Non-invasive Fat Removal and Tissue Tightening: What’s the Truth?

Mathew M. Avram, MD, JD

Non-invasive Fat Removal

This is a technique with limited, but real efficacy. It is important that Dermatologists critically assess these technologies in this emerging field. There are many different technologies for fat removal, the first of which is Focused Ultra Sound, known commercially as “Ultra Shape”.  This is mechanical, non-thermal energy. It is currently not FDA approved.  The initial study looked at 30 patients treated at 3 monthly sessions. The researchers did bilateral treatments, with no control, of thighs, abdomen, and flanks and achieved a circumference reduction of 2-3 cms.  LFTs, lipids, & liver ultrasound showed no adverse systemic effects and there were similar findings in a subsequent study.  The problem that clinicians face is that there was no untreated control so it is difficult to ascertain the true degree of efficacy.  Circumference, when subject to mathematical analysis, is an inherently imprecise measure of improvement.  MRI could provide a more objective improvement; however, it was performed in this study.

A subsequent study in Hong Kong using this device treated 51 subjects, with 3 monthly treatments. They didn’t see any significant change in ultrasound, circumference or caliper measurements and it resulted in poor patient satisfaction.

High-Intensity Focused Ultrasound is commercially known as Lipo Sonix, was recently FDA-cleared. This features rapid heating of adipocytes producing coagulative necrosis and cell death in adipose tissue.  There is a published retrospective study that looked at 85 patients with1 treatment session. On average a 4.6 cm decrease in waist circumference was seen after 3 months and lipids, LFTs, and CBC were within normal limits. Temporary adverse effects in 11.8% of patients (4-12 weeks) included prolonged tenderness, ecchymosis, nodules, edema, and procedural pain in one patient that required discontinuing the procedure. Unfortunately, this was not an ideal study because it was retrospective and diet was not controlled. Dr Avram felt that this, in fact, undermines the findings of the study.

In a recent poster presentation, diet was controlled and there was a statistically significant circumference improvement at 12 weeks in treated patients versus sham patients. Yet, it was unclear how circumference measurement was validated.

Adverse events were more common than in the published study and included procedural pain in 90% of patients, post-treatment pain in 57%, bruising in 66%, and swelling in 9%.

Monopolar radiofrequency has been shown to produce lipoatrophy in some patients and is still awaiting clinical studies. Bipolar radiofrequency which is combined with infrared light and vacuum massage, is FDA approved; however, its efficacy is yet to be determined.

Low level light therapy (LLLT), which is, FDA-cleared, is a multiple head low-level diode laser at 635 nm. An LLLT study (blinded bi-lateral treatments) looked at 59 patients who received three treatments per week for 2 weeks some improvement was reported however, at a minimum, further study is needed.  There were no data of efficacy more than 2 weeks out. There were no data on ultrasound or other non-invasive evidence of decreased fat layer and no histology.

Cryolipolysis is a technique that was developed at Massachusetts General Hospital and is FDA-approved for non-invasive fat removal.

Cryolipolysis is the non-invasive cooling of fat to selectively cause fat cell death without damage to surrounding tissue types. It is based on the concept of the clinical phenomenon of “popsicle panniculitis”.  The mechanism of action involves the selective crystallization of lipids in fat cells at temperatures above freezing. This results in apoptotic fat cell death followed by slow dissolution of cells and gradual release of lipids; therefore, causing an inflammatory process resulting in fat layer reduction over 2-3 months. After the animal studies, there was a human study where 32 subjects in the “love handle” group were analyzed. One side was treated and there was a contra-lateral side untreated control. The parameters ranged from CIF 33 (-64 mW/cm2) for 60 minutes to CIF 42 (-72 mW/cm2) for 45 minute. The researchers evaluated efficacy 4 months post-treatment utilizing visual assessment as primary a endpoint, as well as ultrasound and histology. Ultrasound showed a   22.7% decrease in fat layer thickness. Post-procedure side effects included redness that lasted for a few minutes to a few hours, bruising and temporary dulling of sensation in treated area. There were no changes in pigmentation and type VI skin types have been successfully treated.  No laboratory abnormalities were detected. A  rare side effect (1 in 1,500) is the report of significant pain lasting about 2 weeks and resolves without sequelae. The mechanism for this side effect is unknown.

Treated and Control Side

In conclusion, the data regarding cryolipolysis (Zeltiq) indicates clear, but limited non-invasive fat removal. It not a replacement for liposuction and is not a weight loss device. It is best suited for local fat removal resistant to exercise in relatively fit patients. The best areas to treat are the love handles and lower abdomen. It is important that clinicians recognize that patient selection is crucial.

We can see that non-invasive fat removal is here. It cannot be compared to liposuction. There are several different technologies presently available. Proper patient selection is important as some devices work, and others do not.

Tissue Tightening

Many different technologies exist for tissue tightening.  They all attempt to tighten skin laxity by the deposition of heat.

The temperature-related effects will differ depending on the amount of heating that one chooses to perform:

42-52 ºC reversible injury, heat shock
> ~52 ºC cell apoptosis, necrosis
> ~68 ºC type I collagen denaturation
> ~100 ºC vaporization

The mechanism of action  is tissue contraction; therefore, each device produces heating of the dermis in order to cause significant shortening of collagen structures.  The devices also want to achieve a secondary wound healing response with collagen deposition. This has been demonstrated using monopolar radiofrequency (Thermage technology) using animal histology.

