated that even a six-month delay from symptom onset to the first visit with a rheumatologist contributed to the development of peripheral joint erosions, sacroiliitis, and worse long-term physical function.

Diagnostic Criteria for PsA (CASPAR)

The diagnostic criteria for PsA includes an established inflammatory articular disease (joint, spine, or entheseal), plus three or more points from the following five categories:

  • Psoriasis
    • Current-psoriatic skin or scalp disease present today (2 points)
    • History-a history of psoriasis
    • Family history-history of psoriasis in a first or second degree relative
    • Nail Changes-typical psoriatic nail dystrophy
    • A negative test for RF-by any method except latex (preferably ELISA or nephlemetry)
    • Dactylitis
      • Current-swelling of a current digit
      • History –history of dactylitis
      • Radiological evidence of juxta-articular new bone formation-ill-defined ossification near joint margins (but excluding osteophyte formation) on plain X-rays of hand or foot

The CASPAR criteria are very sensitive and very specific; but, in the clinic, the question lies as to whether or not the patient has inflammatory arthritis. That is a tougher question and we don’t have a perfect answer for that. Several questionnaires and screening tests have been developed for this, such as the Psoriasis Epidemiological Screening ProjecT (PEST), Toronto Psoriatic Arthritis Screen (ToPAS), and Psoriatic Arthritis Screening and Evaluation (PASE). All of these instruments did relatively well in the development studies; however, remember that with these screening tests come trade-offs. The more sensitive an answer is, the less specific it is and vice versa. There is no perfect questionnaire and how they perform is based upon how you define them. The difficulties are the oligoarticular and differentiating osteoarthritis from inflammatory arthritis. The utilization of more sensitive imaging (ultrasound and MRI) can help to determine what is inflammatory versus what isn’t inflammatory.

GRAPPA PsA Treatment Recommendations

The chart below outlines the GRAPPA treatment recommendations; however, these guidelines are currently being updated to incorporate some of the newer treatment modalities.

Screen Shot 2014-03-20 at 3.04.49 PM

 

Treatment choices are based on the severity of the different domains.

Clinical Pearl-PsA requires a clinician to really listen to the patient, examine the patient, and formulate and appropriate treatment plan with the patient.

We know that the data on the TNF blockers for the treatment of PsA is very positive for both joint symptoms and skin symptoms. Currently, we even have data that demonstrate the effects of TNF blockers on issues that are important to the patient, such as nail involvement, enthesitis, and dactylitis. In the past, we didn’t have we didn’t have quantifiable ways to measure these, but now we do.

Data also demonstrate that TNF inhibitors slow down the damage to the bone. Getting patients under good control allows them to be functional and go about doing the things they do in their daily life.

Certolizumab Pegol

Certolizumab Pegol (CZP) was approved for the treatment of PsA in September of 2013 and is the fifth TNF inhibitor available for the treatment of PsA. The RAPID-PsA study is important to us, as clinicians, because the researchers looked at switching, i.e., may have failed a previous TNF inhibitor.  The phase III results of the 24-week, double-blind, placebo-controlled study showed that the ACR20 response at week 12 was significantly higher in the CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (58.0% and 51.9% vs. 24.3%) and PASI75 response at week 24 for patients with ≥ three percent psoriasis body surface area at baseline (61.6% randomized set) was 62.2 percent with CZP 200mg Q2W and 60.5 percent with CZP 400mg Q4W versus 15.1 percent with placebo.  This data demonstrate that CZP is effective in PsA, including patients with prior TNF inhibitor exposure. This is very important for our patients who may not have responded to previous therapy. This data as also been confirmed in other registries; therefore, indicating that switching from one TNF inhibitor to another in PsA is a viable option.

In PsA, we don’t know whether a TNF inhibitor plus methotrexate (MTX) is additive or synergistic. In Rheumatoid Arthritis, there is data that demonstrate that even a dose of MTX as low as 10mg gets you synergy. This is something that as a practitioner, you need to negotiate with your patients.

What about obesity and weight loss?

