Pediatric Dermatology

Our expert panel of pediatric dermatologists reviewed various topics in the field of pediatric dermatology including, hemangiomas, nail diseases, atopic dermatitis, inflammatory disorders, and skin lesions.

Drs Friedlander and Frieden began the pediatric dermatology session with a discussion on infantile hemangiomas (IH). Dermatologists need to continue to understand the incidence and pathogenesis of IH and when to recognize when intervention is required. A large prospective study showed that overall 4.5% of infants were affected by IH. Where do infantile hemangiomas come from? There are three theories: 1. Placenta embolization; 2. Somatic mutation in gene mediating endothelial cells (VEGF); 3. A hypoxic location elicits production of HIF.

How do we treat IH?

Over the last four years, Beta Blockers have emerged as a novel therapy for the treatment of IH. Guidelines were recently published for the use of propranolol in patients with IH. (Drolet et al. Pediatrics 2012 December 24. Epub ahead of print) A recent systematic review compared the improvement of IH with propranolol versus steroids and the results were 98 percent and 71 percent, respectively. The adverse events were also higher in the steroid group versus the propranolol group. All patient vital signs should be monitored when given propranolol; the most frequent side effect is hypoglycemia.

What if propranolol is not an option? The topical beta blocker, Timolol (which has been use for years in glaucoma patients with great safety), has encouraging results and appears to be well tolerated. This has been effective in facial lesions particularly around the eye.  For lesions near the eye in neonates 1 drop BID is the generally accepted dose.

Other therapy for IH includes corticosteroids, systemic therapy, pulsed dye laser, cryotherapy and Imiquimod.  An important concept with the overall management of hemangiomas is that management is not a “one size fits all” approach and therapy needs to be individualized.

Hand-Foot-Mouth and Beyond…

Over the last few years, atypical cases of HFMD have been reported to the CDC. Many of these cases looked like eczema herpeticum, but oral erosions and palmar lesions looked like HFMD. Coxsackie A-6 infection seems to be a virus that is now appearing in clinical practice. Fortunately, multiple PCR panels are commercially available and can aid dermatologists in the detection of these worrisome viruses.

What about onychomycosis?

Dermatologists need to remember that fungal nail infections DO affect children and the incidence may be increasing due to occlusive foot lifestyle and genetics. **Utilizing a curette is a good way to obtain a nail specimen in a child without provoking fear or fuss. Terbinafine 5mg/kg/d is an effective systemic therapy used to treat onychomycosis as well as fluconazole. Data has also shown that that children, with Onychomycosis not involving the matrix, can be effectively treated with topical ciclopirox lacquer.

Atopic Dermatitis

Dr Eichenfield addressed atopic dermatitis in the pediatric population. Key takeaway messages included:

What is the association between filaggrin and AD? Not all patients have filaggrin mutations and fillagrin mutations vary in AD patients from country to country. However, filaggrin expression decreases with inflammation even in AD patients without filaggrin mutations. When treating these patients, address the barrier, i.e., hydration.   How do we best treat pediatric AD patients? Anti-inflammatory treatment is effective and proper education can help to improve therapeutic outcomes.  It is also important to remember that microbes are not just bacteria, inflammation decreases diversity and increases staph infection; bleach baths and other products can be used as reasonable adjuvant therapy.  Mental health conditions, such as ADHD, are associated comorbidities among AD patients. Family attention and appropriate screening may be necessary.  In conclusion, don’t forget about allergy in AD patients; selective testing for foods may be beneficial.

Inflammatory Disorders

Dr Cordoro discussed inflammatory disorders in pediatric patients and what to do when creams aren’t enough to effectively manage these conditions. Because of the lack of data and treatment guidelines currently available for the pediatric population, managing these disorders with systemic and biologic therapies can be challenging for dermatologists. Different factors can affect and determine the appropriate therapeutic choice.

Practical Pearls for the Use of Systemic Therapy in the Pediatric Population
  • Let explosive –onset psoriasis evolve a bit before committing to systemic therapy
  • When you need speed, choose cyclosporine
  • Oral retinoids are often the best initial choice for sever guttate and pustular psoriasis in children
  • Is there a place for biologic therapy in children with psoriasis? The answer is yes.
  • Remember to assess which is worse: the disease or the treatment. Do not withhold treatment because “nothing is approved for use in children”

Cutaneous Oncology Part 1

Eggert Stockfleth, MD & George Martin, MD

 

Viral Skin Carcinogenesis – Eggert Stockfleth, MD

Dr Stockfleth reviewed the latest data and the role of the human papillomavirus (HPV) in skin cancer.  SCC is prevalent on 80% of sun-exposed areas in cutaneous SCC and the main risk factor is UV radiation (UVA and UVB).  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.

