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Reversing the ravages of time
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New injectable agents help dermatologists meet growing demand for anti-aging treatments

Less than 10 years ago, the launch of two injectable products ushered in a new era for aesthetic dermatology. OnabotulinumtoxinA (Botox), approved by the U.S. Food and Drug Administration (FDA) for cosmetic use in 2002, and the first hyaluronic acid-based dermal filler (Restylane), approved by the FDA in 2003, provided nonsurgical alternatives to rhytidectomy, forehead lifts, cheek implants, and other surgical procedures that target the effects of aging. According to a 2010 report from the American Society of Plastic Surgeons (ASPS), the number of rhytidectomy procedures declined 16 percent in the past decade (to 112,955), while the number of botulinum toxin type A procedures increased 584 percent in the same period, reaching a total of 5,379,360 sites injected in 2010. Minimally invasive procedures using soft tissue fillers increased 172 percent to 1,773,328, with hyaluronic acid procedures accounting for nearly 68 percent of the 2010 total. (These statistics represent procedures performed by board-certified physician specialists.)

A confluence of factors is driving the trend toward less invasive procedures, according to leading aesthetic dermatologists. Changing patient demographics and the desire to appear younger in a competitive workplace environment are growing the overall market for anti-aging procedures, and minimally invasive options are more subtle, less expensive, and less disruptive to daily routine. “Patients want procedures with less downtime — office-based procedures that let them resume normal daily activities,” said Seth L. Matarasso, MD, clinical professor of dermatology at the University of California, San Francisco School of Medicine. “They don’t want to look like they’ve had work done — they’re looking at staying refreshed and staying ahead of the curve. It’s a pretty exciting time because science has really kept up with patient demand.” Within the category of injectable products, an influx of new agents and enhancements to older products provide dermatologists with a broad array of options to offer their patients. [pagebreak]

Hyaluronic acid dominates fillers

Bovine and human collagen products, once the mainstay of the dermal filler category, have virtually disappeared from the U.S market, Dr. Matarasso said. “I think it’s a shame, because they were fine products that had a niche; the problem was they didn’t really last that long,” he said. “Now the hyaluronic acid fillers, Restylane and Juvederm, are the gold standard.” The effects of hyaluronic acid fillers can last from six to 12 months, compared to a duration of three to six months for collagen products.

Restylane, Perlane, and Juvederm (FDA-approved in 2006) are all composed of cross-linked, nonanimal source hyaluronic acid. Perlane is similar to Restylane but has larger gel particles; both have a hyaluronic acid concentration of 20 mg/mL. Both Juvederm Ultra and Juvederm Ultra Plus have a hyaluronic acid concentration of 24 mg/mL, but Juvederm Ultra Plus has a higher proportion of cross-linking than Juvederm Ultra, giving it a somewhat firmer consistency.

Because the hyaluronic acid fillers cause pain upon injection, dermatologists frequently mixed lidocaine with the fillers prior to injection. Last year, new forms of Restylane, Perlane, and Juvederm became available premixed with lidocaine. “I actually think that the Juvederm product with powdered lidocaine from the company is less painful than when we mixed the lidocaine ourselves,” said Susan Weinkle, MD, affiliate clinical professor of dermatology at the University of South Florida College of Medicine. “I also like Restylane with lidocaine, because the manufacturer puts in liquid lidocaine, which alters the viscosity and improves the flow characteristics.” [pagebreak]

When choosing among hyaluronic acid fillers, dermatologists take into account patient preference and their own perceptions of the subtle differences among the products. “I do a lot of volume replacement and frequently use Perlane for that because it’s a deeper hyaluronic acid filler,” said Mark Nestor, MD, PhD, associate professor of dermatology at the University of Miami’s Miller School of Medicine. “I use Restylane for places such as the tear trough and nasolabial fold, where I want extra lift. I use a lot of Juvederm in the lips, and in the nasolabial fold of patients who want a softer look and don’t necessarily need as much lift.”