Currently, the data on obesity are very strong and very consistent. We know that PsA patients have shown an increased prevalence of obesity. A study by Di Minno and colleagues demonstrated that within 12 months of starting a TNF inhibitor, patients with PsA achieved minimal disease activity (MDA). The prevalence of obesity was lower in the group achieving MDA.  Patients who lose weight and then begin a TNF inhibitor have a much better chance of doing well, than those who are obese. When you look at the CORRONA database, a study of 392 patients starting a TNF inhibitor showed that only obesity was significantly associated with the discontinuation of treatment. This tells us that patients who are obese do not do as well on therapy and have more disease activity. This is true not only for fixed-dose treatment, but weight-based treatment, such as infliximab, as well. Obesity is inflammatory and this is a very dramatic effect. In fact, it has changed the way Dr Kavanaugh approaches his patients regarding discussing the importance of weight loss.

Biosimilar (CT-P13)

A randomized, double-blind, phase III study of 606 patients demonstrated the clinical equivalence of CT-P13 to infliximab when co-administered with MTX in patients with active rheumatoid arthritis. The results were maintained after the switch from infliximab to CT-P13 from weeks 52 to 104.  CT-P13 received a favorable opinion by the EMA and is now available in Europe.  CT-P13 was studied in rheumatoid arthritis and ankylosing spondylitis and because it was clinically equivalent it received approval for all of the indications for which infliximab is approved.  The FDA has not yet weighed in on how it will approach biosimilar approvals; however, they are here and this is coming. Cost is a major issue, i.e., they could be available at 20-25 percent less than the branded products.

Emerging Therapies

We know that TNF inhibitors work well in GI disease, skin disease, rheumatoid arthritis, etc.. Dr Kavanaugh points out that we have made a somewhat switch from “bench to bedside” to “bedside to bench.” He states that “we are dissecting these diseases by our therapies” with hopes to find more specific treatments for specific groups of patients with these distinct diseases.

Ustekinumab (USK) was approved for PsA in September of 2013. The PSUMMIT trial included 615 adult PsA patients with active disease despite DMARD and/or NSAID therapy. Patients were randomized to receive USK 45 mg, 90 mg, or placebo at weeks 0, 4, and q12 weeks thereafter. At week 16, patients with less than five percent improvement in tender joint count and swollen joint count entered blinded early escape (placebo to USK45 mg; USK 45 mg to 90 mg; 90 mg to 90 mg).  Stable concomitant MTX use was permitted but not mandated. Patients treated with prior anti-TNF agents were excluded. The primary endpoint was an ACR20 response at week 24. A significantly greater proportion of USK-treated patients (versus placebo) had an ACR20 response at week 24. Significant improvements were also observed with USK 45mg and 90 mg for ACR50/70 responses and DAS28-CRP responses at week 24 versus placebo. Through week 16, adverse events were similar between patients receiving USK and placebo with infections being the most common AE. No malignancies, serious infections, tuberculosis, opportunistic infections, or deaths occurred through week 24.  PASI 75 response at week 24 also demonstrated positive efficacy among the USK 45mg and 90mg doses versus placebo.

The PSUMMIT 2 study looked at USK in patients with active PsA who were previously treated with an anti-TNF agent. This data show some improvement in ACR 20/50/70 and demonstrate that it is safe and could be modestly effective for PsA TNF inhibitor-experienced patients.

Dr Kavanaugh and his colleagues, utilizing an integrated data analysis of two phase III randomized, placebo-controlled studies, also demonstrated that USK inhibits radiographic progression in patients with active PsA.

IL-17

Genovese, et al. studied brodalumab, an anti-IL-17RA in patients with PsA.  ACR20 was achieved at week 12 by 37 percent and 39 percent of patients in the 140- and 280-mg brodalumab groups, respectively, compared with 18 percent of placebo patients.  The percent of ACR20 responders (observed) increased at week 24 (44%, 51%, 64%, in prior placebo, prior 140 mg, and prior 280 mg groups, respectively). The percent of ACR50 responders (observed) across all groups increased from week 12 to week 24. There were improvements in other secondary endpoints such as DAS 28, CDAI, and several components of the ACR from baseline to week 12 that continued through week 24 in all treatment groups. Adverse events were similar among all treatment groups and placebo. This demonstrates that brodalumab is associated with significant clinical response with continued improvement from week 12 to 24 and further studies of brodalumab for treatment of PsA should be conducted.

