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

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

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…

 

  1. Many clinicians consider hyaluronidase as standard of care, i.e., it is in the office.
  2. 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.
  3. It takes a fair amount of hyaluronidase to erase nodules with Voluma.
  4. How much hyaluronidase should you use? Some use 150 units per mL;  A simple rule of thumb for each 10th 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.
  5. 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.
  6. Hyalnex is 150 units per bottle.
  7. The shelf-life for the hyaluronidases is very short.
  8. Many people use compounded products, but we’re not sure if they are as effective.
  9. There are a lot of issues with compounding and there will be a lot more regulations coming up.

 

Hair Today Gone Tomorrow

Jerry Shapiro, MD

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

In this summary, we will provide an overview of hair loss in women with a focus on Female Pattern Hair Loss.

Hair Loss in Women

It’s important to know that at least one third of women experience hair loss and the effect of hair loss on patients’ emotions is often greatly underestimated by physicians. As a clinician, it is imperative that you spend a good amount of time talking to your patients about their hair loss and trying to assess an approximate duration of time since their hair loss began. Of note, the youngest cases of MPHL and FPHL that Dr Shapiro has seen is age eight and it happens suddenly versus gradually.  Another important step in evaluating hair loss is to assess the pattern. We should all be familiar with the Ludwig classification of Female Pattern Hairloss ranging from classes I to III. Also of importance is to address whether the hair loss is thinning or shedding. The key question for shedding is to ask “is there hair on your pillow” and “is there hair in your food.” You need to lose 50 percent of scalp hair to notice any change clinically. The next step in the evaluation is to determine whether the hair is falling out from the roots or whether it is breaking. Hair loss from the roots can be associated with AGA, telogen effluvium, or alopecia areata; hair breaking with tinea capitis, cosmetics/trichotillomania, or hair shaft abnormalities A thorough evaluation also includes taking a good family history and assessing hair care practices.

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

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

Five Stages of the Clinical Evaluation

  1. Distribution of hair loss
  2. Inflammation, scale and erythema
  3. Scarring vs. non-scarring
  4. Quality of hair shaft
  5. Pull test

There are several new diagnostic tools available for the scalp and these include dermascopy (10-fold magnification), videodermascopy (50-100-fold magnication), and folliscope which magnifies the scalp 50-100 times.

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

Female Pattern Hair Loss

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

Ludwig stages I or II can be treated with topical minoxidil solution for one year. If there is no improvement, you may want to add:

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

If the patient has Ludwig stage III, a hair piece could be considered.

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

 

 

 

 

Tightening Tissue and Zap the Fat

Mathew M. Avram, MD, JD

Dr. Avram provides his clinical pearls regarding the use of lasers in tissue tightening….

The Good News, The Bad News, and Overall Conclusions….

  1. Each of the available technologies can achieve some degree of tissue tightening.
  2. They are the best alternative to surgery.
  3. They are getting better.
  4. For the most part, they are safe in skilled hands.
  5. The benefits, if any, require months to be seen.
  6. Too often, no improvement is seen clinically.
  7. It is difficult to predict who will benefit and who will not.
  8. Tissue tightening can non-invasively provide improvement of skin laxity in a safe manner.
  9. Remember that the results are unpredictable.
  10. The technologies do not approach results of a face lift.
  11. It is very important to educate patients as to the limits of these devices prior to treatment.

