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New Drugs: 2014

January 29, 2014

Neal Bhatia, MD

Ted Rosen, MD

In this presentation, Drs Bhatia and Rosen bring us the latest information on drugs that are, or will be available to the practicing dermatologist.

Apremilast is an inhibitor of PDE4 and is currently in phase III trials for ankylosing spondylitis, psoriasis, and psoriatic arthritis along with orphan status for Bechet’s disease. A published case report for apremilast for lichen planus (Paul et al. JAAD, 2013) demonstrated that 30 percent of the patients experienced a 2-grade improvement. This study was, however, small in numbers, treatment time and dosages.

As Dr Tsao mentioned in his presentation, omalimuzab has demonstrated promising results for the treatment of chronic idiopathic urticaria.

Dr Bhatia commented on the new treatments for onychomycosis, and feels that we have a “flood year of antifungals this year.” What we need to know:

Naftifine 2% gel—tape strips show stratum corneum residual after 4 weeks
Luliconazole is approved
Efinaconazole and Tavaborole are not
Itraconazole 200 mg tablets with new dosing protocol
Ketoconazole gel (Xolegel) and Itraconazole tablets (Onmel) are back
Econazole Foam is coming

In a Phase II study of luliconazole cream 1 percent for the treatment of interdigital tinea pedis, the researchers found that complete clearance was 26.8 percent and 45.7 percent in subjects in the two-week and four-week treatment group, two weeks post-treatment. Four weeks post-treatment complete clearance rates were 53.7 percent and 62.9 percent, respectively. A phase II study of efinaconazole for toenail onychomycosis also demonstrated favorable efficacy. Tavaborole, representing a new class of anti-fungals, met all primary and secondary endpoints in the treatment of nail fungus when compared to ciclopirox lacquer.

Ketoconazole gel 2 percent has the same side effect precautions as oral products, on label, but these are doubtful. It’s important to remember that the brand name in some markets may be cheaper than the generic. Also of importance, rates of mycological cure and effective treatment (secondary efficacy endpoints) were observed in the Econazole Nitrate Foam 1% group relative to the Foam Vehicle in both phase 3 studies (P<0.001). Itraconazole (200 mg) (OMNEL) is available with a new dosing protocol. In a study, 200 mg tablets were found to be noninferior to itraconazole 100-mg capsules at 52 weeks. The safety profile of Omnel is not statiscially different from that of itraconazole.

Dr Rosen began his section of this presentation discussing Pliagils (Lidocaine 7% + Tetracaine 7% Cream). Pliaglis is a topical, local analgesia for superficial dermatological procedures. It is applied 20-30 minutes for most minor procedures and 60 minutes for more major procedures and is available in 30,60 and100gm tubes.

Sitavig (acyclovir 50mg Buccal) is indicated for recurrent oro-labial HSV. The technology is a natural polymer derived from milk which adheres to the mucosa; therefore leading to high local drug concentration, but minimal blood levels. It is one tabe, applied within one hour of prodrome onset and reduces the duration of an attack by 0.5 days based upon a randomized controlled trial of 775 patients. Another advancement includes the approval of carbinoxamine maleate susp (Karbinal ER), which is a mildly sedating H1 antihistamine in an extended release formulation. It is used for the treatment of allergic rhinitis and conjunctivitis, uncomplicated urticaria, angioedema, and dermatographism. Aurstat Anti-itch hydrogel was also approved in early 2013 to treat the symptoms of atopic dermatitis and various dermatoses.

Old Drugs, New News:

Adapalene/BPO 1.2%/2.5% (Epiduo®)
- Now FDA approved down to age 9
Desoximetasone 0.25% (Topicort®)
- Now available as a spray
Ketoconazole 200mg tab (Nizoral®)
- Severe limitations on use due to liver and adrenal toxicity, as well as drug interactions
Certolizumab pegol (Cimzia®)
- Now approved for psoriatic arthritis

In conclusion, clinicians should pay special attention to the Nizoral FDA warnings published in July of 2013. (www.fda.gov) If you use it and there is any hepatotoxic event, that could cause a great problem as a practitioner.

In summary, the dermatology landscape is continuing to grow with promising new drugs and it is imperative to stay on top of the latest data.