Small Molecules

Apremilast, an inhibitor of PDE4, is currently under development for the treatment of PsA. Data from the PALACE 1 study are statistically significant for the apremilast group(s) versus placebo for both ACR 20/50/70 scores and PASI75. At week 24, significantly more apremilast 20 mg BID (36%) and 30 mg BID (45%) patients achieved ACR20 versus placebo (13%). There were also significant improvements in key secondary measures (physical function, psoriasis) with both apremilast doses versus placebo.

One of the major advantages of apremilast is its safety profile. Laboratory monitoring may not be needed with this drug.

Conclusions

Since the availability of biologics, the interest in PsA has increased exponentially. This is exciting for us, as healthcare providers, and very promising for our patients.  Lastly, remember the importance of tight control in early PsA. If patients are not responding the way you feel that they should be, then their management strategy needs to be modified. Data demonstrate that using a treat-to-target approach can significantly improve both joint and skin outcomes for newly diagnosed PsA patients.

 MauiDerm News Editor-Judy Seraphine

New Drugs

Neal Bhatia, MD & Ted Rosen, MD

In this presentation from MauiDerm 2014, Dr Neal Bhatia, an Associate Clinical Professor at Harbor-UCLA Medical Center and Dr Ted Rosen, a Professor of Medicine at Baylor College of Medicine, bring us the latest information on drugs that are, or will be available to the practicing dermatologist.

Part 1

Neal Bhatia, MD

This information is extremely important, as dermatologists need to continue to stay up-to-date with regards to the new data and literature. As healthcare providers, it is imperative to pay attention to the serious drugs for a number of reasons, in that, many dermatologists are losing their skills and letting good medicine pass them by.

 Apremilast

Apremilast is an inhibitor of PDE4 and is currently in phase III trials for a number of diseases, including ankylosing spondylitis, psoriasis, and psoriatic arthritis along with orphan status for Bechet’s disease. A published case report studying cutaneous lichen planus with apremilast (20 mg bid for 12 weeks then a four week holiday) (Paul et al. JAAD, 2013) demonstrated that 30 percent of the patients experienced a 2-grade improvement and all patients had some improvement. This is important because this data will help us to eventually learn the dose and how to titrate the drug. This study was; however, small in numbers, treatment time and dosages.

Apremilast was also studied in discoid lupus erythematosus (DLE). Remember that DLE is Th1 mediated and apremilast blocks the Th1 process by inhibiting the production of IL-12, 23 and Th-17. There is also subsequent suppression of the Th-1 and Th-17 profile. Eight patients started in the study and four patients finished the 85-day course.  There were some gastrointestinal side effects and sensory neuropathy. (DeSouza et al. JDD, 2012) This indicates a need for larger studies.

Omalizumab

There is a lot of good data demonstrating that sub-cutaneous omalimuzab shows promising results for the treatment of chronic idiopathic urticaria with the treatment spaced four weeks apart. The best data was with the 300mg dose, whereby the patients received the four weeks and then were observed for 16 weeks. Most of the patients had very good severity scores as well as significant reduction. For patients with severe chronic urticaria who are done with antihistamines, cannot handle topicals, and do not know the triggers, omalizumab plays a promising role.

Dr Bhatia commented on the new treatments for onychomycosis and feels that we have a “flood year of antifungals this year.” What we need to know:

  • Naftifine 2% gel—data suggest that there is residual active drug available in the stratum corneum even up to 4 weeks after treatment
  • Luliconazole is approved for the treatment of tinea pedis
  • Efinaconazole and Tavaborole are not approved as yet—but the data for both medications show promise
  • Itraconazole 200 mg tablets with new dosing protocol—coincidentally around the time of the oral ketoconazole black box warning
  • Ketoconazole gel (Xolegel) for use on the face and Itraconazole tablets (Onmel) are back
  • Econazole Foam is coming and the data is encouraging with a new vehicle

In a Phase II study of luliconazole cream 1 percent for the treatment of interdigital tinea pedis, the researchers found that complete clearance was 26.8 percent and 45.7 percent in subjects in the two-week and four-week treatment group, two weeks post-treatment. The antifungal effect persisted several weeks post-treatment resulting in increased rates of mycologic and clinical cure. Four weeks post-treatment, complete clearance rates were 53.7 percent and 62.9 percent, respectively.

