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?

 

 

 

 

 

Introduction to Lasers and Light (And a Touch of RF and Microwave)

E.V. Ross, MD

Dr Ross, a leader in the field of laser and light therapy, provided the audience with an in-depth overview on lasers and light. Dr Ross begins by reminding us that we tend to look for the “easy” way out to make our patients look their best with the least downtime. In order to be efficient and effective for his patients, Dr Ross likes to have many lasers in one room; therefore, providing the best possible technology.

It is important that we really understand laser physics. You need to know some math, but it doesn’t have to be difficult math. You can take very complex mathematical relationships and break them down into very simple algebraic relationships. By doing so, you can actually apply your lasers and other technologies quite confidently. It’s imperative to understand how they work because if you don’t, you can get into trouble very fast. Remember to look, listen and feel….listen to the reaction, look at the laser, look at the patient at every pulse to be sure the endpoint is what you want to see because ultimately, the endpoint is more important than the physics.

When we talk about lasers, we need to know some basic definitions. One of the most important terms is fluence; fluence is simply the light dose, i.e., the amount of energy that we are investing per surface area for a particular application.  We used to speak a lot about power, e.g. 7 watts power or 12 watts power. Currently, we don’t talk much about power because most of our lasers today are pulsed lasers. What really matters are wavelength, fluence and pulse duration. Pulse Width is  very important, i.e., the time over which energy is delivered. Spot size, which contributes to the intensity inside the skin, is mainly important for visible light lasers and infrared lasers because a larger spot will penetrate better.

LASER, Light Amplification by the Stimulated Emission of Radiation, is a concept that Einstein predicted back in the 1920s, but it was not realized until May of 1960.

Why is laser different than a lot of other light sources? We can use a lot of non-laser light sources in dermatology and certainly achieve nice results. Intense pulsed light is a great example. There are some features of lasers that make them helpful for dermatology and helpful for certain applications, but not always necessary for every application.  (See http://www.colorado.edu/physics/2000/lasers/index.html)

Why is it important to differentiate laser light from non-laser light? Dr Ross explains that it is because of engineering more than anything else. Most of our targets that we treat in dermatology have multiple wavelengths as far as their absorption. Lasers are a convenient way to deliver light, i.e., deliver photons to the target. This is why lasers are so popular. You can put lasers into a fiber, you can have monochromatic light, and you can deliver very high power. It’s the only way to really deliver very short pulses in nanoseconds and picoseconds for certain applications.

Why do we need to know how/why lasers, etc. work?

Dr Ross states that one important reason is that when your laser breaks down, which can happen, you want to understand why it isn’t working. If you have a good understanding of how your laser works, you may be able to correctly diagnose that. If you see that your laser isn’t working right, often times there’s an error code. It’s important that you write down the code and report that to the technician. Sometimes it’s as simple as restarting the system.

You should be able to troubleshoot laser problems in a logical way…Device malfunction is one problem, an example is a temperature sensor malfunction. However, a bigger problem could be your lack of familiarity with the device; most laser problems are caused by the operator because they’re not familiar with how the device works—sometimes they are rented and sometimes they are only used once per week. Other factors that contribute to laser problems include poor patient selection, operational errors, poor post-treatment care, and simply bad luck.

Dr Ross reminds us that we have to think. Most of the time when we get into trouble with lasers it’s because we weren’t thinking—invest all of your brain power into that particular case while you’re performing the procedure and that means paying particular attention to endpoints.

Four years ago right before the Christmas holiday, Dr Ross had a typical case of a woman who came in for treatment of telangiectasias with a pulsed-dye laser. He used the pulsed-dye laser, 10mm spot, 7 J/cm2, and a 10-millisecond pulse and everything was looking fine. The patient developed some mild purpura and she was incredibly upset. So what happened? She didn’t have any blisters and everything else was fine. Dr Ross went back and looked at the beam profile and found that it was off by about 2mm (8mm instead of 10mm).  What had then happened was that the fiber was damaged so they were delivering the right energy but in a smaller spot; therefore, causing the fluence to become higher and the purpura threshold had become breached. The technicians then fixed the beam profile and there was no more purpura. Dr Ross reminds us that sometimes we may have to do some detective work to figure out what’s going on.

Broken mirrors can also compromise your laser experience.  Particularly with the CO2 laser, if your beam profile doesn’t look good it may be due to a broken mirror.

