Toxins and Fillers – Maui Derm

Neuromodulators for Skin of Color: Maui Derm 2015

June 17, 2015

Valerie D. Callender, MD

In this presentation at Maui Derm 2015, Dr Callender reviews the use of neuromodulators in skin of color. When we think about neuromodulators in skin of color, we need to think about how these aesthetic patients present in our office.

The concept of global beauty is the desire to maintain a beautiful, youthful appearance. This concept crosses all racial, cultural, and economic barriers. It’s more than just symmetry, size, and shape of facial features. So what is global beauty? It’s the appearance of smooth, even skin complexion, as well as the absence of rhytids, volume loss, and skin laxity. Remember that the amount and type of melanin determines one’s skin color. When estimating a person’s age, skin color uniformity was amongst the most important feature.

When we think about race, ethnicity and culture the definitions are very important.

Race: an objective term that includes people of the same heritage who may or may not share genetic similarities but possess similar physical qualities.
Ethnicity: a subjective term, that is self-assigned, each person determines the group that they most readily identify with & feel most connected to.
Culture: refers to a set of patterned beliefs, values, conventions, or social practices of a group & may or may not take into account the concepts of race or ethnicity.

Often times we interchange these terms and it’s important for us to understand that the “Face of America” is changing. Our current population is over 301 million with people of color being the fastest growing segment. Skin lightness is a global concern. Skin color is a sign of health, attractiveness and youthfulness; it also affects job and marital prospects as well as earning potential.

What really changes things is the media as it depicts beauty and youth almost simultaneously. Dr Callender feels that it important for all of our patients, among a variety of ages and skin types, that beauty is really skin deep.

Cosmetic Concerns Among Women of Color

A survey was conducted regarding cosmetic concerns in 100 women (81 African American, 16 Hispanic, and 3 Asian). The mean age was 41 years old. 86% of the women were concerned with hyperpigmentation or dark spots; 80% were concerned with blotchy, uneven skin; 77% found combination oily or oily skin was of concern; 49% claimed sensitive skin; and 40% found that rough skin was an issue. (Grimes PE, Dermatol Clinics. 2000)

Cosmetic Procedures in 2013

Reference: ASAPS.Cosmetic surgery national data bank statistics. http://www.surgery.org/professionals/index. Accessed Sept 2014.

Facial skin again is common across all ethnic and racial groups and varies in severity, age of onset and cultural impact. Skin of color patients demonstrate signs of rhytids at a later age than do individuals with fair skin and signs of facial aging in darker skin occurs 10 to 20 years later than in Caucasians. This is due to the photoprotective properties of epidermal melanin. The mean protective factor from UVB in skin of color is 13.4 versus 3.4 for white skin. Remember that mid-facial volume loss and prominent tear troughs are striking features of skin aging in African Americans and perioral rhytids are less common. Photo-aging differences in Hispanics and Latinos are less characterized, but vary considerably due to the broad range of skin types in this population. As dermatologists, we must be aware of nuances surrounding facial rejuvenation for patients with diverse racial and ethnic backgrounds.

Botulinum Toxin-A in African Americans

There are several published studies looking at neuromodulators in skin of color. One of the early studies of onobotulinum toxin by Grimes and colleagues found that there was really no difference in terms of adverse events in skin of color patients and maximal response was observed on day 30 with 92.4% and 100% response, respectively. (Grimes, Shabazz.Derm Surg 2009;35(3):429-436) Kane and colleagues studied abobotulinum toxin with different dosing and also found no significant racial or ethnic differences in safety. African American subjects had a slightly higher rate ocular adverse events and a lower rate of injection site reactions. The response rates and duration were slightly higher in African American subjects (177 days in AA versus 109 in overall population), the reason for this is unknown. (Kane, et al. Plastic & Reconstructive Surg 2009;124(5):1619-1629.)

When we look at neuromodulators in Asian patients, we see differences in response rates with 10 units versus 20 units; however, there were no differences in adverse events. (Harii & Kawashima. Aesth PS 2008;32(5):724-730.) What are we really looking for among all of these studies is safety issues and that’s what’s important across all of these studies. A study of onobotulinum toxin in Brazilian patients, followed by TCA 35% peel and manual dermabrasion 7 days post-injection resulted in transient PIH in 33% of the subjects. Additionally, significantly less wrinkles were seen from 90 days to three years in subjects treated with onobotulinum toxin versus placebo. (Kadunc et al. Dermatol Surg 2007;33(9):1066-1072.)

Clinical Pearls for Skin of Color Patients

Appropriate lighting and close examination is needed in identifying and avoiding blood vessels in darker skin
Post-inflammatory hyperpigmentation (PIH) is uncommon but may occur from needle injection points
Many Eastern Asian patients desire to have wider & rounded appearance of the eyes. BTX-A treatment using 2u lower eyelid & 12u crows feet is a nonsurgical option for these patients (Flynn, et al. Derm Surg 2001;27(8):703-708.)
In Eastern Asian patients, the dose should be a six-point injection to the masseter (three-points per side for a total of 50-60 units). (Ahn BK, Kim YS, Kim HJ, Rho NK, Kim HS. Consensus recommendations on the aesthetic usage of botulinum toxin type A in Asians. Dermatol Surg 2013 Dec;39(12):1843-60.)

Conclusions

In general, there are no racial or ethnic differences in the treatment of facial lines with botulinum toxin-A. Safety and efficacy in all skin types has been demonstrated in many published clinical studies. As with any aesthetic procedure, understanding and consideration of cultural diversity must be given to each patient’s individual aesthetic ideals.

