Frontpage Article – Page 10

Contact Dermatitis 2014: Diagnosis and Management Strategies

April 7, 2014

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

April 7, 2014

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.

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.

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.

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.

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.

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.

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.

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.

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

New Drugs

March 20, 2014

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.

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.

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.

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

Dermatology Year in Review: 2013

January 28, 2014

Hensin Tsao, MD, PhD

In this first presentation at MauiDerm 2014, Dr Tsao, a leader in Dermatology, provides us with an update on the latest hot topics in the field.

Melanoma

Dr Tsao begins with a short case study of a 45 year old man who presents with:

SSM- 0.80mm/Clark level IV
Mitotic rate: 2 per mm²
Lymphovascular invasion
Ulcerated
TILs present

As a dermatologist, would you recommend a sentinel lymph node biopsy? According to Dr Tsao “there has been a shift in the utilization of sentinel lymph node biopsies.” Han and colleagues conducted a study with a large data set of patients (N = 5,125) with sentinel lymph node biopsies and found that in patients with thin melanomas, thickness and ulceration are the most predictive features of a positive sentinel lymph node. This report can be found in the Journal of Clinical Oncology.

Dr Tsao’s key takeaway messages:

Among thin melanomas, increasing thickness and ulceration most predictive of positive nodal status
- Rate is still low (~5%) and survival high (91% positive)
- MSLT-1 OS: 90% negative vs. 72% positive
- Among patients with 0.75mm/ulcerated lesions, if knowing the difference between 91% and 98% 5-year survival is important, then SLNB is reasonable

Cellulitis

A recent study from the New England Journal of Medicine looked at the use of penicillin for the prevention of recurrent leg cellulitis. The researchers found that prophylactic penicillin (250 mg p.o. BID) reduced the risk of cellulitis recurrence by approximately 50 percent. The duration of the benefit; however, is still unknown. Future studies for penicillin-allergic patients and cost effectiveness need to be performed.

Kidney Transplant

A report by Verneuil and colleagues found that in kidney transplant patients, donor kidney cells have been found in squamous cell carcinoma. SCC arising in kidney transplant patients. In another report by Xiao and colleagues, who looked at 69 studies which reported 104 donor transmitted cancers, they found that renal cell cancer, melanoma, and lymphoma were the most common. The cancer was usually diagnosed within one year from transplantation. For most non-renal cancers, cancers are metastatic at the time of diagnosis. Additionally, immunosuppression is stopped in most instances.

What are Dr Tsao’s key takeaway points?

Although rare, secondary malignancies from kidney transplants have been reported
- Provides biologic evidence of secondary metastases
- Renal cell cancer, melanoma and lung cancers may be most common- could be reporting bias since they may most likely cause death
- Recent malignancy is an absolute contraindication for organ donation

Remember that a solid metastases can create another metastases from a different host.

Basal Cell Carcinomas (BCCs)

According to a 2013 study by Erits and colleagues, topical imiquimod five times a week for six weeks exhibits the greatest efficacy against BCCs. This was a single-blind, non-inferiority, randomized controlled trial looking at photodynamic therapy (PDT) versus topical imiquimod versus topical fluorouracil for the treatment of superficial basal cell carcinoma. The researchers found that imiquimod appears to be superior to PDT in efficacy but also appears to be associated with more side effects and 5-FU was intermediate in terms of efficacy and side effects. Of note, the limitations of the study include short follow-up times (12 months) and lack of cost-effectiveness analysis.

GNAQ

Shirley and colleagues reported, in the New England Journal of Medicine, that an activating mosaic mutation in GNAQ (R183Q) is associated with anomalous skin and brain tissue in Sturge-Weber Syndrome. Its important to know that the variant is not as biochemically activating as the Q209 mutation observed in ocular melanoma. The R183Q variant occurs in 0.7 percent of the general population as a germline variant. Definitive proof of this mutation requires functional verificaton, e.g. model systems.

Spitz Tumors and Spitzoid Melanomas

Recently, Weisner and colleagues found that kinase fusions are frequent in Spitz tumors and spitzoid melanomas. We know that molecular diagnostics are continuing to advance and the paucity of point mutations that are identified in spitzoid neoplasms could be accounted for by gene translocations. Remember that pediatric tumors may be more susceptible to translocations while adult cancers may reflect accumulation of carcinogen-mediated point mutations. Kinase fusions offer new opportunities for treatment, though the market for metastatic spitzoid melanoma is small.

Urticaria

Let’s consider a 35 year-old woman who has had a three-year history of chronic urticaria. A 2013 study demonstrated that omalizumab reduces