Screen Shot 2014-03-20 at 2.24.26 PM

 

Niwano and colleagues looked at in vitro and in vivo antidermatophyte activities of luliconazole and found that it exhibited strong antifungal activity against Trichophyton spp with minimum inhibitory concentrations one to four times lower than lanoconazole or terbinafine. They also found that seven-day topical therapy (0.5% solution) was more effective than lanoconazole or terbinafine (0.5%) and luliconazole was the only drug that achieved complete mycologic cure with a three-day therapy.

Efinaconazole inhibits fungal lanosterol 14α-demethylase, which is involved in ergosterol biosynthesis at concentrations below minimum inhibitory concentrations. Efinaconazole is 4.8 times more potent than itraconazole in inhibiting ergosterol biosynthesis in T. mentagrophytes and is 7.3 times more potent than clotrimazole in C. albicans. Data on efinaconazole for toenail onychomycosis show favorable efficacy.  The chart below demonstrates that you do not need occlusion to see any benefit with efinaconazole.

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Tavaborole, representing a new class of anti-fungals, i.e., a novel boron-based compound, met all primary and secondary endpoints in the treatment of nail fungus when compared to ciclopirox lacquer in two studies and more importantly, demonstrated a negative culture of 87.0 percent vs 47.9 percent and 85.4 percent vs 51.2 percent, respectively. We will begin to see more and more phase III data in the near future.

Ketoconazole gel 2 percent has the same side effect precautions as oral products, on label, but these are doubtful. It’s important to remember that the brand name in some markets may be cheaper than the generic. Also of importance, rates of mycological cure and effective treatment (secondary efficacy endpoints) were observed in the Econazole Nitrate Foam 1% group relative to the Foam Vehicle in both phase 3 studies (P<0.001).

Itraconazole (200 mg) (OMNEL) utilizes Metrex® technology which improves bioavailability. It is now available with a new dosing protocol, which is more convenient for patients.  In one study, itraconazole (200 mg tablets) demonstrated statistically significant efficacy across all endpoints compared to vehicle at week 52 and was found to be noninferior to itraconazole 100-mg capsules at 52 weeks. The treatment duration of 12 weeks allows for 40-week follow-up. Remember that the nail grows out one tenth of a millimeter per day; therefore, every patient who is on any drug will not get a new nail for two hundred days. So, follow-up can be a slower process. The safety profile of Omnel is not statiscially different from that of itraconazole; however, there is a slight elevation in ALT.

Part 2

Dr Rosen continues the presentation with more dermatologic treatment advancements….

Pliagils (Lidocaine 7% + Tetracaine 7% Cream) is a topical, local analgesia for superficial dermatological procedures, such as filler injection, PDL or mild laser abrasion, and tattoo removal, which requires a longer application time. Pliaglis is self-occluding and forms a pliable peel. It is applied 20-30 minutes for most minor procedures and 60 minutes for more major procedures and is available in 30,60 and100gm tubes. A dosing chart is available pending on what area you are trying to anesthetize.

Sitavig (acyclovir 50mg Buccal) is indicated for recurrent oro-labial HSV. The Novel Lauriad® technology is a natural polymer derived from milk which adheres to the mucosa; therefore leading to high local drug concentration, but minimal blood levels. It is one tablet, applied within one hour of prodrome onset, on the upper gum at the incisor on the same side as the HSV lesion. After holding pressure for 30 seconds, the patient should allow the tablet to remain until it falls off (approximately six hours). Sitavig has shown to reduce the duration of an attack by 0.5 days based upon a randomized controlled trial of 775 patients.

Another advancement includes the approval of carbinoxamine maleate susp (Karbinal ER), which is a mildly sedating H1 antihistamine in an extended release formulation. It is used for the treatment of allergic rhinitis and conjunctivitis, uncomplicated urticaria, angioedema, and dermatographism. The advantages of this drug are that it is in a liquid form and there is infrequent dosing (2 times per day). It is also indicated for children as young as age two.

Vashe Skin and Wound Hydrogel, an aqueous-based, emollient containing, non-oily hydrogel, is a hypochlorous acid-containing material. It is intended to relieve pruritus, burning or pain from atopic, allergic contact and radiation dermatitis, as well as thermal burns. The drug maintains a moist environment, encourages autolytic digestion and prevents contamination. It works through the chlorination of histamine, leading to a less active derivative. It oxidizes many groups and subsequently directly and indirectly neutralizes the effects of cytokines, leukotrienes, alpha-1 antiproteinases, and cysteine proteases. This product is Aurstat with which you may already be familiar. It came from a partnership between PuriCore and Onset Dermatologics.