Judy L. Seraphine, MSc-Maui Derm News Editor

Botulinum Toxin: Science and Evidence Data, Dose, Duration, Dogma

April 17, 2015

Joel L. Cohen, MD

In this presentation, Dr. Cohen discusses the neuromodulators that we commonly use and how to best apply the science and evidence into clinical practice. Dr. Cohen spends about 40 percent of time in practice doing Mohs surgery and the other 60 percent is dedicated to aesthetics.

It’s important to remember that we typically don’t focus in one area but rather treat assess patient’s full face and multiple regions, and we tend to use a combination of therapies/treatments (neuromodulators, fillers, lasers, and other energy-based devices such as radiofrequency and ultrasound). Clinical research is important to us, as clinicians, for a number a reasons — not only does it allow us to see what products are coming up on the horizon, but it affords us the opportunity to experience these therapies first-hand in clinical practice.

Currently, we have three neuromodulators approved for aesthetic use; onabotulinumtoxinA ((Botox), abobotulinumtoxinA (Dysport) and incobotulinumtoxinA (Xeomin). The important concept here is that these products are probably more similar than they are different.

BTX-A On-label Aesthetic Uses

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Of note, when you go to other countries, especially in Europe, you will see a different spectrum and wider-spectrum of approved aesthetic indications for these products.

We know, from clinical data, that botulinumtoxin can make patients feel better about themselves and can help them outwardly convey their inner emotions more appropriately. Many patients want to delay the outward appearance of aging as well as simply “look their best”. (Finn, Cox, Earl. Social Implications of Hyperfunctional Facial Lines. Dermatol Surg 2003;29:450-455.)

A double-blind, randomized, placebo-controlled health outcomes survey conducted by Dayan and colleagues analyzed the effect of botulinumtoxin type A injections on quality of life and self-esteem. The researchers found that the injections result in improvements in quality of life (QOL) and self-esteem. Additionally, botulinumtoxin-naïve patients demonstrated greater improvements in QOL and self-esteem than participants previously exposed to botulinumtoxin. Moreover, botulinumtoxin-familiar patients demonstrated sustained improvement in QOL and self-esteem as compared to botulinumtoxin-naïve patients, even when injected with placebo.

All of the approved botulinumtoxin type A products have a 150 kD botulinumtoxinA core neurotoxin protein. Incobotulinumtoxin (Xeomin) lacks the accessory proteins that are naturally produced by clostridial bacteria, which Botox and Dysport maintain.

When you look at the clinical studies, remember that there are different comparisons and different endpoints. Non-inferiority studies tend to compare two products at very specific time points. One noninferiority study compared incobotulinumtoxinA to onobotulinumtoxinA at four weeks and 12 weeks, as assessed by investigators, a panel of independent raters, and patients. This study demonstrated that incobotulinumtoxinA is equally as effective as onabotulinumtoxinA in the treatment of glabellar frown lines and both products were well tolerated — at the specific timepoints studied. There are; however, issues with non-inferiority studies. Because there are two time-points, there may be a missed evaluation of the duration of efficacy and a “waning effect.”

If you look at different demographics of your study cohort in some clinical trials, you’ll see that in some studies it’s really reflective of what we do in clinical practice; however, in other studies, it may not be – such as a disproportionate number of patients being quite young. These are issues that need to be considered when we’re looking at overall responses and comparisons among different products.

We also need to think about “low-powered” comparisons. In a comparison of two botulinum toxin type A preparations for the treatment of crow’s feet (Prager, et al), there were only 21 patients in this study. This may not be enough to tease out any major differences between the products in terms of the number of patients studied.

So, in short, there are 3 botulinum toxin products available in the US. It’s very difficult to make direct comparisons. These are different products and we need to consider the fact that the dosing can be different and the studies can be designed differently in terms of non-inferiority, demographics and power as well as an evolution of different study endpoints (2-grade improvement versus 1-grade).

We are beginning to see a shift towards more stringent primary endpoints. A randomized, double-blind, placebo-controlled phase III trial, conducted by Hanke and colleagues, investigated the efficacy and safety of incobotulinumtoxinA in the treatment of glabellar frown lines using Composite Endpoint Treatment Success (CETS), i.e., looking at a two-grade improvement. If you look at how often physicians saw a two-grade improvement versus patients, you will see about 48 percent.

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Remember that it’s difficult to compare data as previous studies often used a one-grade improvement; therefore, demonstrating a larger responder rate and a longer duration of treatment.

The pivotal trial with Botox for the lateral canthal lines required at least a two grade improvement from baseline on both the investigator’s and subject’s assessment of CFL severity at maximum smile using the 4 facial wrinkle scale. At day 30, we see a responder rate of 25.7%. Dr Cohen states that we know we have seen higher responder rates than this; however, because there has been a chance in the way in which the FDA wants this to be assessed, i.e., patient and physician composite scores, the numbers are lower.

What about conversion ratios?

Again, remember that these are different products and we need to look at them as such. Various studies have looked at the concept conversion ratios, but that may be difficult to compute in clinical practice. Regulatory agencies worldwide have recognized that these products are not interchangeable.