When your calibration doesn’t pass,  the most common reason is because of a bad lamp.

What we’re seeing now is a progressive change in laser technology. Lasers are becoming quieter, cooler, smaller, better and more reliable. We now have small, portable lasers (see figure 1) and maybe, in the near future, we’ll see small lasers that can treat everything from tattoos to resurfacing.

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Remember that with most of the lasers that we’re using today, the light piece is “back in the box” and is delivered through some sort of delivery system; however, in the case of some of the mini diode lasers, the light is in the hand piece. (See Figure 2)

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Over the next few years, we are also going to see more and more LEDs. We are going to begin to see more safety features that will be incorporated into the software with touchscreens. For example, you may have a patient who came in for treatment of a wart so the technician turns the dynamic cooling device off. Then, your next patient is coming for treatment of a port wine stain and the technician forgets to turn the DCD back on and the patient gets a blister from the very first pulse. What if there was a tool that provided a warning signal indicating that the DCD was off? Actually that feature is already built into one popular pulsed dye laser.

What about photon recycling? This is a way to capture some of the photons that were wasted. Whenever we use a laser much of the energy is reflected back off the skin surface. By recycling the energy we have a second chance to use those photons. This preserves energy and puts less stress on the system. We will also see more and more scanning technologies as they are becoming increasingly robust. In the future, we will probably see scanners that will find the target and treat it.

Another concept that Dr Ross discusses is the TRASER (Total Reflection Amplication of Spontaneous Emission of Radiation). The traser is not a laser, nor an IPL. This is one device with many wavelengths that is tunable, has high peak power and variable pulse duration. This device is actually less expensive than a laser and you can change the dye very quickly. The traser uses total internal reflection. We know that if we take light beyond a critical angle, the light will come back towards the same direction.

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Overall, with lasers in dermatology, you only have to know the chromophore spectra of three targets: blood, melanin, and water. If you know the relative absorption for specific wavelengths for these three targets, you will be a fairly well-armed laser surgeon.

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When you model a laser-tissue interaction, you want to look (in your mind) at the way that the light propagates through the skin to the target. You have to get the light to the target. Then, depending on the pulse duration and the wavelength you’re going to have a certain amount of temperature increase leading to a response from that target due to the temperature and time combination.

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What about skin optics? It’s important that you determine the penetration, the absorption and scattering, and the internal dosimetry.

Laser Tissue Interaction Types

There are different types of interactions. The main type that we use in dermatology is thermal, in that we are basically converting light into heat. Other types of interactions include mechanical, chemical, and plasma. Dr Ross feels that one of best ways to learn about laser tissue interaction is through laser hair reduction. The laser comes down, and a certain amount of the light is going to reach the hair bulb, based on the optical properties of the skin. Typically for 1064nm, about 30 percent of the light is going to get about 3mm down which is the typical depth for a hair follicle. Depending on the pulse width, the wavelength, and the fluence, you will have a certain temperature elevation of that hair bulb and some of that heat is going to diffuse to the surrounding skin. So long as the temperature and the time combination is relatively small, you won’t have too much collateral damage—you will only damage the hair follicle.

Selective photothermolysis was a formal termed coined by Dr Rox Anderson 32 years ago. What it says is that if you have the right wavelength, the right pulse duration,  the right target, and sufficient energy,  you will achieve extreme localized heating. This really revolutionized the way in which we treat vascular and pigmented lesions.

As a dermatologist, you should always remember the graph below, where the wavelength is on the X axis, and you have the relative chromophore absorption in the Y axis. If so, you will be a well-armed laser surgeon. Just like a neurologist looking at an EEG and a cardiologist looking at an EKG, this should be second nature to you.

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How can we exploit laser physics? An example of this is a scar. When we have a scar, there is usually some feature that makes it different from the surrounding skin. You can take a laser and exploit that, whether its redness or pigment in the scar.

This is the temperature equation that basically tells us how hot targets get…the temperature elevation of any target is proportional to the relative absorption of that target for that wavelength of light times the energy div over by a constant. This is very simple concept as its basically energy balanced. Where is the equation??

As you go to longer pulses, the selectivity of the heating becomes poorer but the violent nature of it becomes less.