Acne: Part 2: Pediatric Acne

January 28, 2014

Larry Eichenfield, MD

Remember that acne can be categorized by age, i.e., neonatal (0-6wk), infantile (0-1), mid-childhood (1-7), preadolescent (7-12), and adolescent (12-19). Dr Eichenfield emphasizes that for dermatologists, mid-childhood (age 2 – 7) acne is the most worrisome. It can be associated with premature adrenarche, Cushings Syndrome, CAH, gonadal/adrenal tumors, and precocious puberty. Mid-child acne is very uncommon and dermatologists may want to consider a referral to an endocrinologist. The evaluation for mid-childhood acne includes testicular size (males), hirsutism, clitoromegaly, androgenetic alopecia, increased muscle mass, and deepening of the voice (males). If the acne is persistent, severe, or virilizing, tests/examinations include a growth chart, evaluation including bone age, tanner stage, Total/Free testosterone, DHEAS, androstenedione, LH, FSH, prolactin, and 17OH-progesterone.

What do the new guidelines say?

These guidelines were developed by the American Acne and Roseacea Society and endorsed by the American Academy of Pediatrics, which is the first time that the Academy has a set of guidelines for the management of acne. One of the main reasons this was done was to address the gap between pediatric dermatologists and pediatricians. It’s important to know that pre-adolescent (7 ≤ 12 years) acne is common and may precede other signs of pubertal maturation. Work-up beyond history and physical is generally unnecessary unless there are signs of androgen excess, polycystic ovarian syndrome, or other systemic abnormalities. There is evidence that acne, and possibly puberty, are now occurring at an increasingly earlier age.

A recent analysis of the National Ambulatory Medical Care Survey (NAMCS) database assessed trends in the age of children seeking treatment for acne. NAMCS data from 1979 through 2007 were analyzed for all physician visits in which acne vulgaris was listed as a diagnosis in children aged 6 to 18. The analysis revealed a significant decrease in the mean age of children seeking treatment for acne over this period.

Over the past several years, clinicians have noted an earlier onset of acne—that is, the appearance of acne in patients as young as 8 or 9 years. Indeed, it has been suggested that 12 years of age should no longer be considered the low end of the “normal” range for the onset of acne.

Acne may be the first sign of the onset of puberty in children aged 7 to 11 years. The general clinical impression of earlier puberty is, in fact, supported by epidemiologic data in the US and elsewhere. In general, the trend toward earlier puberty is stronger among girls than among boys. In any event, the earlier onset of acne has mirrored the downward trend in puberty timing.

Acne Guidelines: Highlights

Topical retinoids may be used as monotherapy or in combination products and in regimens of care for all types and severities of acne in children and adolescents of all ages. It is important to remember that topical antibiotics are not recommended as monotherapy and if a topical antibiotic treatment is to be used for more than a few weeks, topical benzoyl peroxide should be added, or used in combination products. The guidelines also suggest that fixed-dose combination topical therapies may be useful in regimens of care for all types and severities of acne. With regards to oral antibiotics, they are appropriate for moderate to severe inflammatory acne vulgaris at any age. Tetracycline derivatives should not be utilized in children 8 years of age and below. Second generation tetracyclines are sometimes preferred to tetracycline because of ease of use, fewer problems with absorption with food and minerals in vitamins and other supplements, and less frequent dosing. It’s very important that patients are educated and monitored for potential adverse events when utilizing oral antibiotics for acne. Combined oral contraceptives may also be useful as second-line therapy in regimens of care in pubertal females with moderate to severe acne; however, tobacco use and family history of thrombotic events should be assessed. Due to concerns about growth and bone density, many recommend withholding OCs for acne until one year after onset of menstruation. Isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents and may be utilized in younger patients. Remember that extensive counseling, particularly regarding the avoidance of pregnancy, as well as careful monitoring of potential side effects and toxicities, is recommended.

Psoriasis Update 2013: Emerging Therapies

November 27, 2013

Craig Leonardi, MD

It is crucial that dermatologists recognize the major advances in the management of psoriasis. Psoriasis affects approximately one to two percent of the general population in the United States, plaque psoriasis being the most common form accounting for approximately 90 percent of all cases.