Some Other Things to Consider…

When we look at patients, specifically speaking about the lateral canthus, not everyone needs the exact injections that were used in clinical trials. There have been studies, dating back to 2003, looking at different patterns of injections and the way that different people look. It’s important to identify these features in your patients and individualize therapy. When Dr Cohen looks at a patient and he/she is superior dominant, he may give more of the neuromodulator up high, and a little bit less in the middle or below. Keep in mind that on that same horizontal is the bunny line and the contraction of the nasalis. Also along this horizontal is the pharmacologic brow lift.

If we understand the anatomy that the orbicularis oculi pushes our brows down and the frontalis lifts them up, then if we inject the one site where you’re getting the maximum pull down below the lateral, you may see better improvement in the lateral brow lift we can sometimes see when we treat the lateral orbicularis oculi.

Drs Cohen and Dayan conducted an open-label, randomized, dose-comparison study of botulinum Toxin Type A in the treatment of dermatochalasis. They found that a single-site injection of botulinum toxin type A in the lateral infrabrow can offer effective treatment for mild to moderate upper eyelid dermatochalasis—with perhaps a couple of millimeter lateral brow lift at best.

We know that when we look at patient’s brow positioning, there are some that should not be injected with a neuromodulator in the off-label area of the forehead. There was an important article that was published in JAMA Dermatology last year that looked at not only a grading scale for dermatochalasis, but it also discussed the factors associated with dermatochalasis. (Jacobs L, et al, 2014) From a grading scale, there are four categories for sagging eyelids (mild, moderate, severe, very severe). Specific risk factors associated with sagging eyelids include, age, male sex, lighter skin color, smoking status and higher BMI. In many cases, people “blame” genetics for sagging eyelids; however, we can see that there are things that we can do to intervene to help reduce the risk.

Combination Delivery

After the approval of Radiesse with in-office adding of anesthesia in the same syringe, some physicians began to use the same adaptor to combine fillers and neuromodulators. Dr Cohen doesn’t feel that this is a good idea; in fact, he believes that it probably does not save time, leads to an unstandardized mixture, and likely leads to less precise injections – as there are simply some areas where you don’t want toxin but you do want filler. So combination in the same syringe of toxin and filler in Cohen’s view is not a good idea, but combination of toxin and filler in their respecitive different syringes is still a good concept.

When it comes to the lower face and the area around the mouth, a study conducted by Carruthers et al indicated that both physicians and patients saw a greater improvement when the patient was injected with both the hyaluronic acid dermal filler and a neuromodulator. (Carruthers A, et al. Dermatol Surg. 2010;36:Suppl4:2121-2134.

And other studies have shown synergy with the combination treatment of different regions with toxin and filler. A 2003 study of Botox plus Restylane demonstrated that if you inject patients with Botox and then have them come back for Restylane, it has a longer tissue residence time in terms of filler and correction than if you injected Restylane alone (18 weeks versus 32 weeks.)

Dosing

Many of us have seen an overall change in practice patterns when it comes to dosing. In some areas, like especially the forehead, we have shifted from higher doses of toxin to lower doses in order to achieve a more natural, relaxed look for our patients. In the forehead, for example, Dr Cohen and other colleagues who participated in the more recent PRS journal consensus, now inject about half of the dose they previously used in the forehead — thus creating often a more natural look, simply softening the musculature, and maintaining brow shape and positioning better. There’s a lot to consider with regards to neuromodulators. We have seen where NOT to inject, but it’s important to maintain brow positioning and shape as well as symmetry.

There are very specific grading scales that can be useful in clinical practice and Dr Cohen recommends incorporating them into your regimen. This is helpful when discussing the goals of therapy with patients—for instance, for the forehead “softening of the musculature”.

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

Botulinum Toxin 2014: Tips, Thoughts, Science, & Different Formulations

March 4, 2014

Joel L. Cohen, MD

In this presentation, Dr Joel Cohen, a leader in aesthetic dermatology, and the Director of AboutSkin Dermatology and DermSurgery in Colorado, provides us with an update on the use of botulinum toxin. Dr Cohen begins the session by reminding us, as Dermatologists, that every day we have an opportunity to blend our modalities, i.e., medical, surgical, and aesthetic in order to provide our patients with the best possible outcomes.

Currently, there are three FDA-approved botulinum toxins type A; these are Botox (Allergan), Dysport (Medicis/Galderma), and Xeomin (Merz). All three products are approved to treat glabellar lines; however, Botox was also recently approved for the treatment of Crow’s feet.

Cox and Finn a decade ago, found that botulinum toxin type A injections have been beneficial for patients who feel that their faces are not communicating their emotions properly, want to delay the outward appearance of aging, and/or patients simply want to look their best. Data also suggest that botulinum toxin type A injections can also affect self-esteem. A 2010 health-outcomes survey (randomized data), conducted by Dayan and colleagues, found that the injection of botulinum toxin type A injections demonstrated improvements in quality of life (QOL) and self-esteem and injection-naïve patients demonstrated greater improvements in QOL and self-esteem versus those who had received previous injections.

All three of the FDA-approved products contain a core neurotoxin protein (150 kD BoNT/A), this is where the mechanism of action lies. Botox and Dysport are wrapped in protein, which is part of the neurotoxin complex. Xeomin; however, lacks these accessory proteins. All three products have demonstrated efficacy and have established good safety profiles, but remember that it is difficult to make direct comparisons among the approved botulinum toxins. Keep in mind that the products are different, the dosing can be different, the studies were all designed differently and there are differences among the various study endpoints.