Fat

Dr Ross states that we are still woefully poor at targeting fat, whether it’s radiofrequency or laser. There are a couple of wavelengths that can be useful for exploiting fat; 1210nm and 1720nm. Those are the wavelengths where fat absorption is in excess of water absorption. However, the ratio of absorption from fat to water is only 1.2 or 1.1 to 1. When we treat a vascular lesion, our absorption rate for the blood is more like 100 to one vs water. So relatively speaking, fat shows poor selectivity, but if you deliver heating and cooling right, there is some selectivity for fat absorption.

Other Key Points

With regards to cooling and heating, we always want to preserve the epidermis and a dynamic cooling device can do so. It is also important to know the photochemistry with regards to chemical reactions and pay attention to these reactions; an example of this can be seen with patients who have previously been on Gold.

Microwaves and Radiofrequency

Microwave and radiofrequency devices are becoming increasingly commonplace within our armamentarium. They rely on heating water, the resistance of water molecules turning causes heat. The  microwave device is around 6GHz. Problems like underarm sweat can be treated with systems like MiraDry. Basically what happens is that the microwaves come down and there is a discontinuity of the dermal-fat junction and it heats up the sweat glands about 4mm below the skin. MiraDry offers another application in clinical practice and can complement other procedures. It also has little downtime.

We are going to begin to see more and more radiofrequency (RF) reactions. It is important to understand SAR, i.e., the specific absorption rate at which energy is absorbed when exposed to an RF electric field. By delivering the right time and the right temperature, one can establish very nice reliable heating of the skin.

 

MauiDerm News Editor- Judy Seraphine

 

 

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

Sheila Friedlander, MD and Ilona Frieden, MD

Part 1: Look What the Wind May Have Blown In

Dr Friedlander began this session with a case study….A child presents to your office with an unusual rash.  The pediatrician called it maculopapular,  others migth call it polymorphous. The rash is papular ,  erythematous and fairly generalized.  Dr Friedlander states that most of the time when a child comes into your office with this type of rash, the history is often not that helpful. Be sure to ask about systemic signs, fever, or anyone else sick in the house.  Obtain a drug exposure history. . What is it reasonable to think about? Most of the time, it is a virus. Enterovirus is a reasonable possibility When in doubt, some physicians will blame EBV, especially if the child has had amoxicillin. Occasionally, it could even be measles with this sort of polymorphous eruption,  so it is important to look for cough, coryza, and conjunctivitis. It could also be Parvo virus so check to see if the  child had “slapped cheeks” appearance at any point, or a lace-like appearance to the body rash. . This particular child has had high  fevers for four days and the family is starting to get anxious.  The patient is fussy and his  lips are cracked. The parents also inform you that the child took amoxicillin two days ago and some NSAIDs yesterday. What do you think this is?  Dr Friedlander again emphasizes that it is important to go through his history of drug exposure;  fortunately  in this case, the rash predates any medications.

When you examine the eyes, you note the conjunctiva are red with a rim or halo of white around the cornea,, which is called limbal sparing—In  the diaper area, there is superficial desquamation that is really faint superimposed on confluent erythema. .  What can cause superficial desquamation in this pattern. What about staph scalded skin? The kids who have staph scalded skin do have intertriginous area involvement, but also often have erythema  in the perioral and periorbital areas along with radiating fissures around the mouth. They may also have blisters or bullae.

When you see a patient like this, you need to think about virus, drug, and staph scalded skin. Remember, this child has a polymorphous rash, has lip and tongue involvement, and a very distinctive diaper-area rash that developed  early in his course. The child also has conjunctivitis with limbal sparing and one enlarged lymph node.

So, what should we be  thinking about? Kawasaki Disease…Dr Friedlander reminds us to consider this whenever we see a child who has had prolonged fever  and a rash.

A 2013 article by Bayers S, et al was published in the JAAD, and is an extremely useful review  for dermatologists interested in  Kawasaki Disease. This disease is a small and medium size artery vasculitis.  One of the diagnostic criteria is fever for more than five days; however, if you have a child that fits all of the criteria at day four, you should move ahead with treatment. The earlier you start intervention, the less likely the child is to develop coronary artery disease. The palms and soles are  often red and swollen, and the aforementioned findings of conjunctival injection along with crusted lips and oral mucous membrane erythema are often present.  Cervical l adenopathy is often present but usually asymmetrical—this is helpful to remember.  If you suspect Kawasaki disease, get an expert in the area to help you manage this patient.