Laser Treatment of Pigmented Lesions

Mitchel P. Goldman, MD

Dr. Goldman provides us with some key takeaway points regarding the laser treatment of pigmented lesions…

  1. Nevus of Ota respond to Q-switched laser—we’ve never seen a report of it becoming melanoma; Picosecond is efficacious as well perhaps with fewer treatments.
  2. There are various approaches to treating lentigines—multiple treatments with lasers combined with bleaching agents, sun screen and sun avoidance In addition, resurfacing and chemical peels may also be effective.
  3. Both congenital nevi and aquired nevi can go away with laser treatment; acquired nevi may be easier to remove (sometimes only 1 treatment is needed); Picosecond also shows benefit with perhaps fever treatments.
  4. Melasma—this is one of the most difficult conditions to treat; it typically has a peak in ages 40-50 and is more around the central face. The most important part of treatment is protection from both sun and other light. Laser and IPL treatment is best when combined with skin bleaching agents. We have found Lytera™ to work best.
  5. Infraorbital Pigmentation-Q-Switch Ruby Laser can help with this; PDL and non-ablative and ablative fractionated and confluent resurfacing is also helpful.
  6. What about lentigo maligna? Q-Switch Alexandrite Laser + zyclara may be an appropriate procedure; however, long-term results are unknown; this is also an alternative approach to patients who do not want to undergo surgery.

 

BeautiPHIcation-Clinical Pearls

B. Kent Remington, MD

Dr Remington, a leading expert in aesthetics, provides us with clinical pearls with regards to the aesthetic consult…

  1. The patient consult is extremely important-spend ample focused time with your patients and find out the “real” reason that the patient wants to look more youthful, not the “stated” reason.
  2. Remember that patients come to physicians for direction.
  3. Pay special attention to details—as dermatologists we are image enhancers and we do all of the creative work—this full face enhancement project is what changes the patients personal self concept and self esteem.
  4. Remember to see in “double vision”—the first vision is to see what the face needs and demonstrate these needs to your patient, so they can visualize it as well ; the second vision is to able to see the end result before you start.
  5. Look for the patient’s best feature and point these out to the patient as they often already know what it is or used, combine this observation with a positive sincere compliment  and enhance that feature by performing subtle changes to the face.
  6. Remember that we never really finish a face, maintenance therapy is required.
  7. Educate your patients about the importance of maintenance therapy, most patients intuitively know that they already maintain their house, car, teeth their hair and the face is no different.
  8. Insist on baseline photos of your patients—this allows you to share before and after photos with your patients; therefore, showing them the positive changes.
  9. Have your patients bring an older good resolution  photos of themselves front relaxed view usually in their early 20’s—be sure that the photo is in high resolution. The patient needs to understand we are not trying to make them look like this 25 year old photo ,but it is to look at past symmetry, harmony and balance of the face and compare where they  are now.
  10. Have a careful planned approach with each patient—each patient has a different recipe for a successful outcome.
  11. When taking baseline photos of your patients, take more than just a frontal view—3/4 and profile views are extremely important.
  12. Patient perception and reality needs to be managed closely.

Beauty and the Signature Feature™

Ava Shamban, MD

Dr Shamban is a renowned dermatologist and recognized as a skin care expert. In this presentation, she discusses the concept of beauty and how, as dermatologists, we can improve the aesthetic outcomes for patients by recognizing their Signature Feature™, a concept developed by Dr Shamban.

Dr Shamban reminds us that beauty is an expression of sight, smell, and sound. We want to make beauty memorable and we experience beauty at every level of our brain. Unfortunately, the media is always sending us messages about what we “should” like and this isn’t realistic. It’s important to remember that beauty can really affect one’s self-esteem. Lifestyle issues, such as stress, poor nutrition, diet, alcohol, and sleep can also affect beauty.

We now have a redefinition of aging and that has led to heightened expectations, i.e., what is normal and what is expected with regards to aging.  Dr Shamban also reminds us that reaction to beauty is hard-wired, in that “we know it when we see it.”

We have to remember what makes faces and bodies beautiful…

Form

  • Symmetry
  • Proportion
  • Averageness
  • Defined contour

Surface

  • Smoothed draping
  • Texture
  • Pigment

Another concept that Dr Shamban discusses is that of the positive feedback loop. How we feel affects how we look and it’s a circular concept.