It is important to look at where dermatologists have been with the use of biologics over the last decade. The first set of drugs were the T-cell inhibitors. T-cell inhibitors work by blocking T-cell activation; it is a multi-step process. The primary signal was the presentation of antigen; the secondary signal was that of the binding of accessory ligand pairs; therefore, forming immunologic “synapse.” According to Dr Leonardi, this was a wonderful rationale, but since then these drugs have fallen by the wayside for a number of reasons. For example, alefacept (withdrawn from market in 2012) was probably one of the least efficacious drugs approved. Efalizumab had serious infections (i.e., progressive multifocal leucoencephalopathy (PML)) and was taken off the market in 2009. From that point, attention then drifted over to cytokines and cytokine inhibitors for the treatment of chronic inflammation.

The 2^nd generation biologics are what Dr Leonardi characterizes as the TNF-alpha inhibitors. Etanercept, in its usually approved dose of 50 mg once weekly, achieves a 45-50% PASI 75 response and you can see even more improvement with the double dose of 50 mg twice weekly.

Infliximab, three infusions in the first six weeks, will carry patients up to about an 80% PASI 75 achievement rate, and then you will see a slow loss of response over time; however, there will still be about 60% PASI 75 achievement rate over the long term.

Adalimumab achieves a 71% PASI 75 at week 16.

Third generation biologics include ustekinumab and briakinumab (which never completed the FDA-approval process for psoriasis). Phase III data on ustekinumab was positive in both the PHOENIX 1 and PHOENIX 2 studies, and demonstrates that it is a high performance drug blocking IL-12 and IL-23 showing a sustained PASI 75 response of approximately 67-75% (depending on dose) as compared to placebo. Ustekinumab also has a nice, durable effect.

What about breakthrough early on with ustekinumab? In between doses of ustekinumab it’s very common to see patients who have some return of disease prior to their next dose, but Dr Leonardi urges clinicians to encourage patients to continue and hold on to see the positive effects.

Ustekinumab Safety Data

Over time, adverse events on ustekinumab are coming down, infections are low and stable over time, and SAEs that lead to discontinuation seem to be low and stable as well. One caveat to keep in mind is that in any long term analysis like this, patients are coming out of the trial because they either are not responding or are not tolerating the drug well. From this perspective, long-term safety data from open label extension studies usually looks favorable.

New Development Efforts

There are several new drugs currently in development of the treatment of psoriasis. These therapies target IL-23 (without targeting IL-12) and IL-17. Ixekizumab, an IL-17 inhibitor, appears to be a very promising drug in the pipeline with almost 50 percent of patients in the studies achieving a PASI 100. As far as adverse events (AEs) are concerned, there were no serious AEs and this is extremely comforting.

The IL-17 receptor blocker, brodalumab, was studied in a variety of different dosing strategies. Brodalumab showed about an 80 percent PASI 75 achievement rate, demonstrating a very high performance. There were a couple of serious adverse events (four), but they seemed to be unrelated to medication and no serious infections or cancers were reported.

The data on secukinumab, another inhibitor of IL-17, is difficult to explain as the studies are rather disjointed, in that, as a dermatologist, one has to look past the published data. The higher dose of secukinumab (150mg) was selected for the phase III trials because of its PASI 75 response rate of approximately 81%. There were no serious adverse events with secukinumab.

Conclusions

Dermatologists have seen an explosion of biologic drugs that are mostly targeting the IL-17 and IL-23 pathway
There are a variety of novel small molecules that are under investigation
JAK inhibitor may be a new topical approach
Short and long-term safety issues will depend on the results of the ongoing phase III studies and subsequent post-marketing data capture.
Assess benefit/risk ratios when deciding on appropriate treatment strategies

Cutaneous Oncology: Part 2

June 24, 2013

Actinic Keratoses

George Martin, MD

Unfortunately, field therapy for the treatment of AKs continues to remain underutilized in clinical practice even though we have a number of therapies available. Recent studies on dermatologist treatment practices demonstrate that 92% of patients treated for actinic damage are treated with cryotherapy alone; 7% with cryotherapy plus a prescription for a field therapy; and 1% of patients leave the office with a prescription for a field therapy alone. Why is field therapy underutilized? This is, in part, due to prolonged downtime, patient compliance issues, the costs of medication, and patient discomfort during therapy. Therapies such as ingenol mebutate and short duration 0.5% 5-FU and combination therapies have been developed to address the above noted issues.