Tissue Tightening Technologies

The good news is that these technologies can achieve a certain degree of tissue tightening and they are continuing to improve and, for the most part, they are rather safe. The bad news is that the results can be unpredictable and in many cases are not seen. Each patient has to be looked at individually and they must realize that the results can take months before they are actually manifested. These treatments can often be painful and quite expensive and many times patients may require multiple treatments. It is important that physicians counsel patients and give them a proper sense of potential results.

Ablative Fractional Resurfacing

Ablative fractional resurfacing can produce some modest tissue tightening.  However it is very important to resist the temptation to be aggressive in order to maximize the clinical benefit.  Hypertrophic scarring of the neck has been reported with ablative fractional resurfacing.  (Avram MM, Tope WD, Yu T, Szachowicz E, Nelson JS. Hypertrophic scarring of the neck following ablative fractional carbon dioxide laserresurfacing. Lasers Surg Med. 2009 Mar;41(3):185-8.)

Radiofrequency

There are monoploar, bipolar and fractional bipolar radiofrequency devices. The mechanism of action of monopolar radiofrequency devices is that the current runs through the dermis but does not conduct well in the fat however it conducts along the septae in the fat causing heating of the septae and surrounding fatty tissue. Monopolar radiofrequency devices that are combined with a superficial radial cooling component (Thermage device) allows the user to change cooling and heating parameters to deliver heat to the deeper tissue in a given targeted area while protecting the epidermis with the cooling system. There is also no patient recovery time. It often takes up to 3-6 months to see the results.

Biopolar radiofrequency consists of two electrodes.  The heat runs between them and many of these devices are coupled with a suction device to maximize the tissue between the electrodes allowing clinicians to achieve deeper penetration. It may provide a mild benefit for tissue tightening.

Fractional bipolar radiofrequency utilizes a fractional pattern of bipolar RF heating that is delivered by a micro-needle electrode array directly into the deep dermis .It provides real time dermal temperature monitoring.  The treatment is painful and requires significant anesthesia.  However, its efficacy is yet to be determined.

Focused ultrasound (US) allows for deep, non-invasive treatment at any tissue depth. US can treat far below the dermis.  Treatments are guided by real time imaging.  The key to success and avoiding complications is to target carefully using imaging to guide the treatment of the skin and SMAS.  It is important to remember that one should avoid targeting any arteries or nerves.  It has great potential for not only targeting tissue for aesthetic purposes but for other medical therapies.

Skin Imaging Slide

Skin Imaging

Issues around US include clinical questions regarding pattern, depth, density and the number of necessary treatments. US looks like a promising technology; yet, its efficacy still requires more proven results.

Its important to remember that there are limits to tissue tightening technologies. It is important to discuss these issues with patients and consider that the current treatment paradigm may need to be approached in a different manner. Perhaps dermatologists need to consider restoring elasticity, rather than tightening. We do know that tissue tightening can improve non-invasive skin elasticity, the results are unpredictable, this should not be looked at like a face-lift and patient education and communication is key its the success.

Psoriasis Update 2011: Psoriatic Arthritis (PsA)

Arthur Kavanaugh, MD

In this presentation, Dr Arthur Kavanaugh, of UCSD, discusses the newest concepts in the management and treatment of patients with psoriatic arthritis (PsA).

A major question still exists among healthcare professionals…Is methotrexate (MTX) effective among our PsA patients? Dr Kavanaugh states that in a room full of Rheumatologists, everyone would agree that MTX is effective; however, the data doesn’t necessarily indicate its effectiveness, as it is somewhat lacking.

For more information on the history and data around MTX, Dr Theodore Pincus recently published a study in Clinical and Experimental Rheumatology focusing on the use of MTX in various disease states, including skin disease and PsA.

There are very few studies utilizing MTX in psoriatic arthritis and little support for its use in PsA patients. There were a total of 4 double-blind, placebo-controlled randomized clinical trials in the published literature.

There is not a lot of support for MTX in patients with active PsA. A number of studies utilized higher doses of MTX; therefore, we can see a dose effect, (patients taking over 15mg/week of MTX) in patients with psoriatic arthritis, which shows that there is some benefit to its use.

The MIPA study, a 6-month, double-blind placebo-controlled trial, was based out of the UK. The entry criteria required one swollen joint. The researchers were able to recruit only 221 patients over the course of eight years.  There were lots of drop-outs and in conclusion the results were questionable as to the value of MTX in patients with active PsA. There are a few issues with this study and the researchers reported that healthcare providers need to see the full data and the question still remains:  is the 15mg dose of MTX really effective?

Dr Kavanaugh recently participated in a PsA panel that was organized through EULAR (European League Against Rheumatism), with the intent to develop guidelines for the management of PsA. The panel concluded that patients with active PsA should be on MTX before one would be given a biologic. This recommendation would be questionable to many US dermatologists, and, in turn, the EULAR panel did revise their statement to allow for patients in “exceptional” cases to be started on a biologic.  It is really up to the clinician and patient to decide on the appropriate therapy based upon the data, quality of life, benefits and risks.

Data do exist around the efficacy of TNF inhibitors plus MTX in Rheumatoid Arthritis patients; yet, the data are limited in patients with PsA.  A systematic review of the TNF inhibitors demonstrated a risk ratio response of about 11 for an ACR 50 and a risk ratio of 17 for a PASI 75.

Is there synergy when utilizing MTX plus a TNF inhibitor in PsA? It is known in Rheumatoid Arthritis patients, yet it is unknown among our PsA patients.