Conversation Ratios

Keep in mind that the three neuromodulators approved for aesthetic use are separate products; therefore, there is no TRUE or EXACT “conversion ratio”. As dermatologists, we must learn how to use each product differently in clinical practice. The injection techniques are similar; however, there are no direct specific or perfect conversion ratios. Regulatory agencies around the world, including the United States, have recognized that these are different products, and there is no interchangeability among botulinum toxin neuromodulators.

Xeomin

Sattler, et al published a non-inferiority trial comparing Xeomin to Botox in the treatment of glabellar frown lines. The independent rater and patient assessment between both products were very similar at weeks four and 12. Because this was a non-inferiority study with two time-points, you can miss the “duration of efficacy” and the “waning effect.” The authors concluded that Xeomin is equally as effective as Botox and both preparations were well tolerated.

Other Considerations

When we look at the FDA studies for the available neuromodulators, they dose the medial corrugator exactly the same as the lateral corrugator and for the convenience of an FDA study. For Botox and Xeomin, it was four units in five injection points and for Dysport it was ten units in five injection points. The reality of our practice is that patients typically have a much more prominent medial corrugator than a lateral corrugator, and when you inject the lateral corrugator with a large dose you risk unwanted spread to the frontalis, which can knock-out the lateral frontalis function of keeping the brow up. So consider lower doses in the lateral corrugator when appropriate, and consider orienting the needle tip more medially to avoid lateral spread to the frontalis.

Combination Delivery

Combining fillers and neuromodulators in the same syringe is not something I would recommend and is considered controversial. It is ok to consider combination therapy, as there is good data on this, but not in the same syringe. In 2013, Drs Cohen and Mariwalla wrote a letter to the editor of Journal of Drugs in Dermatology referencing an article whereby these products were mixed in the same syringe, cautioning practitioners about the potential pitfalls of this sort of approach. Keep in mind that combination same-syringe delivery (e.g. botulinum toxin-A and hyaluronic acid filler ”mixed together”) can be imprecise on many levels, from not uniformly mixed to potential unintended spread of one of the agents. I personally think it would take more time to mix the neuromodulator in the filler syringe, then to simply draw up and inject the Botox on its own—and on its own seems much more precise.

Another important consideration is that of combination neuromodulators and chemical peels on the same day. Swelling can potentially carry a neuromodulator, even a centimeter or two. Use caution on the same day and in same region as procedures that may cause significant swelling with regards to migration, such as non-ablative fractional, ablative fractional, higher concentration chemical peels, and even tightening devices.

Dosing

Remember that dosing, dilution, and reconstitution are different concepts. Dr Cohen reconstitutes his neuromodulators differently by region, using 1cc dilution per 100 units (Botox/Xeomin) in most areas (glabellar, lateral canthus, DAO, and mentalis); however, he uses 5cc for the perioral lines, forehead, platysmal bands, and hyperhidrosis.

When looking specifically at dosing, aesthetic physicians have historically used high-dosages in the forehead, which often caused them to look completely “flat”. “Many patients prefer simply softening the musculature in the forehead without totally knocking it out — achieving a relaxed and natural look. Over the years, Dr Cohen and colleagues have found that they can basically cut the forehead dose in half. This helps in achieving a natural look, softens the musculature and maintains brow shape and positioning–many patients prefer. There are published consensus statements and recommendations on how much product to use and how best to use it for each of the products available. As dermatologists, we also need to consider the anatomic differences between men and women and how we approach the use of neuromodulators in the forehead.

Summary

Remember that all three products have demonstrated positive efficacy and safety profiles. As clinicians, it is important to understand how to use each product, their differences and most importantly, how to individualize treatment and set realistic expectations for our patients. Utilizing the Merz scales or other scales can help with achieving aesthetic treatment goals, by explaining to patients their point on a scale now versus where you are striving to get them to after treatment.

It is critical to understand the changes and differences in the FDA requirements in the studies for neuromodulators. When Botox was approved, studies were designed differently—and improvement was scored differently with follow-up evaluations looking at persistence of some degree of improvement (but not 2-grade improvement necessarily). With Xeomin, a two-grade improvement was required, which was a much higher standard. This is an important concept to keep in mind when looking at responder rates over various studies. With the recent approval of Botox for Crow’s feet, Allergan similarly was held to the 2-grade improvement scale as well.

How to Use Hyaluronidase: Clinical Pearls

February 12, 2014

Joel Cohen, MD

Derek Jones, MD

Dr Joel Cohen and Dr Derek Jones, two of the leading experts in cosmetic dermatology, provide us with some important information on the use of hyaluronidase…

Many clinicians consider hyaluronidase as standard of care, i.e., it is in the office.
Be aware with Voluma because it is a vycross technology not a hyal-cross technology—therefore, its not as easy to dissolve with hyaluronidase, so it may take more concentration.
It takes a fair amount of hyaluronidase to erase nodules with Voluma.
How much hyaluronidase should you use? Some use 150 units per mL; A simple rule of thumb for each 10^th of a cc of Restylane, use about 5 units of Vitrase; (remember that the units across every brand may not be the same); 10 units if you’re trying to dissolve Juvederm; and probably about 15 units for Voluma.
A bottle of Vitrase has 200 units per bottle-so you actually do have to reconstitute with some things so you get more out of it.
Hyalnex is 150 units per bottle.
The shelf-life for the hyaluronidases is very short.
Many people use compounded products, but we’re not sure if they are as effective.
There are a lot of issues with compounding and there will be a lot more regulations coming up.