What about cellular networks? Researchers are looking to identify the “guardian genes”.  We have found that 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 which lead to persistence and accumulation of further mutations.  Research is still ongoing regarding vaccination and treatment.

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 have not been completed.

Actinic damage on the chest of women poses a great challenge to the practitioner. Because of permanent depigmentation, 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 a three to four day regimen. To date there are no published studies looking at a longer treatment regimens for this area.  It is important to remember actinic damage is a chronic disease which requires vigilance and therapeutic intervention.

Cutaneous Oncology Part 2

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.

New Drugs in 2013

Ted Rosen, MD & Neal Bhatia, MD

Drs Ted Rosen and Neal Bhatia discussed new drugs and devices in 2013.

Ted Rosen, MD

Modified release prednisone (Rayos) is now on the market. Why would this be a reasonable therapeutic choice? For many inflammatory diseases, the cytokines peak overnight; yet, steroid administration is often done in the morning. This treatment delays the bioavailability for about four hours. The idea is to take this at bedtime so that it releases overnight and; therefore, reduces morning symptoms associated with inflammatory diseases. Rayos is approved for steroid-responsive inflammatory disorders.  It is available in 1, 2 and 5mg doses.  Larger size tablets will be come available soon.

Cellulite is seen in 90 percent of women over the age of 40. Cellulaze Laser was approved in January 2012. It is a side-firing 1440nm wavelength laser that destroys fibrous bands and excessive fat. Dr Rosen feels that it may actually work and there may be a reasonable rationale for its use. However, there is not a lot of published data (n= 10) and it is rather costly ($5,000-$10,000 per treatment). There have also been instances of bruising, swelling, pain, and numbness associated with its use.

Vismodegib, a hedgehog pathway inhibitor, is a novel therapy for basal cell carcinoma (BCC). 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 BCC patients a new option.

Recent FDA Warnings that dermatologists should keep in mind

  • Minoxidil 15%- may cause hypotension
  • Vicrelis and Incivek (PIs for Hep C) Incivek- serious skin reactions (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- may contain mercury
Neal Bhatia, MD

Dermatology has become reliant on botany with regards to some of the newer therapies. These include:

  • Ingenol mebutate for AKs
  • Polypodium leucotomos (Heliocare) is an anti-inflammatory agent with antioxidant effects and an impact on photodamage
  • Sinecatechins (Veregin) for HPV-related dermatoses also has antioxidative effects, antiviral effects, and is immune-stimulatory.  This is probably not an option for AKs; could be used for Molluscum, maybe more so than genital warts.

Photodynamic therapy

What is the appropriate incubation time?  Two hours and maybe even one hour. This is not just treating spots, but also surface areas.

It is important to choose patients wisely and avoid overexposure.

 Atrapro versus Aurstat: Battle of the Hydrogels

  • Microcyn is the active ingredient in Atrapro. This causes stabilization of mast cells and leads to a direct anti-itch effect
  • Hypochlorous acid and sodium hydrochloride are the active ingredients Aurstat Hydrogel; therefore leading to the reduction of itching in mild to moderate atopic dermatitis
  • Both of these products may reduce the need for steroids and antibiotics and that may be where we see their potential utility

Nuvail was recently approved as a product for restoring the health of nails. Polyureaurethane is the active ingredient. Clinical data demonstrated 62% improvement after six months of treatment.

Pigmented Lesions

This session began with a series of interactive case challenges and discussions on the optimal management congenital melanocytic nevi. Our panelists included Drs Hensin Tsao, Ashfaq Marghoob, Keith Flaherty, Whitney High, Ilona Frieden and Ken Tanabe.

Understanding the medical and surgical management of nevi and melanoma is extremely important for the practicing dermatologist.  Nevi are benign tumors composed of nevo-melanocytes and can arrive during fetal development (congenital nevi) or after birth (acquired nevi). The presence of many acquired nevi and the presence of dysplastic nevi, independent of each other, are two of the strongest risk factors for melanoma.