The RESPOND study compared MTX (15mg/week) to INF (5mg/kg)+ MTX (15mg/week) and showed that the patients in combination did better than those on MTX alone.

Assessing Psoriatic Arthritis

When assessing PsA, it is imperative that healthcare providers look at each patient individually. It is important to consider peripheral arthritis, and look at swollen joints and the composite scores; clinicians need to consider axial arthritis, quality of life, radiographs, skin disease and other issues such as dactylitis (swelling of the entire digit) and enthesitis.

The CPDAI (Clinical Psoriatic Disease Activity Index) is a new instrument for disease activity and various clinical domains of PsA. This has been borrowed from the GRAPPA group, and broken into its individual domains. When we have these tools, we can then begin discussing remission. It’s important to consider all of the different facets of this disease (skin, joints, spine dactylitis, etc…) The important thing to consider regarding patient management is that each patient has to be looked at individually, as it is not an algorithmic treatment/management strategy.

Video: Treatment Options for AKs

The Science of Aging Skin

Michael Gold, MD

How do we look at all of the skincare products available? What does it mean to our patients? It is important that clinicians recognize what drugs and therapies work for dermal aging. Sunscreens, i.e., those with UVA and UVB protection, can prevent melanin production and collagen and elastin degradation. Dermatologists need to be aware of what ingredients are in these various sunscreens. Retinoids have also changed the management paradigm of aging skin showing a clinical improvement in skin texture, wrinkles, and pigmentation. Hydroquinone is probably the most effective inhibitor of melanogenesis. It exerts its depigmenting effect by selective action on melanocyte metabolism which results in more even skin tone and reversal of abnormal pigmentation. Hydroquinone helps prevent/reduce PIH and has been proven safe and effective by the FDA for over forty-five years. Many clinicians use hydroquinone in conjunction with retinoids.

Because of the increasing aging population, there as been a consumer demand for anti-aging products. The average patient is 30 to 55 years old and well educated. Because of the number of products available, there is also a lot of confusion around choosing what products would be the most efficacious and safe.

What is a Cosmeceutical?

According to Dr Al Kligman, the physician who termed this word, it is “something between a cosmetic and pharmaceutical”. They are topical cosmetic products that exert a pharmaceutical, but not necessarily a biologic, therapeutic benefit. Their use is mainly for anti-aging purposes, designed to improve the appearance of lines and wrinkles, skin discoloration and other defects.

How do we evaluate these various compounds? Healthcare providers know that a biologically sound rationale exists for their cutaneous effect. The therapeutic concentration range of the ingredient is known, the formulation science stabilizes the ingredient in the product, and the trans-stratum corneum delivery science for the ingredient is incorporated into the formulation. However, we need more clinical blinded trials conducted by third-party companies in order to better represent the data, as clinicians want to see patient satisfaction.

What Cosmeceuticals Exist?

Pierre Fabre

Pierre Fabre has a water-based dermocosmeceutical that hydrates the skin and has many uses as a moisturizer and anti-inflammatory agent. One of the company’s products, Retrinal™, comes in three doses for hypersensitive skin and the eye area, all skin types, and intensive skin rejuvenation. Clinical studies show that these retinoid products, which can be purchased OTC, are as effective as prescription retinoids. Another one of their products, Gel d’eau Thermale™, is a water-based gel that can be used in post-laser procedures such as laser hair removal and has an immediate cooling effect, and analgesic effect, and a soothing, anti-inflammatory effect. Pierre Fabre also has positive data around its product Avene Thermal Spray Water™. Glytone™, a vitaceutical facial serum, provides all day anti-oxident protection through its continuous release of free Detla-Tocopheryl. Six month studies on photodamaged skin showed efficacy.

Recently, the European Journal of Dermatology published a series of peer-reviewed papers showing the clinical efficacy of these water-based products in in photoaged skin as well as disease states such as eczema and psoriasis.

Neocutis

Neocutis has many products using multiple fetal fibroblast cell lysates. Several papers have been published discussing how this novel human growth factor and cytokine skin cream and improve skin surface topography of aged facial skin.

Blanche

Blanche Skin Lightening Cream with Melaplex™ represents a novel and first time approach to target the pathway of melanin formation at multiple levels. Blanche contains a prescription strength Hydroquinone (4%) for effective skin lightening when used with Melaplex™, which is a unique skin-brightening complex that is used to restore the youthful appearance of even skin tone. In a head to head study Blanche produced equivalent results to Triluma in the treatment of dyspigmentation.

Perle

Perle is a Skin Brightening Cream with Melaplex™. Many clinicians do not like to utilize hydroquinone, and some of these newer products, such as Perle, are well-tolerated and hydroquinone-free. A 45% reduction in pigment was found after a 12 week study protocol. Many clinicians have used hydroquinone products for 12 weeks and then switch to hydroquinone-free products. The advantage of this product is that there is no restriction on how long you can use this product and it can be used safely in pregnancy.

Both of these products have enabled clinicians to help block the pathway of melanin formation.

Syneron

Elure, which is a skin-lightening product, is based on Melanozyme™ containing lignin peroxidase (LIP). LIP is a naturally occurring enzyme deriving from a tree fungus. For many years, LIP has been identified as the enzyme that breaks down lignin in decaying trees, causing rapid decolorization. Because the molecular structure of lignin is similar to that of melanin, recent research confirmed that LIP also has the potential to improve the appearance of skin by reducing eumelanin. Data suggest that Elure is significantly more efficient that 2% hydroquinone.