Toxins: What’s New, Are There Differences Among Toxins, and What We Have Learned

January 8, 2014

Michael H. Gold, MD

Dr. Gold spends a lot of his time in Asia and, in this presentation, he shares some of the knowledge that he has acquired overseas with regards to toxins. The neuromodulator market is huge and the global medical aesthetic market is expected to post growth of 10.8 percent per year from 2010 to 2015.

Medical Insight, Inc. “Global Aesthetic Market IX Research Report April 2011”, “Facial Injectables Report July 2011” ,“EU Facial Injectables Report July 2011

As mentioned in Dr Cohen’s presentation, it is extremely important to remember that the goal, when using neuromodulators, is a natural and relaxed look for your patients.

Data on Neuromodulators

When looking at the Xeomin clinical trials, dermatologists should remember that responders at maximum frown at day 30 had to have an improvement of two points on a four-point Frown Wrinkle Scale (FWS) compared to baseline by both the investigator as well as the patient. Neither Botox nor Dysport required assessments by both parties. So while the data on the 2-point responders did not look quite as compelling, the numbers for the 1-point responders appeared good.

Mentor, which was purchased by Johnson & Johnson, has completed their clinical trials on a new botulinum toxin, PurTox. Many are hopeful that J&J will submit this data to the FDA in which case we will see this product at some point in the future. Of note, both Xeomin and PurTox are pure toxins. Whether that actually makes a big deal clinically, Dr Gold does not think so; however, it is a wonderful marketing point.

Medy-Tox , which was purchased by Allergan in 2013, is the company that developed a product called Neuronox. It is currently approved in South America and Korea for blepharospasm and tortilcollis. Dr Gold and others feel that Neuronox will not come to the United States market anytime soon. A double-blind, multi-center trial of 173 patients compared Neuronox to Botox in patients with hemifacial spasm. The efficacy evaluation was similar between both groups. A recent clinical study demonstrated the proven efficacy and safety of Neuronox on glabellar frown lines.

Another Korean company, Hugel, makes Botulax. Dr Gold mentions that this company is at many of the meetings to which he goes and they claim to have the Korean version of an FDA approval.

ChinaTox is a product made by Lanzhou Biological Products Institute. It is important to know that many of the other toxins are actually fake ones. An open label study between Botox and ChinaTox looked at 785 patients with focal spasm and dystonia. They found that ChinaTox was less powerful than Botox; therefore, higher doses were required. There were also five cases of skin rashes seen in the ChinaTox group. ChinaTox is; however, cheaper than Botox. Of note, the strain of clostridium botulinum type A was donated from the University of Wisconsin to Dr Yinchun Wang. ChinaTox was approved in China in 1989 and by 2002 the drug has been exported to several foreign countries and is currently in Brazil for both clinical and cosmetic use. ChinaTox has several different names in other countries. This is important to keep in mind as you’re reading various pieces of literature.

Prosigne-Brasil
Redux-Peru
Lantox-Russia
Lanzox-Indonesia

ChinaTox demonstrates similar efficacy as far as other neuromodulators. In Asia, calf hypertrophy is an issue. ChinaTox has shown positive benefits when injected into the calf muscle.

In Russia, there is a toxin, Relatox, with the “Russian FDA-approval.” It was produced at the Federal State Unitary Enterprise Research-Division of Microgen of Russian Ministry of Health. It is available in two dosages, 50µ and 100µ. Relatox is indicated for blepharospasm, cervical dystonia, and facial wrinkle correction and is recommended only for adults. A published article claims that Relatox is comparable to other toxins.

A topical toxin has been developed by Revance using a proprietary platform that enables transcutaneous flux. The first commercial applications will be topical BoNTA in lateral canthal lines and hyperhidrosis. The product is well tolerated and demonstrates up to 89 percent response rate. The median duration of effect is 113 days.

In the US, Myoscience is developing a hand-held medical device for the treatment of facial wrinkles. Essentially, the device uses cold-induced modulation of facial nerves. This has demonstrated promising results in difficult patients and is a new option for toxin-averse patients.

Clinical Pearls

Physicians should only use branded products that are FDA-approved in the US or CE marked in Europe, or products that have received regulatory approvals in your country. There have been instances in the US where non-approved Botox was used and patients ended up paralyzed in the hospital. Physicians are also subject to major sanctions, fines, loss of license, etc. There are many fake products out there….this important to keep in mind as there are serious issues involved with the use of unlicensed botulinum toxins.

Botulinum Toxin 2013

January 8, 2014

Joel L. Cohen, MD

In this presentation, Dr Cohen, a leader in aesthetic dermatology, discusses where we are right now in terms of botulinum toxin. Currently, there are three FDA-approved botulinum toxins type A; these are Botox (Allergan), Dysport (Medicis/Galderma), and Xeomin/NT201 (Merz). Neuromodulators that are on the horizon include PurTox, Neuronox, and China ToxThe three approved botulinum type A products are approved for the use of glabellar lines; however, they are used off-label for other aesthetic purposes.

All three products contain a core neurotoxin protein (150 kD BoNT/A), this is where the mechanism of action lies. Botox and Dysport are wrapped in protein, which is part of the neurotoxin complex Xeomin, however, lacks these accessory proteins.All three products have demonstrated efficacy and have established good safety profiles.

Xeomin

Xeomin has both medical and aesthetic studies. In 2005, Benecke and colleagues published a double-blind non-inferiority trial of 463 patients comparing Xeomin to Botox and concluded that Xeomin is at least as effective and safe in treating cervical dystonia as compared to Botox. Of note, one of the criticisms of a non-inferiority trial is that it utilizes two timepoints, and you don’t know where the subsequent timepoint ends.