Our expert panel (George Martin, Eggert Stockfleth, Ted Rosen, Neal Bhatia, Neil Swanson, and Marc Brown) reviewed various challenging clinical cases with AKs. Some of the recommendations and comments are as follows:

How does a dermatologist optimally treat AKs? For facial AKs, 5-FU remains the basis of field therapy in most clinical practices. During phase III clinical trials, clearance rates in excess of 70% were measured 30 days following daily treatment for 1 week using 0.5% 5-FU. Lengthening the therapy to 4 weeks results in better efficacy but is in Dr. Martin’s opinion not worth the additional downtime and patient local skin reactions. Dr. Martin protocol involves treating daily for seven days, then the patient has a rest period of 1 month, then he treats again for 2 weeks or longer depending on the desired clinical result. What about 3.75 imiquimod? The 2 week on-off-on for facial AKs results in significant downtime. Investigator initiated studies are looking at using 3.75% imiquimod daily for 7 days followed by a 2 weeks rest and then instituting once weekly applications. Ingenol Mebutate has also proven to be efficacious as a full-face field therapy using a single tube application to cover the entire face. Complete healing with excellent clinical responses have been observed in larger area therapies. Large controlled studies quantitating efficacy on full face and scalp, large surface areas on the trunk and extremities have not been completed. Be sure to have your patients refrigerate their ingenol mebutate as soon as possible after picking it up.

Actinic damage on the chest of women poses a great challenge to the practitioner. Because of permanent depigmentation when used on chest areas, imiquimod 3.75% should be avoided. While PDT has shown to be effective, it is off-label for use on the chest and does not have any well-controlled studies to support its use. Both ingenol mebutate and 5-FU are viable options for treatment of AKs on the chest. Ingenol mebutate 0.05% QD x 2 days results in a “chemical peel” like reaction but produces excellent AK clearance and cosmesis.

What about the management of a patient with significant AK damage on the dorsal hands and forearms? Combined use of 5-FU QD in the morning for seven days with 5% imiquimod QD in the evening for six days followed by three to four weeks of “rest” and repeating the cycle for a total of three cycles has proven effective. Using 0.5% 5-FU QD for ten days followed by ALA PDT (3 hour incubation) is also effective but painful. Ingenol mebutate .05% applied QD for two days, while approved by the FDA for treatment of the hands/forearms, lacks significant efficacy and might benefit from future clinical studies examining the efficacy and safety of a three to four day regimen. It is important to remember actinic damage is a chronic disease that requires vigilance and therapeutic intervention.

Cutaneous Oncology: Part 1

June 24, 2013

Viral Skin Carcinogenesis

Eggert Stockfleth, MD

Dr Stockfleth reviewed the latest data and the role of the human papillomavirus (HPV) in skin cancer. HPV is a very stable, host-specific virus, which it is why it is referred to as “human” papillomaviruses. HPV is a frequent virus in most everyone. The most known strains of HPV are 16 and 18. HPV also has a very special DNA from the oncogenic type (E6 and E7). Currently, there are two prophylactic quadrivalent vaccines available, which harbor HPV 6, 11, 16 and 18.

It’s important to know that the target cell for HPV is the keratinocyte. HPV types can infect skin tumors and mucosa tumors.

Currently, there are over 150 human papillomavirus types. These types can be distinguished by either alpha type, the wart-associated types, or cutaneous types, which are mainly the beta- or gamma-PV types.

Genital HPV, as we know, is one of the most frequently transmitted diseases; however, don’t forget that most of us already have these viruses for life.

Cutaneous HPV

Transmission of cutaneous HPV is through skin contact. Yet, the virus is very stable so can remain for several days. Probably, the best known oncogenic HPV types for cutaneous HPV are types 5 and 8.