Looking ahead, Dr Gold stated: “In 2011 pigment will be the new wrinkle.”

Biopele Growth Factors (GFs)

GFs work as chemical messengers between cells to turn on or off specific cellular activities. They can be derived from a number of sources, including epidermal cells, placental cells, colostrum and plants. GFs promote fibroblast and keratinocyte proliferation and induce extracellular matrix formation. SCA Biorepair technology (Tensage) is a novel fibroblast growth factor. Secretion of the snail Cryptomphalus aspersa (SCA) is an active, glycosaminoglycan secretion generated by the snail during times of stress such as exposure to radiation, burns, etc. SCA is shown to repair the snail’s skin in as little as 48 hours and eliminates concern expressed over VEGFs. Data suggest that this product shows marked improvement in skin texture and moisture, enhanced collagen deposition, increased hyaluronic acid content and a reduction in solar elastosis.

Biopele also makes non-prescription retinoids to counteract the effects of photoaging.

It is important that dermatologists realize that we now have the opportunity to change the function of skin. Cosmeceuticals are showing a great improvement in this ability.

Obagi

ELASTIderm is a topical eye treatment that is clinically proven to show increased elasticity and a reduction in visible wrinkles.

Obagi’s Nu-Derm System is an OTC product designed to be used in conjunction with a prescription retinoid to transform damaged skin cell functions in order to reverse photoaging. The data suggest that Nu-Derm System demonstrates a superior efficacy at 2 weeks as compared to other therapies.

The 4-step Obagi hydroquinone/tretinoin-based skin care system helps to correct premature skin damage, reduce future skin damage. Care in customizing the system to the individual is important. The sequence of application of component products is:

  1. Skin preparation (cleanser + toner)
  2. Skin correction (4% hydroquinone + exfoliant)
  3. Skin stimulation (4% hydroquinone + 0.05% or 0.1% tretinoin)
  4. Skin protection (sunscreen)

The published data suggests that there are benefits of using a hydroquinone/tretinoin skin care system for patients particularly when used in conjunction with light based devices such as IPL.

Coffeeberry

CoffeeBerry® is the fruit from the coffee plant (Coffea arabica), from which the commonly known coffee bean is derived. When harvested at a sub-ripe growth stage, the flesh of the CoffeeBerry® fruit is at peak antioxidant concentration. RevaleSkin utilizes coffeeberry and has shown a decrease in the appearance of fine lines and wrinkles.

Priori Skincare

Priori now has their own coffeeberry line, the Priori Coffeeberry Natureceutials with all of their products designed to improve skin renewal and decrease fine lines and wrinkles. Idebenone is another product of Priori’s, again showing a reduction in pigmentation and rosacea.

Allergan

Allergan’s product, Vivite, which combines glycolics and antioxidants, has shown improvement in the appearance of fine lines/wrinkles, skin roughness and hyperpigmentation after 8 weeks of treatment.

LATISSE®

LATISSE® is the first and only FDA approved therapy for the treatment of hypotrichosis of the eyelashes. LATISSE works by increasing eyelash growth including length, thickness, and darkness. The exact mechanism of action for LASTISSE® is unknown. LATISSE® solution is a structural prostaglandin analog that exerts its action by selectively mimicking the effects of naturally occurring prostamides. The physiochemical properties of LATISSE® solution favor its effective skin absorption into the dermis where the hair follicles reside.

LATISSE® is associated with enhanced eyelash growth and most subjects in clinical trials noticed favorable changes in their eyelashes.

NIA24

The NIA company uses a Pro-drug system that turns into an active within the skin. The company utilizes iacin in order to improve skin function. Pro-Niacin has shown to dramatically strengthen the skin barrier, improve cell turnover/differentiation, improve moisture retention and increase sun protection. Its visible improvements include increased smoothness and firmness, improved texture and tone, reductions in the appearance of fine lines and wrinkles and improvements in chin and jaw firmness.

Skin Medica

TNS is another Growth Factor. Its work has been verified time and time again, by seeing improvement in fine lines and skin elasticity. TNS is unique for several reasons: patented advanced manufacturing process; physiologically balanced growth factor mixture; stability of a high concentration of growth factors; proven safety of growth factors over time.

Clinical studies have demonstrated the efficacy of TNS and it has an excellent safety profile with over 7 years of use.

Recently, SkinMedica has come out with TNS Essential Serum that is both a Recovery Complex (same TNS) and a Corrective Complex. It is an interesting synergy of the products and several independent studies have verified its effectiveness in skin texture roughness, peri-ocular wrinkles, smoothness and skin tone.

SkinMedica also makes a variety of antioxidants and retinoids. In comparator studies the Tri-Retinol performed as well as tretinoin .025% in the treatment of photoaging but with less irritation.

Anti-redness Products

According to Dr. Gold, in addition to pigment disorders, another “huge” area being targeted by the cosmeceutical companies is redness. There are lots of reasons that patients become red in their skin. Some of the most common reasons are blushing, acute redness/flushing, which can be due to sun exposure, cosmetic procedures or drug-induced as well as chronic redness associated with skin disorders such as acne, rosacea or atopic dermatitis. Most of the products being developed in this space target prostaglandin E2 (PGE2) that is a bioactive molecule in the prostanoid family of lipids responsible for vasodilation. It is elevated by a number of stimuli including UV exposure, chemical exposure, neuronal and hormonal stimuli and inflammatory skin conditions such as rosacea.