In 2006, Roggenkamper and colleagues published a double-blind, phase III trial comparing the efficacy and safety of Xeomin with Botox in patients with blepharospasm. No significant differences were found between the formulations and the non-inferiority of Xeomin compared to Botox was concluded.

It is critical to understand the changes and differences in the FDA requirements in the studies for neuromodulators. When Botox was approved, a one-grade improvement was required. With Xeomin, a two-grade improvement was required. This is an important concept to keep in mind when looking at responder rates over various studies.

Two recently published, identical randomized, double-blind, multi-center, placebo-controlled trials looked at 547 patients. 366 patients received 20µ Xeomin and 181 patients received placebo. Success was defined at a two-grade improvement on a four-point scale. The median onset of effect occurred within seven days after injection and the duration effect was typically up to three months. Single and repeat treatment was well-tolerated. The majority of adverse events were mild or moderate with headache being the most common. There was a 0.2 percent incidence of blepharoptosis following a single treatment.

Sattler, et al published a non-inferiority trial comparing Xeomin to Botox in the treatment of glabellar frown lines. The independent rater and patient assessment among both products were very similar at weeks four and 12. Because this was a non-inferiority study with two timepoints, you can miss the “duration of efficacy” and the “waning effect.” The authors concluded that Xeomin is equally as effective as Botox and both preparations were well tolerated.

A small study of 21 patients by Prager and colleagues compared Xeomin to Botox for the treatment of Crow’s feet. Both products demonstrated high efficacy and good tolerability at a dose ratio of 1:1 with no statistically significant differences between the two. Also of note, the high response rates observed after four months suggest a good effectiveness beyond this observation period.

Conversation Ratios

It is important to remember that the three neuromodulators approved for aesthetic use are separate products; therefore, there is no TRUE or EXACT “conversion ratio”. Dr Cohen emphasizes the importance of learning how to use each product differently in clinical practice. The injection techniques are similar; however, there are no direct specific conversion ratios. Regulatory agencies around the world have recognized that these are different products, and there is no interchangeability among botulinum toxin neuromodulators.

Controversies

It is also important to keep in mind that combination same-syringe delivery (e.g. botulinum toxin-A and hyaluronic acid filler ”mixed together”) can be imprecise on many levels from not uniformly mixed to potential unintended spread of one of the agents.

Another big controversy is that of zinc supplementation on botulinum toxin treatments. A publication in 2012 advocated a proprietary zinc formulation to “extend the durability of botulinum toxin” and “make non-responders, responders.” Dr Cohen found that there were HUGE problems with this study. Zinc deficiency does not seem to be an issue with healthy aesthetic patients, and the article assumes that basically everyone is zinc deficient. Another major issue with this study is that the only physician who injected the product has a financial interest in the product, identified all of the patients for the study, and was an active participant in the study design. In summary, the effect of zinc supplemation with a phytase has yet to be clearly elucidated.

Dosing

When looking specifically at dosing, aesthetic physicians have historically used high-dosages in the forehead, which often caused them to look completely “flat”. “It is important to understand the importance of achieving a relaxed and natural look. Over the years, Dr Cohen and many colleagues colleagues have found that they can basically cut the forehead dose in half. This helps in achieving a natural look, softens the musculature and maintains brow shape and positioning, which is very good for patients. There are published consensus statements and recommendations on how much product to use and how best to use it for each of the products available.

Botulinum Toxin has also shown to improve facial wound healing. Dr Cohen has incorporated its use when performing Mohs closure. This leads to less tension in the scar; therefore less scar spread and a better overall aesthetic look through “chemo-immobilizaton” (Mayo 2006, Flynn 2009)– similar to what has been described peri-procedure with peri-ocular resurfacing (Carruthers) and peri-oral resurfacing (Kadunc).

Dueling

There are many attempts in the literature to try to compare the various neuromodulators. This started from an article published in 2008 in the Journal of Cosmetic and Laser Therapy looking at patient satisfaction with different botulinum toxin type A formulations in the treatment of moderate to severe upper facial rhytids. The patients were switched from Botox to Dysport and, by and large, the patients wanted to go back to Botox. Unfortunately, when studies like this are introduced, Dr Cohen comments that there is a tremendous amount of bias. Often time we see “novelty bias.” Patients return after a second injection and they don’t see the “wow” effect, and there could be “recall bias” as well in trying to remember the effect of the first treatment versus subsequent treatments.

Onset and Duration

The original Dysport trials demonstrated that median time to onset ranged from two to four days. This data; however, was not captured in the original Botox trials. A subsequent JDD trial did actually capture the effect of Botox starting to “kick-in” within the first few days as well.

It is imperative that clinicians be critical of study designs when they are comparing these various products. A meta-analysis looked at the Botox duration effect in the treatment of glabellar lines. Overall, the effect was about four months in 50 percent of patients.

Repeat injections in the same area tend to extend the duration of the product. This has been demonstrated in several studies among all three of the approved neuromodulators.

Summary

Overall, we have good safety and efficacy data among these three products demonstrating that people respond and seem to have better self-esteem (Dayan). Data suggest that, overall, patients look and feel better.

Combining Lasers with Toxins and Fillers

January 24, 2013

Suzanne Kilmer, MD

In this presentation, Dr Kilmer reviewed the techniques for combining the various technologies that are currently available for facial rejuvenation in order to obtain optimal cosmetic improvement for patients.