Cutaneous Squamous Cell Carcinoma

SCC is prevalent on 80% of sun-exposed areas in cutaneous HPV and the main risk factor is UV radiation (UVA and UVB). Dr Stockfleth and colleagues found that 118 genes were identified as differentially expressed in skin cancer.

There are multiple risk factors during skin carcinogenesis. With a functional immune system, your body can repair DNA image or lead to programmed cell death, i.e, apoptosis. Chronic UV exposure leads to a local down-regulation of immune response; therefore, leading to an increased risk of developing skin cancer. HPV blocks apoptosis and the repair mechanism which can lead to SCC.

What are the criteria to define a causal role in disease by infectious agents?

Biology of HPV

Presence of HPV in (pre)cancer cells
Expression of viral genes in (pre)cancer cells
Transforming properties (in vitro and in vivo models)

Epidemiology

Relative Risk (RR) and Odds Ratio (OR)

What about cellular networks?

Research on cellular networks over the years has led researchers to look for the “guardian” genes.

A 2011 publication by Dr Stockfleth and colleagues, looked at the interaction of cutaneous HPV 23. Of note, HPV 23 and 38 are the most prevalent types of virus and play a role in development of skin cancer. These HPV subtypes (23 and 38) induced anti-apoptotic effects in UV-damaged cells through the expression of two oncogenic proteins E6 and E7 that lead to persistence and accumulation of further mutations. Data from this paper suggest that cutaneous HPV23 E6 protein directly targets HIPK2 function; therefore, HIPK2 was identified as the guardian gene.

Research is still ongoing regarding identification of other viruses, vaccination and treatment.

New Drugs 2013: Part 1

April 1, 2013

Part 1

Ted Rosen, MD

Rayos

Modified release prednisone (Rayos) is now on the market. Why would this be a reasonable therapeutic choice for healthcare providers? It’s important to remember that for many inflammatory diseases, proinflammatory cytokines peak overnight; yet, steroid administration is often administered in the morning. This treatment delays the bioavailability for about four hours. The idea is to take this at bedtime (~10:00pm) so that the medication is then active during peak cytokine secretion and; therefore, reduces morning symptoms associated with various inflammatory diseases.

Rayos is approved for steroid-responsive inflammatory disorders such as RA, PsA, AS, polymyalgia and asthma (when steroids are indicated). It is available in 1, 2 and 5mg doses. Larger size tablets will be come available soon. The adverse events associated with Rayos are comparable with those of regular prednisone including hypertension, cataracts, glaucoma, bone density decrease, mood swings, GI irritation, ulceration or perforation, and TB re-activation. No live vaccines should be administered during treatment.

Cellulite

Cellulite is seen in 90 percent of women over the age of 40. The question then remains…. Can cellulite be cured? The Cellulaze Laser was approved as a device in January 2012. It is a side-firing 1440nm wavelength laser that works by destroying fibrous bands and vaporizing excessive fat. Dr Rosen feels that it may actually work and there may be a reasonable rationale for its use in that, it is only one treatment, it may have a long-lasting effect, a rather short recovery time and minimal scarring. However, there is not a lot of published data (n= 10) and it is rather costly ($5,000-$12,000 per treatment). There have also been various instances of bruising, swelling, pain, and numbness associated with its use.

Vismodegib

Vismodegib, a hedgehog pathway inhibitor, is a novel therapy for aggressive or metastatic basal cell carcinoma (BCC), where surgery or radiotherapy may be deemed inappropriate.

This treatment has dermatologists thinking a little more like oncologists, i.e. is the tumor stable? is it shrinking? In other words, some response is a good thing even if it isn’t a complete response. It is important to remember that even with ongoing therapy, there may be a recurrence of BCC. This is a unique and outstanding therapy and has a place in the dermatological armamentarium. It really offers the small subset of refractory, recurrent or metastatic BCC patients a new option.