CalmPlex is a novel product containing patented ingredients and has shown its effect on skin redness. Most cosmetic products hide redness or temporarily reduce blood flow to the skin using vasoconstrictors. However, CalmPlex prevents UV and chemical induced release of inflammatory mediators, especially PGE2. Several studies have shown its effectiveness in reducing skin redness.

Summary

It is important to know what products your patients are already using at home to avoid patient confusion. Patient education and staff education are keys to the success of these products and patient satisfaction. Aestheticians must spend a lot of time with patients going over their regimens in order to achieve success. Taking lots of before/after photographs can help your patients, build confidence and trust and it serves as a nice cross-referral.

Evolving Landscape of Therapeutics for Actinic Keratoses (AKs)

George Martin, MD

George Martin, MD

Watch video of Dr. Martin’s full talk

At the podium during Maui Derm 2011, I discussed the evolving landscape of therapeutics for actinic keratoses (AKs).  In the US nearly 60% of “at risk” individuals over the age of 40 have at least 1 AK.  Therapy for AKs has resulted in over 5 million office visits with an estimated healthcare burden of over 1 billion dollars.

As healthcare initiatives examine and reward patient therapeutic “outcomes”, the clear lack of efficacy of cryosurgery as a “field therapy” for patients with numerous AKs will cause a shift in therapeutic algorithms toward field therapies.  However; field therapies, when performed according to the package insert, are associated with prolonged side effects that dramatically affect patient compliance.  As a result, small investigator initiated studies examining short course, combination and interval therapy in efforts to enhance patient compliance while maintaining efficacy are becoming more prevalent in the literature. Additionally new drugs such as the plant derived ingenol mebutate gel are ready to be brought to the marketplace and new formulations of existing drugs such as imiquimod 3.75%, which employs a more “user friendly” protocol compared to 16 weeks of twice daily 5% imiquimod, have been introduced.

I presented the work of Prof. Eggert Stockfleth of Charite Hospital in Berlin who has published compelling molecular data on the role of human papilloma virus (HPV) 21 as a co-carcinogen along with UV.  The role of HPV 21 is analogous to the role of certain oncogenic HPV sub-types in cervical cancer.  HPV 21 has been found in 95% of AKs and 100% of cutaneous SCCs in Prof. Stockfleth’s study. Tumour-inducing effects of HPV 21 have been attributed to its production the viral protein E6.  E6 interacts with pro-apoptotic Bak-protein and the p53 protein resulting in inhibition of apoptosis.   A vaccine directed against the HPV 21 is in early stages of development. Because of the increased risk of SCC development in organ transplant patients  (>20x the rate of SCC development compared to non-immunocompromised individuals) the efficacy of pre-operative immunization in preventing AKs and SCC in this high-risk group will be studied first.

Figure 1: Fluorokinetic Analysis

Figure 1: Fluorokinetic Analysis

ALA PDT has come a long way from its lengthy 14 – 18 hr. incubation times in efforts to become user friendly.  However, I presented data that the shorter 1-hour ALA incubation times may have sacrificed significant efficacy for convenience.  Based on fluorokinetic data on the accumulation of the photosensitizer protoporphyrin IX (PpIX) inside AKs following ALA application (Figure 1) and patient observation, we now regularly treat patients using a minimum of 3-hour ALA incubation period to allow more PpIX accumulation inside AKs.  In patients with “stubborn” AKs we pre-treat with 5-FU daily for 7 days on the face and 10 days on the scalp and extremities followed by PDT using 1 – 3 hour incubations.  Lastly, for the patient with extensive AKs on the face and scalp who I never seem to get close to clearing, pretreating with 3.75% imiquimod for 1 week followed by ALA PDT using a 3 hour incubation has produced remarkable sustained clearance not achieved in either ALA PDT alone or in combination with 5-FU.

Figure 2: Therapeutic "Downtime"

Figure 2: Therapeutic “Downtime”

I addressed the issue of pharmaco-economics involving our currently available field therapies.   Medicare insurance covers the cost of ALA PDT, which is a decision factor for cash strapped seniors unable to afford the several hundreds of dollars for topical field therapies.   In terms of downtime for working individuals, ALA PDT affords the least amount of downtime (generally 1 week) compared to other field therapies (Figure 2).

5-FU remains a cornerstone of  field therapy in most our practices.  I was noted that phase III data on 0.5% 5-FU showed that 1 week of daily use of 0.5% 5-FU cleared nearly 75% of individual AKs.    I think that it is time that we should re-examine the scorched earth policy of 4-week 5-FU therapy!

Figure 3: AK of the Lip

Figure 3: AK of the Lip

What’s been overlooked for actinic chelitis?   3% diclofenac gel applied twice daily for 3 months is particularly effective for this problem. It is very tolerated and results in excellent clearance data with over 80% of individual lesions clearing and patient satisfaction was rated as very high.  (Figure 3) For those patients not wishing at least 2 weeks of downtime following any of the current modalities ranging from PDT, CO2 laser resurfacing, 5-FU or imiquimod this is a tolerable option that allows people to continue socializing.  Recent data on 3% diclofenac has shown significant long-term clearance during the phase IV study involving 1-year follow-up evaluations.