Dr Kilmer stresses the importance of remembering the 5 Rs:

Relax
Refill
Rejuvenate
Resurface
Reassess

Relax

It is important to relax the skin with a botulinum toxin to keep both the muscles and the skin from moving as much as it otherwise would. If she is going to laser the skin, the results are improved when the skin/muscles are not moving. Dr Kilmer also uses fillers, in conjunction with the toxins and lasers to fill in lines, tighten up the skin and remove brown/red spots.

Clinical Pearl: Never use toxins, lasers, or any other device that can cause significant swelling on the same day. This can result in the toxin migrating to other places where you do not want it.

Refill-Restore Volume Loss

When using dermal fillers, the objective is to restore volume based on a patient’s specific needs. Fillers can be placed in various areas locally such as the nasolabial folds, marionette lines, deep glabellar rhytids, tear troughs, scars, and the nasal bridge. Fillers can also be used globally in the cheeks and temples. It is important to remember that there may be a lag time resulting in delayed gratification. It is very important to keep in mind that one can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed.

Rejuvenation

There are various approaches to rejuvenation. These include:

Vascular approach (more specific?)
- Stimulated by injury to microvasculature, which initiates cascade of events.
Pigment approach
- Targeting melanin can remove pigmented lesions and may also improve textural changes.
Thermal approach
- Non specific heating leads to injury response/wound healing and possible collagen tightening.
Fractional approach
- Nonablative and ablative

Resurface

Dermatologists can resurface the skin with the chemical or mechanical removal of the epidermis. Devices that be used for resurfacing can be both selective and nonselective.

Combination Treatment

Best order

Start with toxins to stop movement and relax muscles.
- Relax frown, smile and lip lines when doing facial rejuvenation
- Relax DAOs and neck bands when doing fillers, tightening or resurfacing
  - May need less filler and patients are happy sooner with tightening devices
Then filler or laser depending on a patient’s specific needs (and ability for downtime)
- Never do toxins and lasers that cause swelling at the same time because toxins can migrate.
Typically end with filler if still needed after toxins and laser
- Sometimes the combination will diminish the need for filler
- If able to tell that will need volume, can do before or at same time as laser

Caveats of Combining Treatments

Toxin with Filler
- Can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed
Toxin with Laser
- Can’t do toxin same day as Fractional lasers – swelling can lead to migration
- Can do botulinum toxin with PDL, IPL, CoolTouch, SmoothBeam, Thermage, Titan
Filler with Laser
- Can do filler same day but do first if doing fractional as swelling can mask need for filler.
Fractional with RF tightening
- Same day – do Thermage 1st because need intact skin but when you do the fractional laser the skin may still be sensitive

Combining Fractional with other Devices

Fractional laser with other lasers/txs
- Lentigines – pre-tx QS lasers, KTPs, etc
- AKs – LN2
- Sebaceous hyperplasia, nevi – 1450 nm
- Vascular lesions – PDL, KTP, Alex
- Downtime from other treatment is simultaneous and shortened
Fractional resurfacing with ablative resurfacing
- Almost always do fully ablative to upper eyelids
  - More tightening/more predictable – do inner canthi
- Can ablate/sculpt edges of scars, upper lip lines and elevated lesions
Ablative fractional and nonablative fractional resurfacing
- Nonablative fractional to face, ablative to neck for more tightening /crepiness – useful for those with hx ablative resurfacing/chemical peels/dermabrasion

Other combination treatment includes fat loss and tightening, fractionated RF + QS/KTP/PDL and, fractionated US + QS/KTP/PDL.

Reassess

Remember that combination treatment may minimize the need for other treatments and may increase the interval for maintenance. It is extremely important to assess whether or not the patient’s needs have been met. Ask yourself and the patient if new things have become noticeable now that the initial needs have been met? And remember, with time, additional needs may become apparent.

Summary

Botox, fillers and lasers can all be used synergistically to minimize the signs of sun damage and aging.
Expertise in technique, use of the best possible modalities, and watching for and treating any possible complications will produce the best results.
Combining these modalities may obviate the need for more invasive procedures, such as facelift

Fillers: Part 3

January 23, 2013

Managing Complications

Joel Cohen, MD

In this presentation, Dr Cohen reviews the complications that can occur when utilizing fillers and best practices on how to manage these various complications. Dermatologists use fillers across the world, millions of times per year, and most of the time, everything is fine; but understanding the complications and how to manage them is imperative for dermatologists.

Clinicians should be aware that there are new filler agents and new indications for the agents currently available, so it is important to understand these products and recognize what can potentially go wrong when using them in patients.

Filler complications include:

Superficial injection
Vascular compromise
Bruising
Sensitivity
Granuloma

Superficial Injection

When injecting the peri-ocular area, it is critical that dermatologists understand the anatomy and how to inject these areas. When Dr Cohen injects these areas, he defines them by either “infra-orbital hollow” or “tear trough”.

Approach to Infra-Orbital Hollow injection

Dr Cohen uses anesthetic eye drops, a jaeger retractor to protect the globe, and a 32-gauge needle above the level of the muscle. He discusses the importance of the 32-gauge needle, as he believes it slows down the injection. This is an off-label usage of an HA injection and should be done very superficially. It is also important to avoid superficial nodules.

Injecting the Tear Trough

Dr Cohen injects very deep, below the muscle on the level of the periosteum. An anterior approach may help to lessen bleeding encounters.