Recent FDA Safety Warnings that all Dermatologists Should Keep in Mind

Minoxidil 15%- may cause hypotension
Vicrelis and Incivek (protease inhibitors for Hepatitis C, used in conjunction with Interferon) Incivek- serious skin reactions, including fatalities
- All patients who develop a skin reaction should receive urgent medical care
Nature Relief-Recall because calcium oxide that burns the warts and moles can burn the skin
Bleaching creams/skin lightening products- may contain mercury resulting in renal injury, CNS injury, fatigue, anorexia, weight loss, or a rash

New Drugs 2013: Part 2

April 1, 2013

Part 2

Neal Bhatia, MD

Over the last few years, dermatology has become reliant on botany with regards to some of the newer therapies. These include:

Ingenol Mebutate “Petty Spurge”
Polypodium leucotomos
Sinecatechins (Veregin)

Ingenol Mebutate

Ingenol Mebutate is a topical gel derived from the Euphorbia peplus plant, and is approved for its effect on actinic keratosis. (Of note, Ingenol Mebutate is applied twice a day for the body, three times per day for the face)

Polypodium leucotomos

Polypodium leucotomos is an aquatic fern origination in Central America. For centuries it has been used by native Americans because of it anti-inflammatory effects. Polypodium leucotomos has significant antioxidant activity and can positively affect photodamaged skin. The product is marketed as Heliocare and can be purchased over-the-counter or through a physician for about $30.00. It does not have an FDA indication for chemoprevention or treatment of AK/NMSC.

Sinecatechins (Veregin)

Catechins have antioxidant, antiviral and immune-stimulatory effects. The graph below demonstrates the antioxidative activity of Veregen for the clearance of external genital warts.

This product is probably not an option for the treatment of AKs based on the studies conducted; however, it could be used for Molluscum, maybe even more so than genital warts.

Photodynamic therapy

What is the appropriate incubation time Levulan PDT Treatment? Using a noninvasive dosimeter, PpIX fluorescence 5 replicates were taken at 20-minute intervals for two hours following ALA application. Results demonstrated improvement of 48% of all lesions by 20 minutes, 92% of lesions by one hour, and 100% of lesions by two hours. PpIX accumulation correlated with changes in lesional erythema post-PDT and high levels PpIX are produced in AKs in two hours.

Regarding incubation and light strategies the label says to incubate for 14 hours, i.e., treat the day before and stay indoors to avoid activating the light. Reality tells us to incubate for two hours if possible, though one hour is more realistic. The light is on for 16 minutes and 40 seconds which is enough exposure to provide a 10 J/cm2 light dose.

But, are there better options??

A Phase II study of photodynamic therapy for Levulan topical solution plus blue light versus Levulan topical solution vehicle plus blue light using spot and broad area demonstrated that ALA was statistically superior to vehicle at 12 weeks for all treatment groups. The one-hour data seems to be slightly lower in efficacy indicating some dose response. There also appears to be some long-term benefit to Broad-Area versus Spot application, in that a much higher number of Broad Area patients who are clear at 12 weeks remain clear at 24 weeks compared to Spot treated patients.

Clinical Pearls

Assess available devices and practical applications
Understand rationale for therapy
Choose patients wisely and avoid over-exposure

Atrapro versus Aurstat: Battle of the Hydrogels

Microcyn is the active ingredient in Atrapro, it enhances wound healing by inducing vasodilation and it has an anti-inflammatory affect. Microcyn is also a biomodulator that denatures endotoxin and causes stabilization of mast cells; therefore, leading to a direct anti-itch effect. It’s important that dermatologists recognize that Microcyn is different than antibiotics in that it works via multiple mechanisms of action. Microyn causes damage to cell wall, membrane and intracellular components. In an open-label pilot study looking at the results of the use of Atrapro Antipruritic Hydrogel alone, data demonstrated a reduction in pruritus severity by day 14 in 88 percent of the patients (N = 17). There was a subjective reduction of itching by day three in 82 percent of the patients, and 76 percent of the patients improved at day 14 by investigator grade.

Aurstat Hydrogrel, which was cleared by the FDA as a medical device, contains hypochlorous acid and sodium hypochlorite. Hypochlorous acid and sodium hypochlorite function as preservatives; hence, providing an anti-itch effect. A study by Draelos, et al. demonstrated the ability of Aurstat Hydrogel to reduce pruritus in patients with mild to moderate atopic dermatitis over a seven-day period (N = 20).

What’s the difference between these products?