The evolution of imiquimod therapy for the treatment of AKs has undergone an evolution since the introduction of 5% imiquimod applied twice weekly for 16 weeks.  While the efficacy of this regimen is significant, the tolerability and patient compliance is wanting.  In Europe the use of 5% imiquimod 3-times weekly 4 weeks followed by a 4-week rest period and repeated produces excellent clinical and histologic clearance long term (1 year) clearance but is once again associated with significant patient downtime.  Limiting therapy to only 4 weeks results in only <30% clearance compared to two cycles that result in approximately an 85% clearance.  The introduction of 3.75% imiquimod applied daily for 2 weeks-2 weeks off- 2 weeks on has resulted in better patient tolerance and impressive individual lesion clearance (>80%). Long-term complete clearance (1 year) data for those phase III study patients initially completely clearing was 40%. In light of the role of HPV 21 as a co-carcinogen responsible for the development of AKs and cutaneous SCCs, the use of imiquimod as an immune modulator used either alone or in combination would seem to have a therapeutic advantage.

Finally, ingenol mebutate 0.015% gel when applied for 3 consecutive days during phase III studies, produced very nice and consistent clearance data (80% range) as a field therapy for the head area (face and scalp).  The 3-day topical therapy had excellent patient compliance, which is a major challenge for other field therapies.  Downtime following ingenol mebutate was on average 2 weeks.  It will be interesting to see how this drug will be used as a field therapy because of the inability to “titrate” its response following application.  Likely most of us will begin using it a “limited area” field therapy. However the future seems very bright for this latest pending addition to our therapeutic toolbox.

 

Anti-IL12/23p40 Antibodies in the Treatment of Psoriasis and Psoriatic Arthritis

Craig Leonardi, MD

The much anticipated introduction ustekinumab (Stelara®) for the treatment of moderate to severe psoriasis came about in 2010.  This fully humanized monoclonal antibody directed against the p40 subunit of IL 12 and 23 has demonstrated in phase II and III studies that it is a “high performance” drug: fast acting, long duration of action and great efficacy.  However, according to Craig Leonardi, MD, a principal investigator for ustekinumab, there appears to be a potential cardiovascular safety signal which came in the form of MACE events (Major Adverse Cardiovascular Events ie myocardial infarction, stroke and sudden death).  These MACE events appear to be a “class effect” as it is also found in the other anti p40 antibody briakinumab, which is in phase III development.  When both phase II and III data were analyzed for both anti-IL12/23 blockers there were 10 MACE events in the 3,100 drug treated patients and none in the 1,400 placebo treated control group. Because these studies are not powered to demonstrate statistical significance of this small but finite signal none was found.   It should be noted that MACE events do not encompass other cardiovascular signals such as angina, coronary bypass surgery or TIAs. The incidence of these non-MACE events is unknown.  This MACE safety signal has not found in the numerous trials involving thousands of moderate to severe psoriasis patients who received anti-TNF therapies who presumably have the same metabolic risk factors for MACE events.  Comparator groups such as those found in the Framingham study population really do not apply. Drug study populations preselect for healthy patients.  The placebo-controlled group is still the best comparator group and there were at least 1,400 patients in that group for both.

Dr Leonardi pointed out that MACE events occur early in the course of the drug therapy, usually within the first 8 months and level off.  Speculation regarding a mechanism for the MACE events would likely involve some form of plaque disruption. There is some independent investigational data that demonstrate a significant rise (a 13-fold increase) in serum p40 levels at week 12 which decrease back to baseline by 8 months after injection of these anti- p40 molecules.  This finding seems counter intuitive to what one would expect after introducing an antibody against p40 cytokines.   The elevation likely comes from an intracellular reservoir that enters into the serum over a period of time. Interestingly, the course of p40 subunits in the serum roughly parallels the development of MACE events. It is known that p40 can dimerize and become pro-inflammatory which if we continue on our speculator path could lead to plaque disruption and a MACE event.

Briakinumab’s application to the FDA for approval has been pulled and in July of 2011 Abbott halted all clinical trials involving briakinumab pending further evaluation of MACE events. Additionally there are many questions to be answered including regarding briakinumab’s early SAE’s such as infections  cutaneous and systemic squamous cell carcinomas reported in the first 28 weeks following the introduction of the drug in study patients.

Unlike the history behind TNF inhibitors which had long-term safety profile in the rheumatology and gastrointestinal field the IL 12/23 blockers are new and dermatology specific. In light of the current cardiovascular signal where does ustekinumab fit in our therapeutic tool box for psoriasis patients?

Dr. Leonardi’s Recommendations:  It should be understood that this is a “class effect” of the IL 12/23 blockers not observed in analysis of TNF inhibitor safety data.  Consider all options when selecting a biologic therapy.  Patients with moderate to severe psoriasis typically have cardiac risk factors.  Consider starting with a low dose regardless of the patient’s weight.  Although there is not data to support its use consider starting a patient on 81 mg of ASA.  Await further analysis of the safety data. Unlike the anti TNF therapies that came to us from rheumatology and gastroenterology, the IL 12/23 blockers have no point of reference.  Scientific analysis of the p40, IL 12 and IL 23 serum levels during long term treatment.

To add to Dr. Leonardi’s recommendations, in my patients with early signs of psoriatic arthritis such as enthesitis (inflammation of the insertions of ligaments and tendons into bone) with possible early join involvement I still favor the use of anti-TNF therapy when considering a biologic agent because of their longstanding efficacy in psoriasis patients with early signs of psoriatic arthritis.

Post Maui Derm Footnotes:

Since Dr. Leonardi’s presentation a paper co-authored by Dr. Leonardi discussing this potential safety signal among antii-IL 12/23 antibodies was published in JAMA (JAMA Aug 24/31 Vol 306 No. 8 (864 -871).  The article concluded: “Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF treatments. This study may have been underpowered to identify a significant difference.”