The purpose of aesthetics is to highlight the natural beauty of the individual. Dr Shamban’s  Signature Feature™ is comprised of three points:

  1.  Feature the particularly beautiful feature of the individual
  2. Persona-the signature feature should be tied to who that person is
  3. Showcase/highlight the signature feature

The goal of cosmetic work is to showcase the signature feature by reducing background noise, which in dermatology is composed of fine lines, wrinkles, textural changes, and brown spots. A blink-test will easily identify the positive feature on a person. As dermatologists, we need to remember that beauty is very important to our patients and we need to use insight and intuition along with the guides and tools that are available in order to help our patients look their best.

 

10 Most Important Take Home Points: Psoriatic Arthritis

Arthur Kavanaugh, MD

Dr Kavanaugh, a renowned Rheumatologist, provides the ten most important take home points in psoriatic arthritis to help practicing dermatologists…

  1. Psoriatic Arthritis (PsA) is common, occurring in about 20-30% of patients who have skin psoriasis. Patients almost always have psoriasis before developing PsA, sometimes by a decade or more. At present, we are unable to predict which psoriasis patients will go on to develop PsA.
  2. PsA is under-recognized, under-diagnosed and under treated. With more treatment options available, it is likely more PsA patients will be seen in the clinic and we will have more options for treating them.
  3. There is no single screening test or set of questions for determining which psoriasis patients have PsA. Sometimes it is hard for rheumatologists to tell. It is hardest for people with less abundant joint involvement (oligoarticular), and hardest to differentiate PsA from osteoarthritis (which can be inflammatory). Highly sensitive imaging techniques such as musculoskeletal ultrasound are sometime used.
  4.  Important areas of potential involvement for PsA, in addition to the skin and nails, include: 1) peripheral joints (e.g. small joints of the hands and feet,  of the wrists and ankles, the  knees, etc); 2) spine arthritis (essentially ankylosing spondylitis [AS] in a PsA patient),  3) enthesitis (inflammation of the insertion of tendons and ligaments into bone) and 4) dactylitis (swelling of an entire digit) Treatment depends upon the activity in these different areas.
  5. Greater understanding of the immunopathophysiology of PsA has led to the introduction of novel therapies, particularly TNF inhibitors . TNF inhibitors are the “go-to” biologic in PsA, and are sometimes used even before DMARDs.
  6. TNF inhibitors can be effective for all manifestations of PsA, although not all patients respond. Factors that affect response include obesity, which decreases the severity of disease as well as attenuates the response to treatment. Potentially tapering drugs, particularly biologics, is an area of increasing interest in rheumatology.
  7. Biosimilar TNF inhibitors have been approved in several countries worldwide, and a biosimilar infliximab received a favorable review from the European Medicinal Agency (EMA) and is almost certain to be introduced in European countries this year. Although the biosimilar was studies in RA and AS, it is likely to receive the full approval that the originator infliximab has, including psoriasis and PsA.
  8. Switching of TNF inhibitors can be effective in PsA. Many rheumatologists believe, although it is not proven, that TNF inhibitors and methotrexate offer synergistic benefit in PsA.
  9. Newer therapies for diseases like PsA, such as IL-12/23 inhibitors and IL-17 inhibitors, have been effective for some patients and are helping to define a novel approach to autoimmunity. Different than for the TNF inhibitors, autoimmune diseases seem to have varied responses to these other specific agents.
  10. Other new agents for PsA include oral inhibitors such as apremilast (a PDE4 inhibitor). The seemingly very good safety profile of apremilast has attracted particular attention.

 

10 Clinical Pearls in Psoriasis

Bruce Strober, MD, PhD

Dr Strober, an expert in psoriasis, provides 10 clinical pearls from the psoriasis presentations presented at MauiDerm 2014.