Persistent Swelling

Persistent swelling has been documented across the board with various fillers. It is important to remember that this is an off-label area and dermatologists choose their agents based on personal preferences. Experts are not sure if the swelling is related to etiology, e.g., Botox a few weeks prior. Treatment for persistent swelling includes time, massage, caffeine, oral HCTZ, and hyaluronidase. Hyaluronidase can be helpful for an area that was superficially injected (very localized).

When injecting the glabella, you would want to see a little bleeding, you do not want to see it blanche. Seeing a blanche means that you have compromised a blood vessel and this is an emergency.

Botulinum toxin, in combination with fillers, may provide a better, more durable response.

Vascular Compromise and Necrosis

The glabella is an area at significant risk for impending necrosis. Vascular compromise and necrosis, albeit rare, are caused by compression and intravascular injection. In 2006, Dr Cohen and colleagues published a prevention and treatment protocol for injection necrosis of the glabella (Derm Surg, Feb 2006).

Understanding the facial arteries is of great importance for dermatologists who do soft tissue augmentation.

If you see a blanche, immediately stop the procedure. With some warm tap water gauze, try to tap the area and the warmth will facilitate vasodilation. If you have nitro paste in your office, you can apply that as well along with giving your patient aspirin to manage the headache associated with nitro paste.

Understanding the vessels and patterns is important not only to dermatologists, but to patients and office staff as well. Hyaluronidase with multiple stabs and perhaps into the adjacent artery has been demonstrated as a novel treatment for impending necrosis. It is very important as a healthcare provider to intervene immediately and NOT “wait and see what happens” in the cases of impending necrosis.

Scars

Fillers can be for postsurgical depressed scars on the ears, nose, and cheeks. Dr Cohen and colleagues published various case reports in 2008 on the use of fillers for postsurgical depressed scars after skin cancer reconstruction. The use of hyaluronic acid and calcium hydroxylapatite has proven successful to fill and blend these scars.

Bruising

Bruising may occur regardless of the injection site. The injection pattern is extremely important and it is critical that dermatologists understand the various approaches to injection. There are some things that patients can do to reduce bruising, such as avoiding aspirin. Patients on anticoagulants also have to be managed. There are vitamins that can potentially interfere with bleeding; so again, something to keep in mind. Clinicians need to be realistic with their patients, so they can expect some bruising and/or swelling which may last up to ten days. It is important to communicate with patients prior to the procedure.

Cannulas

There are two cannulas available in the US. Dr Cohen uses cannulas in the hands, cheeks, infra orbital, and décolleté. They seem to decrease bruising along with potentially decreasing pain in some areas.

What about the legal issues?

Dr. Matthew Avram MD, JD, one of the faculty members in the audience, commented on the legal issues surrounding complications involving dermal fillers. According to Dr. Avram: “Regarding the use of fillers, there is a standard of care regarding complications of vascular occlusions, which include some of the following issues:
– Office staff should be informed regarding potential side effects/symptoms (Suspicion Index); therefore, recognizing possible complications
-Consent forms should include, but not be limited to the possibility of:

Scars
Ulceration
Blindness
Discoloration of skin

Physicians should also ensure that adequate “on-site” aid is available, i.e., Nitropaste, hyaluronidase, etc…

With regards to the use of toxins:
Actually, it is quite amazing that among the millions injections that have been utilized over the past decade, we found only two reported cases involving the use of botulinum toxins for aesthetic purposes.”

Summary

In conclusion, there are a variety of fillers available for patients. It is important that dermatologists understand the anatomy of the face in order to optimize injection results and minimize potential complications. If there is a complication make sure that your staff who answers the patient’s phone call has a high index of suspicion regarding complications and act when necessary to bring the patient to the office on an urgent basis.

Fillers: Part 2

January 23, 2013

Update on Fillers

Michael Gold, MD

Recently, Dr Gold published an article on an International Perspective on Fillers. In Europe, Restylane is a very large family of products. It is made by a company called Q-Med who is now owned by Galderma. Before the merger, Q-Med licensed all of the products to Medicis (now owned by Valeant). In the US, we have four Juverderm products. In Europe, they have various versions of Juvederm. We’re hoping to see Voluma by the end of 2013.

There are three Belotero products available outside the US. (Soft, Balance, and Intense.) We have the Balance product here in the US. Remember the term CPM that takes the cross-linking one step further, giving the product a longer duration. There are many fillers in Europe (150 companies) and Asia out there, but they may not be on the radar in the United States.

Atlean is often referred to as a second generation Sculptra. There is some hope that we may see Atlean in the US.

Anteis makes three products using the CPM technology as well. In the US, we will never see the Anteis products (because they are Belotero). In the rest of the world, where Merz doesn’t have the distribution rights, we will see the Anteis products—they are exactly the same and show some very nice results. Anteis also has another product, Modelis, which does some very deep filling. The Anteis Injection System reduces erythema and swelling and provides a significant improvement in injection technique. Dr Gold has used this in Europe and finds it easy to use and patients seem to do well.

Emervel is a product owned by Galderma. There are five Emervel products marketed in Europe without lidocaine, and four with lidocaine. These products are going to be marketed by Valeant because of the Q-Med agreement. There are two of them pending with the FDA (with lidocaine).

Summary

Europe has more fillers than the United States
FDA is more stringent
Costly to bring products to market

The China Filler Market

There are lots of counterfeit fillers. Doctors are buying this stuff and injecting it into patients and this is a real problem. “Don’t buy fake products.” We have great companies with great products. We need to embrace the new technology and treat patients with these new options.