Centocor recently released Stelara’s 4-year safety data, which did not demonstrate any new safety signals. This comes as good news particularly when one considers that the appearance of Raptiva’s (efalizumab) safety signal (PML) occurred at year 4.

 

Telomeres and Human Aging

Barbara Gilchrest, MD

Telomeres and Human Aging

In this year’s session on “The Science of Aging Skin” Dr. Barbara Gilchrest asked the question:  “Why do we age and what does aging mean?”  After posing this rhetorical question she went on to explain that there are two essential components to aging. The first is that there is a genetic program that assures that cells likely to be damaged over many decades stop dividing after a finite number of divisions and will not carry on their dysregulated program.  The second component is “wear and tear” and refers to the environmental insults to individual cells and organized tissue that cause cells to advance to a senescent state more rapidly.

When we speak about aging of the skin we refer to two components: intrinsic and extrinsic aging.

Intrinsic aging refers to the clinical, histologic, and physiologic changes in sun-protected skin of older adults. This is also called chronological aging.

Extrinsic aging, which is also referred to as “photoaging”, refers to the clinical, histologic, and physiologic changes in habitually sun-exposed skin of older adults.  Photoaging occurs primarily on the face.  There are striking differences between chronological aging and photoaged skin in chronically sun-exposed areas.

Intrinsic aging has a minor impact on the appearance of the skin but over time results in multiple functional deficits such as slow wound healing and the loss of immune competence observed in older skin. By contrast photoaging has a major impact on the appearance of the skin, results in a further loss of immune function, and probably exaggerates the loss of other cellular functions.  Most importantly, photoaging is strongly associated with photocarcinogenesis.

Extrinsic aging is not only the result of UV light but also cigarette smoke, which accelerates the aging process. The effect of cigarette smoking on aging skin has been repeatedly documented since the 1960’s.  Very recently the role of air pollution in extrinsic aging of the skin has been documented in middle-aged women.  The study involved a comparison between women living in the countryside away from highways vs. those living in cities closer to highways.  The women experiencing air pollution near roadways were found to have accelerated skin aging.

Current Concept: “The processes of aging and photoaging are consequences of safeguarding the genome”

Dr. Gilchrest contends that nature is concerned about the genome with little regard to the actual aging process. Cancer is the failure of this safeguard mechanism.

Research in the later half of the 20th century has identified and documented major mechanisms of aging.   These include “signaling imbalance” due to the inter-related factors of retinoic acid deficiency, corrected by retinoic acid replacement (Voorhees); increased activity of NFκB (a transcription factor that contributes to dysfunction of senescent cells); oxidative stress due in part to aerobic metabolism; UV damage; and other cumulative DNA damage to cells of body, particularly the skin.  More recently telomere shortening, a newly understood aspect of aging, has led to a greater understanding of the aging process.  The Nobel prize in 2009 was given to 3 scientists whose work beginning in the 1980s greatly advanced our understanding of telomeres. Appreciating their role in the aging process promises to lead to novel therapies for aging.

The Role of Telomeres:

Chromosome Caps

Figure 2: Chromosome Caps

Telomeres (Figures 1 and 2) are the terminal portions of chromosomes, in man about 10,000 DNA base pairs that shorten to around 6,000-7,000 base pairs with age.  Telomeres are composed of a repeating base pair sequence of TTAGGG and its complement.  Telomeres form a loop structure that caps the end of DNA strands that are otherwise interpreted as double stand breaks. Without telomeres you get chromosomal fusion, mutations and cell death.  (Figure 2)

Telomere caps on chromesomes

Figure 1: Telomere caps on chromesomes

Critically short telomere lengths cause cells to go into a senescent state such that the cell stops dividing after 50 – 60 post natal cell divisions.  Nothing is capable of stimulating the cell to divide at that point.

In addition to their role as a “biologic cellular clock” in which telomeres limit the number of cell divisions (Harley et al. Nature 1990), it has been found that telomeres also trigger DNA repair responses   (Karlseder et al. Science, 1998).

The Role of Telomerase:

Telomerase is the enzyme complex responsible for lengthening telomeres by adding TTAGGG sequences to the tips of chromosomes.  Telomerase is expressed in germline cells, stem cells and >90% of malignant cells. Telomerase is also expressed transiently in S (DNA synthesis) phase in normal cells (Masutomi et al. Cell, 2003).  Telomerase slows but does not prevent telomere shortening in normal cells. However, its absence in genetically engineered mice is associated with acceleration of the intrinsic aging program.

Telomerase Activation

Telomerase activation in otherwise normal cells immortalizes the cells, which then divide indefinitely but are not malignant because these cells are still subject to the local environmental commands.  In an animal you get a younger animal but promote carcinogenesis because you remove the essential telomerase shortening that turns off cell division and limits the life of the environmentally mutated cell.