What are other KD  skin findings that are of interest to dermatologists?

  • Micropustular follicular rash (uncommon)
  • Nail discoloration, onychomadesis
  • BCG site rash
  • New onset psoriasis

Kawasaki Disease: Epidemiology

The typical age at presentation is six months to five years of age and the highest incidence of the disease is in Asian countries. In the United States, the highest incidence is among those of Asian ethnicity. If a child has this disease, the risk for a sibling to develop the disease is six to 30 times higher than normal and  for any progeny of KD patients, , the risk for his/her child is two times higher. The recurrence rate is two to four percent.

Why is this disease so important? Coronary artery aneurysms and cardiac disease!

It is extremely important to make the diagnosis because cardiac complications can occur. These include:

  • Coronary ectasia and aneurysms
  • Decreased coronary arterial compliance
  • Myopericarditis
  • Arrhythmias
  • Ischemic heart disease
  • Pericardial effusion
  • Valvular regurgitation
  • Myocardial infarction
  • Sudden cardiac death

Cardiac complications affect 15 to 25 percent of untreated patients.

Treatment for Kawasaki Disease

Again, refer to a specialist to help manage these patients. Treatment can decrease coronary risk by at least a factor of five. Treatment includes IVIG 2gram/kilogram over 12 hours, ASA High (80-100mg) divided qid, then low-dose (3-5mg) around day 14. Corticosteroids may be useful in refractory patients. Biologics, such as infliximab and etanercept, may also be useful. IVIG should be repeated if there is no defervescence at 36 hours.

What causes this disease?

We know that cases tend to occur close to each other temporally and there is a prediliction for winter and spring. It occurs mostly in children and is self-limiting. It takes a  course similar to that of  infectious processes  where  immune-mediated response is apparent. Lots of organisms  have been implicated; yet the etiology remains elusive..

Over the last  few years, researchers have found that a correlation exists between wind currents that track from Asia to Japan which  traverse the North Pacific and the occurrence of Kawasaki disease. There have been three epidemics in Japan in May, March, and April, which correlate with times of highest intensity wind currents The belief is that there may be a wind-borne environmental trigger. Investigators are now utilizing  planes and are collecting samples of air in the middle of these wind currents. Many scientists believe that there is a wind-borne agent that is causing this disease. Stay tuned, we may have more information next year.

Part 2: What is a Birthmark?

In the broad sense, a birthmark is a developmental anomaly that is present on the skin. As you know, they do not necessarily need to be present on the day of birth and they can range from common to rare.

Dr Frieden discusses the six questions that you should ask when you see a child with a birthmark.

  • What is the diagnosis? Is this a port wine stain or is this a premonitory mark of an infantile hemangioma. It is extremely important to pin down the diagnosis.
  • Is there a risk of extracutaneous associations?
  • What is the prognosis/natural history?
  • What (if anything) needs to be done? Are there good treatments?
  • Is there a “window of opportunity?”—an example of this would be infantile hemangioma whereby early intervention can really make a difference if treatment is needed
  • What is the cause?

Dr Frieden has been a pediatric dermatologist for a little over thirty years and she states that parents always ask: “what caused this?”  Previously, the answer was “we don’t know”.  Often times, especially for mothers, they ask themselves if they did something wrong during the pregnancy.

So to answer the sixth question, according to Dr Frieden, “2013 has really been a watershed year.”  Researchers are now using deep sequencing of birthmark tissue, not germ-line DNA in order to understand the genes that cause birthmarks. Most of the birthmarks that appear are post-zygotic somatic mutations. Knowing the cause of the birthmark may help to pave the way for newer therapies.

In 2013 Mutations In….

  • GNAQ cause Sturge-Weber
  • KRAS and HRAS causes of nevus sebaceous
  • NRAS cause of giant nevi
  • GTPase BMS1 cause of familial aplasia cutis congenital (germ-line)

What’s exciting about this? New therapies will be developed to address activating mutations because these are also mutations that can cause cancer. We know that researchers are looking for ways to stop activating mutations in these pathways. So you may ask “how does this affect a birthmark?” Dr Frieden provides an example where it may be very important and that is in Sturge-Weber. In Sturge-Weber, children are generally born with Sturge-Weber and they are neurologically normal, there are exceptions to this; however, Sturge-Weber is really a progressive disease. Children will develop heavy paralysis and seizure disorder despite the fact that they are normal at birth. It may be that if we treated these patients with something that inhibited an activated mutation GNAQ only for a couple of years, for example, we may be able to avoid some of the developmental changes that occur. Scientists don’t really know whether or not this is true, but it is an example of where we may be able to halt progression. This is an incredibly exciting time because, as physicians, we may be able to look parents in the eye and provide them with some information about the cause of the birthmark.