Both studies authored by Dr. Zoe Draelos
Both have small number of patients (17 vs. 20)
Both have short durations (14 d vs. 7 d)
Atrapro has two vehicles, Aurstat has a kit
Atrapro works to prevent mast cell degranulation to stabilize itch, Aurstat acts via hypochlorous acid
Both claim anti-microbial activity without antibiotic properties

Take Home Message:

Both of these products may reduce the need for steroids and antibiotics and that may be where we see their potential utility in clinical practice.

Nuvail- A New Approach to Damaged Nails

Nuvail, a new and unique patented polymer that leaves a breathable, elegant, invisible film when applied to nails, was recently approved for restoring the health of nails. Polyureaurethane is the active ingredient.

What’s the rationale for polyureaurethane?

Polymer adheres to nail plate
Solvents evaporate upon application
“Vapor permeable” waterproof seal formed with nail and periungual skin folds (provides a better feel for the patient)
Changes in nail from sealant effect impairs further growth of fungal elements
Drying effect of nail plate and bed from waterproof seal

Clinical data demonstrated a 60 percent improvement in nail color, nail plate involvement, onyycholysis, thickness, and hyperkeratosis after six months of treatment.

The recommended application of Nuvail is qHS, the product should be applied in even strokes to affected nail plate (in entirety), proximal and lateral folds, and the distal tip. It is important that patients allow the product to dry completely before applying pads or clothing. Patients should know that nail polish may worn on top of Nuvail; however, nail polish should not be applied until Nuvail is completely dry. Prior to the next application of Nuvail, nail polish should be removed. The affected nails should be cleaned with nail polish remover once a week.

Overall Conclusions

Assess history of dosages, onset of eruption, and patterns
Monitor systemic issues of patients
Carefully assess labels of “allergy” and do not hesitate to reconsider label

Dermatology Year in Review Part 1: New Observations

March 15, 2013

Hensin Tsao, MD, PhD

Dr Hensin Tsao, Director of the Melanoma Clinic at Massachusetts General Hospital, lead off the 2013 Maui Derm meeting by providing the audience with an overview of some of the top stories in dermatology in 2012-2013.

Melanoma

Dermatologists should know that melanoma is the 5^th most common cancer in males and the 6^th most common cancer in females affecting one in 36 men and one in 55 women. Most of these numbers are not including melanomas in situ, which would then most likely make the numbers higher. (American Cancer Society 2012)

Unfortunately, melanoma incidence and mortality continue to increase. There is also a disparity in survival among races, i.e., African Americans tend to have a survival disadvantage compared to whites and other races, especially in Stage III.

Another interesting fact is that there are twice as many deaths from melanoma for men than for women; therefore, there is a thought that there is a female survival advantage. Based on the graph below, one can see that the mortality for rate for males, after age 65, really begins to take off. There appears to be some sort of lethal phenotype associated with melanoma in elderly men, especially in the head and neck. This is a group to whom one should pay particular attention.

A study in the Journal of Clinical Oncology demonstrated a superior outcome of women versus men with Stage I/II cutaneous melanoma. This was based upon a pooled analysis of four European Organization for Research and Treatment of Cancer Phase III trials.

The bulk of the effect appears to come from the tumor thickness (especially in tumors greater than 2 mm). Overall, males seemed to do worse than females.

When the studies are aggregated, almost every study conducted around the world shows a hazard ratio of approximately 0.6 to 0.7. This is consistent across many studies; therefore, this does not show a detection or reporting bias.

Clinical Pearls

Melanoma incidence and mortality rates continue to increase
There may be a disparity in survival between races
There appears to be stronger evidence for a “female advantage” in survival although biologic basis is unclear
- Unlikely reporting bias since it has been observed worldwide

Injection Infection

Another hot topic is that of blood-borne viral infections linked to tattooing. Most of the time it is due to the tattoo artist being substandard in hygiene. Recent studies have demonstrated that M. chelonae infection has been associated with tattoos. Molecular analysis showed M. chelonae was found in 11 clinical isolates and in an unopened bottle of ink. 18 out of 19 patients responded to macrolides and or doxycycline depending on sensitivities. It should be noted that contamination likely occurred before distribution.