Increased Telomerase Activity in Combination
with Cancer Resistance Delays Aging in Mice

Experiments were performed in which mice were genetically modified and made transgenic for TERT (catalytic component of telomerase) and also over-expressed the tumor suppressors p53, p16 and/or p19 ARF. The combination of increasing telomerase activity while overexpressing cancer resistance gene activity resulted in mice with an increase in median and maximum lifespan without an increase in cancer, an increase in telomere length and an improvement in clinical and molecular aging markers, including in the skin. {Tomas-Loba et al. Cell, 2008}

Compared to old wild type or other control mice Telomerase Reactivation Reverses Tissue Degeneration in Aged Telomerase-Deficient Mice

Dr. Gilchrest described a study involving 4th generation telomerase-deficient adult mice which were infertile with widespread tissue atrophy. Four weeks of conditional telomerase expression (TERT knock-in) resulted in: skin fibroblast proliferation increased telomere length, organ cellularity, including brain; increased fertility and litter size; increased olfactory responses; increased survival time and no carcinogenesis and a reduction in DNA damage signaling in tissues. (Jaskelioff et al. Nature, 2011)

 Telomeres Are Strongly Implicated in Human Aging

 Telomeres shorten with age in vitro (50-150 base pairs per mitosis) and in vivo. {Lindsay et al. Mut Res, 1991; Vaziri et al. PNAS, 1994; Dimri et al. PNAS, 1995}. Telomere shortening correlates with progression of age-associated diseases such as diabetes.  Telomere length (measured in peripheral blood lymphocytes) correlates with longevity in persons >60 years old.  {Cawthon et al. Lancet, 2003;  Valdes et al. Lancet, 2005}.  Progeria, Werner syndrome and other progeroid syndromes are characterized by short telomeres.

New information on Telomeres:

Over the last few years new information regarding the activation of telomeres and telomere associated proteins involved in DNA repair have been uncovered.  Telomeres are replicated throughout S phase and DNA damage repair proteins associate with telomeres during S phase and are activated. Homologous recombination proteins help to reconstitute the protective telomeric t-loop in the G2 phase  (Masutomi et al. Cell, 2003; Crabbe et al. Science, 2004; Verdun & Karlseder. Cell, 2006; Verdun & Karlseder. Nature, 2007)

Interpretation for telomere-based activation of DNA damage repair proteins during S phase:

According to Dr. Gilchrest, cumulative evidence regarding the role of telomere-based activation of DNA repair proteins suggests that this process might function as the cell’s final “quality check” before dividing.  This pathway is activated during replication in which telomere-based signaling first acts to reduce DNA damage, to slow senescence, and to protect the genome.  If acute damage is overwhelming or many cycles of cell division make cumulative damage likely, cells are pushed to apoptosis or senescence.  Cancer develops when this mechanism fails.

Melanoma

What’s your strategy in managing this lesion?

  1. In 1970 the overall melanoma survival rate was less than 60%. Today the overall survival rate is over 90%. Much of this improvement in melanoma survival can be attributed to earlier diagnosis.
  2. Diagnosis of melanoma at earlier stages of evolution is, in part, due to increased awareness and increased surveillance.
  3. The notion that the in vivo diagnosis of melanoma is solely dependent on its clinical primary morphology derides the true complexity involved in diagnosing this malignancy. Components of the clinical examination used in the evaluation of skin lesions include touch, patient-derived anamnestic data, analytical reasoning (e.g., ABCD), comparative recognition (e.g, change), and differential recognition (e.g., ugly duckling sign).  The human cognitive process integrates this clinical information, extracting the pertinent information and rendering a diagnosis.
  4. Utilizing total body photography, dermoscopy, and dermoscopic short-term mole monitoring has contributed to the detection of many clinically subtle melanomas (improved sensitivity) and has also increased our diagnostic specificity. This translates into an improved ability to detect melanoma while concomitantly decreasing the number of unnecessary biopsies being performed on benign lesions.  Pigmented lesion experts utilizing baseline photography and dermoscopy remove approximately 5 benign nevi for every MM found. In contrast, non-experts remove as many as 30 benign nevi for every MM found.
  5. Future technologies such as confocal microscopy, computer vision, telemedicine, etc. are likely to continue to enhance the sensitivity and specificity for diagnosing early melanomas.

Maui Derm 2010: Surgical Management of Melanoma   K. Tanabe MD

In the surgical management of melanoma it is critically important to obtain adequate surgical margins. Ken Tanabe, oncology surgeon at MGH, discussed surgical margins for melanoma and the role of sentinel node biopsy and lymphatic mapping.  Recommended margins: melanoma in situ – 0.5 cm;  < 1 mm thickness – 1 cm;  1 – 2 mm thickness – 1 – 2 cm;  > 2 mm thickness – 2 cm.  These recommendations have been developed from the results of prospective randomized trials.  These margins may be modified to accommodate for anatomic or functional considerations in cases of melanomas of the face and hands.

In patients who are potential candidates for lymphatic mapping and sentinel node biopsy what does one need to know?   Dr Tanabe stated that while both offer clear advantages in enhancing accuracy of staging and regional disease control, their value in improving likelihood of long term survival remains a subject of debate. Sentinel node biopsy should be discussed with all patients with invasive, clinically localized melanoma before definitive wide local excision. Sentinel node biopsy should be considered in the following groups of patients with clinically localized melanoma > 1 mm Breslow thickness; < 1 mm Breslow thickness with positive deep margin, or > 1 mitoses, or ulceration. Patients with metastatic melanoma identified in their sentinel nodes should undergo completion lymphadenectomy, since approximately 20% of these patients will have additional (non-sentinel) nodes with melanoma. What can we offer our patients with advanced disease?  According to Dr Tanabe, in patients with hematogenous metastases, immunotherapy with IL-2 produces rare, but durable complete responses.  Conventional chemotherapy (e.g. dacarbazine) has limited activity.  Based on early trial results there is much interest in agents that target specific molecular pathways, such as Braf mutant tumors.