Part 3: Drug Reactions in Kids

This section of the presentation focused on drug reactions.,foc. Why is Dr Friedlander cautious when prescribing  minocycline? There is more and more evidence that minocycline is one of the offenders that can cause Drug Reaction Eosinophila and Hypersensitivity Syndrome (DRESS). It’s important to be aware of this disorder and how frequently we can see it.  It  can occur in one in 1,000 to 10,000 drug exposures. DRESS can be distinguished from other drug reactions in that often times the onset is later, approximately two to six weeks after exposure. It presents with a morbilliform rash, significant facial and periorbital edema, and exfoliative changes. Why is it of concernt? DRESS can affect the liver and other organs and has a mortality rate of up to ten percent. This is a good discussion to follow in that of  Kawasaki Disease because they share a similar differential diagnosis. Patients with DRESS have bilateral, significant cervical adenopathy, there may also be significant facial edema, and  often have what looks like an extensive erythematous, sometimes edematous,  confluent eruption. Husain Z, et al published a very useful review in the JAAD in 2013 regarding clinical perspectives and management and therapeutics for DRESS syndrome.

What are the drugs that we need to worry about?

When considering  DRESS, you want to check to see if the patient has eosinophilia and/or liver involvement because such findings raise the likelihood of life-threatening complications. . The common drugs associated with this problem are outlined below:

Ped 1

 

Pathogenesis

We now know that there are some genetic polymorphisms for drug metabolism that DRESS patients may exhibit. For many of these patients, there may be a genetic difference in how these drugs are metabolized which may be a cause of the disease.  There are two enzymes that have been implicated, epoxide hydroxylase and glutathione transferase. Another fascinating discovery is the association between DRESS and  human herpes virus (HHV-6), CMV, or EBV. Researchers are really not sure whether or not this a secondary involvement, but some scientists feel that re-activation may play an important role. In fact, there are some studies that have demonstrated that those who receive amoxicillin are worse prognostically because amoxicillin, at least in vitro, can help encourage activation and replication of HHV-6. This is an interesting combination of environmental and immune reactions. A number of specific genetic markers have been identified: these include  HLA-A 3101 in association with  carbamazapine; HLAB-5801 with  allopurinol; and HLA DR3 and HLADQ2 with  carbamazapine that put certain patients at risk.

What organ is likely to be involved if your patient gets DRESS?

Ped 2

 

Don’t forget to think about the differential diagnosis. Remember that the interval before onset is longer than Stevens Johnson Syndrome and TEN. Organ involvement is also more common in DRESS. These patients also tend to have more facial swelling and symmetrical nodes as opposed to Kawasaki Disease. If you were to perform a biopsy in these patients, you would see a more predominant  lymphocytic infiltration whereas in  Stevens Johnson Syndrome or TEN you would see a predominance of necrosis.

What can you do if you think your patient has had a reaction to DRESS?

First and foremost, you want to discontinue the drug. . You can also do skin or serum testing; this  provides a positive predictive value; however, it is not widely used. Therapy for DRESS includes supportive care, systemic l corticosteroids if there is liver involvement, and avoiding the use of antibiotics or NSAIDs.

Prednisone 1mg/kg/day  is often utilized, and tapered slowly over three to six months. If there is no response, patients can be given IV methylprednisolone 30mg/kg IV qd for three days. Do not stop these kids abruptly as there  relapse can occur. It is also very important to check thyroid function.

Dysphagia

Some experts believe that ysphagia is an early manifestation of DRESS syndrome and it may come before the rash. Why is this important? Many times children will present to  the pediatrician with a sore throat and will be given amoxicillin empirically. With the advent of rapid Strep tests, Dr Friedlander would encourage all pediatricians to utilize these tests before simply prescribing amoxicillin, as we know that there is a suggestion that it may be detrimental to patients with evolving DRESS.. Dr Friedlander also recommends antipyretics with Tylenol versus NSAIDs. Remember to ask if the patient is feeling uncomfortable or having trouble swallowing.