For Dermatologists, there appears to be a need for better oversight and record keeping.

Sun Avoidance

Sun avoidance is a crucial component of all skin cancer prevention campaigns. Scientists have begun to study the effects of direct light, diffuse light, and reflected light. Modeling revealed that a large amount of diffuse UV radiation occurs. Recent studies indicate that direct UV occurs mostly on exposed sites during summer months; reflected irradiation occurs during winter months.

SimuVEX software was utilized to estimate UV from various ambient sources. Diffuse radiation accounted for 75-85% of the annual sun exposure. It is not clear whether or not shading can protect against diffuse light.

Tanning Beds

The WHO has classified sun lamps as a carcinogenic agent. The true morbidity of tanning bed use is an area of intense scrutiny and better estimates are emerging.

The British Medical Journal published a meta-analysis (27 studies) in 2012 looking at cutaneous melanoma and its association with sunbed use. This study found that there is about an 87% increased risk of melanoma if tanning [beds] are first used before age 35. There is an element of dose-dependence associated with the use. This is becoming a significant public health problem as tanning bed use now contributes to about 10% of melanomas. As expected, the risk of melanoma with tanning bed use is independent of latitude. Public health response is more aggressive these days, but we’re not there yet.

Natural Disaster Dermatology

Murcormycosis is a rare infection caused by molds that are ubiquitous in soil, decaying wood and organic material and if left untreated, it can lead to massive tissue necrosis. Although it usually occurs in immunocompromised patients, the fungus can develop after trauma in the immunocompetent patient.

A 2011 study looked at necrotizing cutaneous murcormycosis after a tornado in Joplin, Missouri. The study found that of the 13 patients with murcormycosis, five patients died; four out of the six patients were not treated with Amphotericin B and one out of seven patients treated with Amphotericin B died.

What are the risk factors that lead to mortality after infection?

Number of wounds that were punctured
Rhabdomyolysis

Clinical Pearls

Outbreaks of rare saprophytic infections after catastrophes have been reported
All 13 cases had DNA evidence of Apophysomyces trapeziformis
Infection needs to be considered early so proper treatment with AmphoB can be instituted
- Increased number of puncture wounds, early signs of rhabdomyolysis

Combining Lasers with Toxins and Fillers

January 24, 2013

Suzanne Kilmer, MD

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

Dr Kilmer stresses the importance of remembering the 5 Rs:

Relax
Refill
Rejuvenate
Resurface
Reassess

Relax

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

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

Refill-Restore Volume Loss

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

Rejuvenation

There are various approaches to rejuvenation. These include:

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

Resurface

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

Combination Treatment

Best order

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

Caveats of Combining Treatments

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

Combining Fractional with other Devices

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

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

Reassess

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

Summary

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

Cutaneous Oncology Part 2

January 20, 2013

Neil Swanson, MD & Marc Brown, MD

Mohs Surgery: Thoughts and Guidelines – Neil Swanson, MD

Dr Swanson begins by stating that Mohs surgery is NOT indicated for all BCC/SCC and this is an important concept for dermatologists. In 2012, a group of experts developed guidelines for the appropriate use of Mohs micrographic surgery published in the JAAD and Derm Surgery. It is important for physicians to familiarize themselves with the guidelines.

High Risk Squamous Cell Carcinoma – Marc Brown, MD

Squamous cell carcinoma (SCC) is the second most common type of cancer and more than 250,000 new cases are reported every year. The incidence of SCC increases dramatically with age and in older patients (80+), there are more skin cancer deaths from SCC than melanoma.

It is important that dermatologists understand the risk factors for SCC development; these include sun exposure, ionizing radiation, HPV infection, immunosuppression, genetic syndrome, chronic inflammation, burns and non-healing ulcers, chemical exposures, older men with fair skin and UV light. In addition, healthcare providers should recognize the risk factors for SCC recurrence and metastasis. This involves assessing the size, depth, histology and clinical features of the tumor as well as the overall immune status of the patient. CLL patients also represent at “at risk” group for metastisis.

The NCCN has recently published guidelines for the treatment of high risk SCC and dermatologists can refer to these guidelines for optimal patient care.