A key advantage of hyaluronic acid fillers is that their effects are reversible with the injection of hyaluronidase. “If there’s an unwanted lump or even an impending necrosis, you can dissolve the material and relieve some of the pressure on the blood vessel,” said Mary Lupo, MD, clinical professor of dermatology at Tulane School of Medicine. The “forgiving” nature of these products encourages dermatologists to branch out to new indications, Dr. Matarasso said. “These fillers are FDA-approved for nasolabial folds, but we’re also now using them around the eye, the neck, the earlobe area, the back of the hand, and in the depressions of scars. There’s more flexibility in these products than in some of the other ones.” Dr. Lupo cited the temples, cheeks, and lips as “the three big off-label areas where we’re injecting hyaluronic acid fillers.”

New hyaluronic acid products in the pipeline (not yet FDA-approved) include Bolotero Balance, a hyaluronic acid-based monophasic gel; Voluma, a volumnizing filler from the manufacturer of Juvederm; Teosyal, a group of eight fillers; and EMERVEL, a group of nine fillers available with or without lidocaine. “Bolotero has a higher extrusion force because it has longer chains of hyaluronic acid,” said Dr. Weinkle. “It has less of a Tyndall effect, so it doesn’t cause the blue discoloration that some other hyaluronic acid products can [when injected too superficially]. Thus, we think it’s going to be very good for treating fine lines.” [pagebreak]

Non-hyaluronic acid fillers add volume, longevity

Two fillers approved in 2009 are gaining popularity for a variety of indications, including facial revolumnization and nasolabial folds. Poly-L-lactic acid (Sculptra) and calcium hydroxylapatite (Radiesse) are thought to increase facial volume by stimulating fibroblasts to produce more collagen. More skill is required to inject these products, and they’re frequently used in combination with procedures using hyaluronic acid-based fillers to achieve optimal results, the experts said. Results can last a year or longer.

“I think the patient gets the most bang for the buck with Radiesse and Sculptra when you need global revolumnization: the cheeks and temples, the marionette lines, the nasolabial folds, the prejowl sulcus,” Dr. Lupo said. “I will use Sculptra in a pan-facial revolumnization, then layer on top of that a hyaluronic acid filler or maybe Radiesse in a deep dermal position for a localized correction. Radiesse is my favorite product for men because it’s stiffer. Men’s skin is thicker and heavier, so I need something a little more robust to give the lift I’m looking for.” Dr. Weinkle said she also combines the non-hyaluronic fillers, occasionally injecting a patient with Radiesse in the marionette lines and Sculptra in the cheeks.

Dr. Matarasso pointed out that great care must be taken when injecting Sculptra because “it’s a little more unforgiving than other fillers. If you get a nodule you didn’t want, it’s difficult or impossible to remove except by the passage of time.” He added that Radiesse and Sculptra are not appropriate for thinner skin of the periocular area, or in the lips, “which are more prone to lumps and bumps.” [pagebreak]

Permanent fillers include polymethylmethacrylate with bovine collagen (Artefill), FDA-approved in 2007, and hydrogel (Aquamid, 97.5 percent sterile water and 2.5 percent polyacrylamide), which is not yet approved. While a permanent filler might be cost effective over the long run, it has distinct drawbacks. “Number one, if the substance starts causing problems, you can’t get rid of it,” Dr. Nestor said. “Also, as we age, the shape and the relationships between different aspects of the face change, so putting something in place permanently isn’t necessarily ideal. For something like acne scarring, or a depression here and there, there may be tremendous benefits, but those are very limited circumstances.”

Toxins lead the pack

Approved by the FDA in 2002 for the treatment of moderate to severe glabellar lines, botulinum type A injections accounted for nearly 47 percent of all cosmetic minimally invasive procedures in 2010, according to the ASPS survey. A new type A agent, abobotulinumtoxinA (Dysport), was approved by the FDA in 2009 and now coexists with Botox as key component of the dermatologist’s anti-aging armamentarium.