MauiDerm News Editor-Judy Seraphine

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

 

Psoriasis: Update on Emerging Systemic Therapies

Craig Leonardi, MD

At MauiDerm 2014, Dr  Craig Leonardi, Clinical Professor of Dermatology at Saint Louis University, presented us with the latest data on emerging systemic therapies for the treatment of psoriasis. According to Dr Leonardi, “the psoriasis space is going to move very quickly over the next year/year and a half…”

Dr Leonardi comments that many of our 2nd generation biologics were developed with these cytokines in mind (see below).

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Remember that drugs come and go and many fall by the wayside; what’s important to us, as practitioners, is finding the best medicine for our patients.

Certolizumab Pegol (CZP)

CZP is a peglyated Fab fragment. It was initially approved for Crohn’s disease and subsequently approved for the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. In 2005, there was a large phase II psoriasis trial of 176 patients with 10 percent BSA and PASI 12. It was conducted in Germany and France to look at CZP for the treatment of psoriasis. There were three treatment arms: 200mg sc qeow, 400mg sc qmonth, and placebo. PASI 75 results demonstrated 75 percent, 83 percent and 7 percent, respectively. PGA results (clear-almost clear) showed 53 percent, 72 percent and 2 percent, respectively among all treatment arms. There were no unexpected safety issues. This data tell us that CZP is both efficacious and safe for the treatment of moderate to severe plaque psoriasis. The fact that it is approved for PsA is also important to patients with PsO/PsA. This data was presented in 2007 at the American Academy of Dermatology and published as a paper in 2012. It appears that currently, UCB, the maker of CZP, has again taken an interest in this medication, as there is some development effort and we should be seeing a psoriasis trial quite soon.

Targeting the IL-12/23 Pathway

Both ustekinumab (IL-12) and briakinumab (IL-23) block the shared p40 subunit. When you block IL-12, you down-regulate a set a cytokines from the Th1 pathway, including INFy, IL-2 and TNF-alpha.  When you block IL-23, you down-regulate IL-17 alpha, IL-17f, IL-6, TNF-alpha, IL-21 and IL-22.

Function of Th17 Effector Cytokines

IL-17a

•Expressed by memory NK and T cells

•Increased in psoriatic skin

•Subcutaneous injection à neutrophilia

•Enhances inflammation

•Enhances angiogenesis

IL-22

•Expressed in high levels by Th17 cells

•Increased in psoriasis (skin and plasma)

•Levels correspond to disease activity

•Induces keratinocyte hyperproliferation (in vivo, in vitro)

•Stimulates keratinocytes to secrete antimicrobial peptides

Ustekinumab is a high-performing drug for psoriasis patients. The data at week 28 in both the PHOENIX 1 and PHOENIX 2 studies, show about 70-79% of patients are achieving a PASI 75; this is a huge achievement for these patients.

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New Development Efforts

Ustekinumab was recently approved for the treatment of PsA, based upon its efficacy data with regards to an ACR 20 response at week 24.

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However, when you compare these numbers with the other TNF antagonists, ustekinumab does not appear to work as well in PsA. It remains to see how our rheumatology colleagues will regard this drug over time. It may be used as a second- or third-line drug for PsA.

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3rd Generation Biologics

There is a down-stream effect from anti-IL-23 blockade feeding into IL-17 and down-regulating IL-22. Many pharmaceutical companies have been studying this pathway; there are two, possibly three, IL-23 inhibitors currently in trial, there are two anti-IL-17 inhibitors, an IL-17 receptor antagonist, and there was an IL-22 blocker that came and went…this is a very rich developmental pathway with many promises.

IL-17 Antagonists

The phase II studies of secukinumab (Novartis) a human IgG1 monoclonal IL-17A antibody demonstrated that the 150mg and 300mg doses were statistically significant as compared to placebo at week 12. This is an incredibly high-performance drug, i.e., in the 300mg dose, between 80 and 90 percent of these patients were achieving a PASI 75. According to Dr Leonardi, “this is absolutely remarkable when you think about the world of chronic inflammation”.