Some of the key takeaway points from the case study presentations are noted below:

  • The transformation of small congenital nevi to melanoma is rare and the vast majority of that risk is after puberty
  • Melanomas tend to arise at the periphery of congenital nevi
  • Family history is associated with an increased risk for melanoma, but not necessarily within the small nevus
  • There is a period of time when most dermatologists would not prefer to perform surgery on children with CMN (18-months to three years)
  • Multiple satellite lesions are associated with an increased risk for neuro-cutaneous melanocytosis (NCM) which is associated with a higher risk for melanoma in the central nervous system.  The number of satellite lesions is more important than their location.
  • Experts now acknowledge that the risk of developing melanoma is dependent on more than just size alone
  • There is little published data for immunotherapy in pediatric populations with melanoma; however, immunotherapy is tolerated children with advanced disease; risk of autoimmune toxicities is there; treatment selection similar to that of young adults
Detection and Management of Melanoma

The goal for the optimal management of nevi is to find early melanoma while avoiding the removal benign nevi. This can be accomplished through periodic screening, dermoscopy, and the use of total body photography and/or digital dermatoscopic monitoring.  If a lesion is found, the best method for biopsy is excisional biopsy.   A broad deep shave biopsy that removes the entire lesion is acceptable.  A punch biopsy may lead to sampling error if used to obtain tissue from larger lesions.  ,

The panel presented several clinical pearls with regards to melanoma:

  • Recognition of melanoma is based on a variety of factors
  • Change in size and change in color are the most significant factors in detection of melanoma
  • Primary prevention of melanoma is UV protection; secondary prevention includes removal of precursor lesions and early melanomas (surveillance)
  • Sentinal lymph node biopsies are of prognostic value only and have not yet been shown to increase survival.
  • Dermatopathology (biopsy, analysis, and report) plays an important role in the management of melanoma
  • Relapse-free survival consistently improved with high-dose interferon
  • Thin 1B melanomas can be aggressive and SLNBx should be considered on a case-by-case basis
  • Knowing if a patient has BRAF mutation (found in 50% of melanomas) can affect therapeutic choice ie selection of a BRAF inhibitor and overall survival rate
  • Ipilimumab has demonstrated improved survival in patients with metastatic melanoma however it can result in life threatening colitis.

Dermatology in Review

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 the top stories in dermatology in 2012-2013.

New Observations
  • Melanoma is the 5th most common cancer in males and the 6th most common cancer in females affecting one in 36 men and one in 55 women. Melanoma incidence and mortality continue to increase, there is a disparity in survival among races (higher level of mortality in African Americans), and women seem to have better survival rates than men.
  • Another hot topic is that of blood-borne viral infections linked to tattooing. 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. Contamination likely occurred before distribution.
  • Sun avoidance is a crucial component of all skin cancer prevention campaigns. Scientists have studied 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 estimates 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.
  • 87% increased risk of melanoma if tanning [beds] are first used before age 35. Sunbeds account for about ten percent of melanomas in women and five percent in men. This is becoming a significant public health problem. Tanning bed use now contributes to about 10% of melanomas. Public health response is more aggressive these days, but we’re not there yet.
  • Murcormycosis is a rare infection caused by molds that are ubiquitous in soil, decaying wood and organic material. Immune incompetent patients are more susceptible. Outbreaks of rare saprophytic infections occur after catastrophes, such as tornadoes, have been reported. Infections need to be considered early so proper treatment with Amphotericin B can be instituted.
New Treatments
  • Most BCCs are removed by surgery or with radiation or topical therapies
  • The small molecule hedgehog pathway inhibitor is effective for metastatic advanced and generalized BCCs. Side effects are pretty significant, recurrences after drug discontinuation, and costs are limiting factors.
  • The emergence of resistance to first line antipediculicides complicates the public health problem of head lice. Ivermectin 0.5% (topical) for the treatment of head lice has a higher success rate versus the control vehicle. It is pediculocidal and ovacidal.  This means that nit combing post treatment is not necessary.
  • Targeted therapy for melanoma (Anti-PD-1 and Anti-PD-L1 antibodies) have demonstrated positive efficacy in tumor reduction and may be less toxic than ipilmumab.
  • The use of Sirolimus (rapamycin) has proven effective in secondary skin cancer in the transplant population.
New Insights
  • Germline and mosaic versions of cancer mutations lead to developmental and harmartomatous conditions. Sequencing these can lead to emerging treatment.
  • The increased use of antibiotics has lead to increased diarrhea. Duodenal infusion of donor feces for recurrent clostridium difficile has demonstrated positive efficacy and data suggest that fecal transfer is superior to vancomycin for recurrent C. difficile.
  • Biologics and small molecules are going to change the way we continue practice medicine.

Rosacea Update

Judy Seraphine, Medical Editor, Maui Derm News

In this presentation, Dr Webster provides an update for the management of patients with rosacea.

There have been a number of theories about rosacea. In the past, clinicians believed that it had to do with blushing but that was never clear. Since then, newer observations have been made trying to explain the cause of rosacea.

Helicobacter pylori and Rosacea

Dermatologists should recognize that rosacea can improve during H. pylori therapy as H. pylori drugs may be active in rosacea independent of effects on the GI tract. It is important to understand that H. pylori is as common in rosacea as it is in normal controls and a blinded study showed no greater effect on the controls for H. pylori therapy. What was found that the therapy used to treat the GI effects of H. pylori, namely doxycycline, also tended to treat the rosacea.