Old Drugs, New News:

  • Adapalene/BPO 1.2%/2.5% (Epiduo®)–Now FDA approved down to age 9
  • Desoximetasone 0.25% (Topicort®) –Now available as a spray
  • Ketoconazole 200mg tab (Nizoral®) –Severe limitations on use due to liver and adrenal toxicity, as well as drug interactions
  • Certolizumab pegol (Cimzia®) –Now approved for psoriatic arthritis, maybe psoriasis at some time in the future

Certolizumab Pegol (Cimzia®)

Cimzia is approved for the treatment of psoriatic arthritis (PsA) at 200mg sq QOW.  A phase III, multi-center, randomized, double-blind, controlled trial (RAPIDTM-PsA study) looked at 409 patients with adult onset PsA. The loading dose was 400mg or placebo at baseline, week two and week four, followed by 200mg qowk, 400mg q4wk, or placebo qowk. Adverse events were found in 62 percent of the patients versus 68 percent (placebo). ACR 20, 50, and 70 response rates at weeks 12 and 24 were higher for each Cimzia dose group relative to placebo; however, patients treated with Cimzia 200mg every other week demonstrated greater reduction in radopgraphic progression at week 24. Patients treated with Cimzia 400mg every four weeks did not demonstrate greater inhibition of radiographic progression at week 24, compared with placebo-treated patients.

Screen Shot 2014-03-20 at 2.24.57 PM

Overall, treatment with Cimzia resulted in improvement in skin manifestations in patients with PsA (62.2 percent to PASI 75). It is important, as dermatologists, to recognize that the safety and efficacy of Cimzia in the treatment of patients with plaque psoriasis has not been formally established and the use in psoriasis is off-label.

In conclusion, clinicians should pay special attention to the Nizoral FDA warnings published in July of 2013. (www.fda.gov) The FDA states that:

  • Oral ketoconzazole should not be used as first-line therapy for ANY fungal infection
  • Ketoconazole should be used only for the treatment of life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or not tolerated
  • Oral ketoconazole is no longer indicated for dermatophyte or Candida infections
  • Oral ketoconazole is not indicated for fungal infections of the skin or nails
  • It is contraindicated in anyone with liver disease

If you use this drug and there is any hepatotoxic event, that could cause a great problem as a practitioner.

In summary, the dermatology landscape is continuing to grow with promising new drugs for our patients and it is imperative to stay on top of the latest data.

MauiDerm News Editor-Judy Seraphine

 

 

 

Actinic Keratoses: Clinical Pearls

George Martin, MD

Are you using 5-FU to treat AKs?

  • To minimize the duration of side effects, compliance issues and phone calls when prescribing 5-FU prescribe 0.5% 5-FU therapy for 1 week.  Phase 3 FDA data on 0.5% 5-FU used for 1 week demonstrate over 70% individual lesion clearance. Is it worth continuing an extra 3 weeks to achieve a > 90% clearance?  No.
  • What does Dr. George Martin do? He cycles 5-FU therapy: 1st cycle—Face: 7 days 5-FU/Non-facial areas: 10 days 5-FU; Rest period for at least one month; 2nd cycle— 5-FU for at least 2 weeks.  Data suggest that 0.5% 5-FU QD is at least as effective as 5% 5-FU BID in percent reduction of AK lesions. The short treatment cycles result in great compliance and minimal downtime.

Treating AKs on the chest?

  • Avoid 3.75% imiquimod. It is likely to result in permanent depigmentation at the AKs treated sites on the chest in the majority of patients. It is not yet FDA approved for the trunk…and with good reason.
  • Try: ingenol mebutate 0.05% x 2 nights. Instead of spot treating, cover the entire sun-damaged AK area of the chest with the entire amount in the tube. Best used on moistened skin post shower because it spreads better. Because of its direct cytotoxic effect, in addition to up-regulation of IL-8 induced neutrophil chemotaxis, it produces discomfort within 4 hours requiring analgesia. Be sure to set patient expectations and prescribe analgesia.  Patients describe it’s use on large areas on the upper chest as feeling like a “really bad sunburn.” Although not FDA approved to treat areas >25 cm2 and there is no efficacy data, Dr. Martin has found it to produce excellent AK clearance and a great cosmetic result.