The results of secukinumab’s pivotal phase III data was released this fall at EADV.  Dr. Leonardi reported that the ERASURE study evaluated secukinumab doses of 150 mg and 300 mg in a placebo controlled study.  PASI-75 response rates in the secukinumab groups reached a peak at week 16 (80% – 90% range).  IGA scores of “clear or almost clear” were reported in the 60% to 75% of patients. Treatment benefit was maintained through week 52 on q4 week injections following an induction period. Other phase 3 trials included the FIXTURE study included etanercept as an active control.  In this comparator study patients showed a more rapid response to secukinumab vs etanercept (3 vs 8 wks) to achieve a PASI 50 and greater number of patients achieving PASI 90 (72.4% vs 41.5%). The third secukinumab Phase 3 trial SCULPTURE compared fixed-interval q4 weeks maintenance dosing with an “retreatment-as-needed” regimen. Data from follow-up to week 52 showed fixed interval therapy with SEC 300 mg and 150 mg q4wks sustained significantly greater PASI 75, 90 and 100 clearance rates over 1 year compared to “retreatment-as-needed”. “Retreatment as needed” is not a good regimen for any biologic”, says Dr. Leonardi.

We haven’t seen any of the safety results from the secukinumab phase III trials; however, the drug was well tolerated overall according to the phase II data according to Dr. Leonardi.

Ixekizumab (Lilly), is another anti-IL 17 monoclonal antibody, is another high-performance skin-clearing drug based upon its phase II data. Studies looking at 10, 25, 75 and 150 mg demonstrated that at the two highest doses, 80 percent of patients were at the PASI 75 range. There were no serious adverse events in this trial and the drug had a “remarkable safety profile” according to Dr. Leonardi.

The biostatisticians at Lilly, the makers of ixekizumab, utilized Youden’s Index to create a sensitivity and specificity assay. They determined that if they looked at the PASI 50 response at week four, they could make accurate predictions on the chances of success downstream. The likelihood of achieving PASI 75 and PASI 90 correlated with the PASI 50 response.

Brodalumab (Amgen) is an anti-IL-17 receptor antibody, which blocks not only Il-17A but also IL-17E and IL-17C.  It is another high-performance drug for the treatment of psoriasis. The phase II studies, which were completed some time ago, demonstrated positive efficacy results along with a good safety profile. The long-term maintenance of clinical response with brodalumab has been demonstrated through week 96 of an open-label extension study. The one caveat with this open-label extension study is that it is an observed analysis, not an intent-to-treat approach to the data. Remember that the patients who came out of the trial are those who are not doing well so as you move through the trial, the population will continue to improve.

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Positive results were also seen with sPGA over 96 weeks.

Interleukin 23

Remember that the p19 subunit is NOT shared; therefore, an anti-P19 molecule will block just IL-23. Tildrakizumab, a novel anti-IL23p19 monoclonal antibody, demonstrated good results in a 16-week phase IIB trial. There were four doses at weeks 0 and 4 (5mg, 25mg, 100mg, and 200mg) versus placebo.  PASI 75 was achieved in 35, 65.5, 67.1, and 76.2 percent of patients, respectively versus 4.9 percent in the placebo arm and PASI 90 was achieved in 11.9, 24.4, 38.2, and 51.2 percent of patients versus 2.2 percent in the placebo arm. Tildrakizumab appears to be generally safe and well tolerated.

Small Molecules

Apremilast (Celgene)is a novel, small molecule that inhibits PDE-4. It has a variety of immunosuppressive effects, in that it reduces TNF-alpha, IL-2, IFN-γ and several leukotrienes. In Phase III studies (ESTEEM I and II), apremilast (30 mg BID) has achieved a PASI 75 rate of 33 percent. Importantly, scalp, nail and pruritus scores were superior in the apremilast patients compared to controls. Phase III results also demonstrated greater improvements from baseline Dermatology Quality of Life Index versus placebo.  The majority of adverse events (AEs) were not serious and included mild gastrointestinal side effects: nausea 16% and diarrhea 19%.

According to Dr. Leonardi, apremilast also has phase III PsA results that are statistically significant versus placebo although not quite as robust as the TNF inhibitors.  (FDA approval for apremilast for the treatment of PsA was announced during the winter AAD).