  1. Psoriasis is associated with chronic kidney disease.
  2. Psoriasis is associated with 5-yr reduced life-expectancy.
  3. Psoriasis is more highly associated with diabetes risk than is rheumatoid arthritis.
  4. IL-17 inhibition is associated with very high efficacy.
  5. Ustekinumab is an IL-12/23 inhibitor that has some efficacy in psoriatic arthritis, but not as high an efficacy that is displayed by TNF-inhibitors.
  6. Apremilast is a PDE4 inhibitor that has efficacy in both psoriasis and psoriatic arthritis.
  7. Calcipotriene and calcitriol when used in combination with topical corticosteroids may reduce the risk of cutaneous atrophy.
  8. Topical corticosteroids only rarely induce adrenal suppression, even if used on areas of high percutaneous absorption.
  9. Psoriatic arthritis is present in 20-30% of psoriasis patients.
  10. Concomitant methotrexate reduces the immunogenicity and augments the efficacy of biologic therapies for psoriasis.

 

Applying Laboratory Breakthroughs to Treat Pediatric Skin Diseases

Amy Paller, MS, MD

Our great progress in understanding the underlying basis for immune-mediated and genetic diseases has led to breakthroughs in therapy beyond prenatal and preimplantation diagnosis. Newer technology, ranging from next-generation sequencing to microarrays to proteomics, has facilitated these breakthroughs. Gene replacement through skin grafts has been initiated for treating recessive dystrophic epidermolysis bullosa based on early mouse studies and our knowledge of the deficiency of collagen VII and stem cell therapy to replenish cells with collagen VII- or laminin 332-producing skin cells at wounds has been modified to decrease risk and increase efficiency.

The availability of technology to create induced pluripotent stem cells and direct their differentiation into skin cells means designable sources of both stem cells and skin cells for grafts. New technology, such as use of microneedles or topically applied interfering RNA, is being studied as well to suppress the abnormal protein product and correct dominant-negative skin disorders, such as epidermolysis bullosa simplex and dominant dystrophic epidermolysis bullosa. Laboratory-based technology has also delineated the alterations in RNA and protein expression that define cutaneous immune-mediated disorders and tumors.

By understanding pathways that are activated, new therapy has been developed to target specifically these pathways and suppress the overactive immune system or growth and survival pathways. Recognition of the key roles of TNF, IL-23, and IL-17 in psoriasis has revolutionized our intervention through the development of targeted biologics.  The promising ongoing trials of IL-4 receptor antagonist and other blockers of Th2/Th22 pathways suggest that severe atopic dermatitis will similarly be treated with effective biologics. Already small molecules that target the activated signaling pathways in basal cell carcinomas (vismodegib), neurofibromatosis (imatinib for mast cells), and tuberous sclerosis (rapamycin) have suppressed tumor growth. Rapamycin is currently being applied to other disorders in which Akt/mTOR signaling is activated, such as venous malformations and could be considered for the subset of epidermal nevi with Akt pathway activation.

The other pathway leading to growth is the MAP kinase pathway, including through Ras and Raf activation. While a classic example of successful pathway suppression includes vemurafenib for Braf activation/ the Braf V600E mutation in melanoma, this MAP kinase pathway also plays a role in pediatric skin disorders of keratinocytes  (e.g., epidermal nevi), melanocytes (e.g., several forms of pigmented nevi), and endothelial cells (e.g., portwine stains). Finally, protein or lipid replacement therapy is an option used for several noncutaneous genetic disorders and is finding its way to dermatology. Injected recombinant collagen VII protein is now in trials for adults with recessive dystrophic EB and the combination of a statin to suppress the accumulation of cholesterol pathway precursors and cholesterol to replete the deficiency from pathway blockade has been used topically to reverse the skin changes of CHILD syndrome (Congenital Hemidysplasia with Ichthyosis and Limb Defects), which results from an enzyme deficiency in cholesterol biosynthesis.

These examples are just the beginning of what laboratory breakthroughs can yield for our patients. The next frontier is epigenetics and scientists are now unraveling the mechanisms that control cell- and tissue-specific gene expression. We can only imagine what scientists will discover in the future to transform medicine through personalized mutation-based gene and pharmacologic therapy.