“I believe they’re both remarkable products, with a very high patient satisfaction rate,” Dr. Matarasso said. “And I think what we’re finding with time is that they’re more similar than dissimilar in terms of indications, onset of action, duration, and risk of adverse events. However, there’s been a fair amount of confusion with Dysport regarding how much saline to reconstitute with, and what the potential conversion ratio is from Botox to Dysport.” Recounting her struggle with that issue, Dr. Lupo said that at first, some of her patients “were not happy with their Dysport. They didn’t get enough improvement or it didn’t last long enough. Then I had an epiphany last spring, and decided to increase the ratio to three units of Dysport to one unit of Botox. I dilute with two cc’s of saline for both, and that gives me a biological response equivalency. So if there’s ever a mixup in the office and I’m handed Dysport instead of Botox, there’s no risk of over- or under-injecting the patient.” [pagebreak]

With two equally good alternatives, patient preference often determines which toxin is used, Dr. Matarasso said. “If a patient’s happy with one product, I wouldn’t change. But if a patient has heard of the newer product and wants to try it, or says Gee, I’m not getting the duration I used to get,’ I might switch.” Dr. Lupo expressed a strong preference for Dysport in a particular area. “It’s ideal for patients with very high and wide foreheads because you see a little more diffusion with Dysport than with Botox, and thus a wider area of effect,” she said. “In fact, I’ve combined Dysport and Botox in the same patient, same visit, and had very nice results. I’ll use the Dysport in the crow’s feet and the frontalis, and Botox in the glabellar and in the lower face.”

A third type A agent, incobotulinumtoxin A (Xeomin), was FDA-approved in 2010 for the treatment of cervical dystonia or blepharospasm. Unlike Botox and Dysport, Xeomin is a “naked” toxin with no accessory proteins. “I think there’s a great deal of potential there,” Dr. Matarasso said. “They’re saying it doesn’t require refrigeration, and it has a one-to-one conversion ratio with Botox, so you don’t have to do the mathematical gyrations. I don’t think many people are using it off label yet because they’re so comfortable with the toxins they have, and there haven’t been that many publications to offer physicians guidance.” In addition, a topical botulinum toxin type A, RT001 (Revance), is under investigation for the treatment of crow’s feet wrinkles. [pagebreak]

Patient demographics drive market growth

While the aging of the U.S. population expands the traditional market for anti-aging treatments, dermatologists said patient demographics are changing in fundamental ways that predict even further growth. “I’ve seen a tremendous increase in ethnic minority patients coming in for cosmetic procedures,” Dr. Lupo said. “I call it the Obama effect’ more minorities are feeling like they’re part of America, they see the Obamas as glamorous, and they feel it’s okay to have toxins and fillers. Patients are also coming in at an earlier age, which is great because the optimal use of fillers and toxins is as a preventative of aging. The younger you are when you start, the more dramatic the improvement.”

Dr. Matarasso maintained that having a broader palette of minimally invasive procedures is also drawing more patients. “The bottom line is that it’s a new era,” he said. “No longer do we wait too long and just do surgery. We have a more proactive society, and younger people as well as older, men as well as women, are looking to prevent senescence. You’re looking at multi-therapy procedures: optimizing their topical regimen, neuromodulator, and filler. We have so much more to offer patients.”


Disclosures

Dr. Lupo is a trainer and speaker for Sanofi-aventis, an advisory board member for Merz Pharmaceuticals, an advisory board member and speaker for Medicis Pharmaceutical Corp., and an advisory board member, trainer, and investigator for Allergan, Inc.

Dr. Matarasso is a consultant to Medicis Pharmaceutical Corp. and Allergan, Inc.

Dr. Nestor has received research grants from and is a speaker and consultant for Medicis Pharmaceutical Corp. He is a speaker and consultant for Allergan, Inc. and Merz Pharmaceuticals, and has received research grants from Human Med.

Dr. Weinkle is an advisory board member and speaker for Allergan, Inc., BioForm Medical, Inc., Sanofi-aventis, Galderma, Ortho Dermatologics, and Procter & Gamble; an advisory board member for Kythera Biopharmceuticals and Stiefel; a stockholder in Derm Advance; and a consultant for Medicis Pharmaceutical Corp.


 

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