Tofacitinib (Pfizer), a novel, oral JAK inhibitor approved for the treatment of rheumatoid arthritis, is currently being investigated as a treatment for psoriasis among other indications. At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25% (2mg), 40.8% (5 mg) and 66.7% (15 mg), compared with placebo (2%). It appears to work about as good as methotrexate. Of note, in rheumatoid arthritis, the FDA approved only the 5mg dose. The phase II safety data reported five serious adverse events (SAEs), three of which (atrial fibrillation, pyelnephritis, and urosepsis) occurred in one patient on the 2mg BID dose. There was a mild increase in Hgb levels that was greater in the 15mg BID group. There was a transient decrease in PMNs in the 5mg and 15mg BID groups and there were dose-related increases in both HDL and LDL. In the rheumatoid arthritis trials, the FDA found that the numerical increase in malignancy incidence over time was of particular concern and is consistent with a scenario where increasing exposure to tofacitinib increases the risk of malignancies. The FDA also stated that opportunistic infections, including TB, were “not uncommon.” In the RA program, 14 out of 15 patients who died due to infection were on tofacitinib. There were 34 patients with opportunistic infections, all of whom were on tofacitinib. Despite the immunological differences between rheumatoid arthritis and psoriasis patients, this is remarkable data and something that we, as dermatologists, need to pay particular attention to.

Conclusions

In conclusion, we can see an explosion of new biologics in the marketplace with most of the drugs targeting the IL-23 pathway. We still have an unresolved issue with regards to major adverse cardiovascular events (MACE).  Some feel that there is a signal at the IL-12/23 blockade level, it will be interesting to see if the MACE signal populates the IL-17 blockers…there may be more information coming out on that.  We are also seeing a wide variety of novel small molecules demonstrating moderate to robust efficacies and the safety profiles for some of these products are promising.  There has also been a move to explore the JAK inhibitor in a topical formulation to treat psoriasis.

Psoriasis patients are now the “model” of choice for chronic inflammatory disease and we are getting these drugs earlier now than ever before.  Remember that many of the drugs have fallen by the wayside for efficacy and/or safety issues. We need to select drugs that are good for our specialty and for our patients. As dermatologists, we need to consider that short- and long-term safety issues do exist; however, the benefit/risk ratio appears to be favorable overall.

Our treatment paradigm has shifted from a stratified approach, i.e., patients must fail the previous “step” of therapy before initiating a more “aggressive” therapy to an approach whereby the choice of therapy depends upon individual patient characteristics.

 

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

 

 

 

 

Clinical Pearls-Dermal Filler Complications

Wm. Philip Werschler, MD

It is important to keep in mind that complications can occur when using dermal fillers in clinical practice…It’s important that you:

  • Recognize complications and promptly treat them
  • Not hesitate to see patients in follow-up and refer them if necessary
  • Are truthful with your patients and stay in close contact with them

What about impending necrosis? Remember that impending necrosis as a proposed MOA and patient’s actions may have an impact on the development of impending necrosis…Dr Werschler provides us with some practice tips:

  • Educate staff on concept of impending necrosis
  • Educate and consent patients on risk of necrosis
    • “Scabbing, shedding, discoloration and shallow scarring which may result in prolonged healing and/or the need for reconstructive surgery may occur in rare instances”
  • When patients call and complain of increasing pain, discoloration, headache or other unusual symptoms, instruct staff to have pt. take a NSAID, discontinue cold/ice packs, and come to office for evaluation

 

Concern of an impending or acute necrosis is a clinical consideration and you should act immediately! Apply a warm compress, nitropaste, confirm NSAID use, and massage as the first step. You should then evaluate the response and consider the use of hyaluronidase and cover with antibiotic, also consider oral corticosteroids. If frank necrosis occurs, utilize HBO2. If necrosis has already occurred, HBO2 speeds tissue repair and healing. Be sure to consult plastic surgery early.

 

 

 

Contact Dermatitis: Clinical Pearls

  • Recently, several new allergens have been added to the T.R.U.E. Test. For topical steroid sensitive individuals the T.R.U.E Test includes: Tixocortol Pivalate (Class A), Budesonide, and Hydrocortisone Butyrate (Class D). Remember that cross reactivity among the various classes of steroids ie A, B, C , D is unpredictable.
  • If anyone is allergic to ANY of the steroid markers on patch testing put them on clocortolone and desoxymetasone (the only two Class C steroids) are the least likely topical steroids to cause sensitivity reactions.
  • Patients allergic to Tixocortol Pivalate have approximately 10% chance of being allergic to systemic prednisone so use oral dexamethasone (Class C) in these patients instead of oral prednisone.

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