Demodex in Rosacea

It is difficult to say what the role of Demodex is in rosacea. Demodex is present on both normal and rosacea skin, yet elevated demodex counts are seen in rosacea; however, demodex quantification is flawed, prone to error and difficult to do. Demodex is most increased in inflammatory rosacea. Follicles with demodex in normal skin tend to be inflamed. Dr Webster feels that an important study with regards to Demodex is that of it killing Lindane. The results were is ineffective.

B. oleronius in Rosacea

More recently, Dr Frank Powell and his colleagues discovered a Demodex-related bacteria that is more active in rosacea patients. They cultured mites and one mite grew a bacterium that was different from other skin flora, Bacillus oleronius. They found that ruptured activate mononuclear cells [16/23 (73%) rosacea patients versus 5/17 (29%) controls]. Rosacea patients seem to recognize a few antigens in western blots.

Dr Li and colleagues found an even greater reaction between B. oleronius and ocular rosacea. There are problems however, as in the first study only one mite out of 40 contained the bug. In addition to that and more importantly, PCR of many new Demodexs did not reveal the bug.. The cross-reactivity of the bug antigens with other more common bugs hasn’t been investigated. Many patients did not react and some normal patients did.  As of now, this information is on hold.

Etiology of Rosacea

What do we know about the etiology of rosacea? We know that there is excessive vascular reactivity and those who have rosacea tend to be “blushers and flushers.”  We know that the papules and postules, when cultured, are sterile and in some small genetic analyses, the skin does not show bacteria so we know that it is not some sort of infection. Rosacea does respond to anti-inflammatory drugs.  It is becoming clearer and clearer that the nerves are involved in skin “things” that we don’t quite understand, for example the sebaceous gland.  It is also pretty clear that there is a defect in control of the innate immune system. The inflammatory subunits are present in rosacea skin and if you purify them and inject them into mice, you can make rosacea-like inflammation in the back of the mouse.

Neuro-vascular Factors in Rosacea

The blush reflex to thermal stimuli is more easily triggered in rosacea patients than in normal patients. Also, plasma leakage from the blood vessels may incite inflammation. There are multiple flush/blush mechanisms, these include thermal, hormonal, nicotinamide, and autonomic and they are different among each patient.

Clinical Issues with Rosacea

The tried and true topical agents for the treatment of rosacea include:

  • Metronidazole (FDA approved)
    • 0.75 and 1%
  • Tacrolimus/pimecrolimus
    • “overlap” rosacea (e.g. eczema and rosacea)
  • BP/clindamycin
    • acne/rosacea
  • Azeleic acid (FDA approved)
  • Sodium sulfacetamide/sulfur
  • Tretinoin
    • Sun damage or rosacea? (data unclear)
Oral Flush Blockers

The flushing and the redness is the most difficult to treat.

  • Clonidine
    • Blocks carcinoid and menopause flush
    • No effect in chocolate, red wine, thermal flushing
  • Nadolol
    • No effect in rosacea thermal blush
  • Aspirin
    • Blocks Nicotinic acid flush

(Arch Derm 119:211, 1983; 118:109, 1983; Clin Pharm Ther 31:478, 1982; JAAD 20:202, 1989)

Topical Treatment of Erythema

Metronidazole and azelaic acid may diminish peri-lesional erythema. Oxymetazolone has also been shown to reduce erythema. A phase II study with topical brimonidine, which is an Alpha-2 inhibitor, has shown a clear benefit when reducing erythema.  Its effect has been very dramatic and produces 4-8 hours of reduced erythema.

One of the questions when using vasoconstrictors is “Do you get a rebound?”  In Dr Webster’s experience, he has only seen one rebound that lasted about one day.

Rosacea in Darker Skin

It is important to remember that rosacea is not a disease just of the fair skinned. Symptoms of rosacea in darker skinned patients include irritable skin, stinging, facial warmth, and a history of ocular rosacea. Darker skinned patients can be treated using the standard approaches.

Steroid Rosacea

When patients are applying steroids to their face, it becomes very irritable, There are lots of “homeopathic” products that have vasoconstrictor activity.  Rosacea under the nares is a tip-off.  Dermatologists should be aware that a “gentle withdrawal” does not work to treat this condition. TIMs and minocycline/doxycycline is the standard treatment.

Atopic/Seb Derm-Rosacea Overlap

Overlap is common among these patients and can also be very resistant to traditional rosacea treatment. It is important as dermatologists to remember to avoid irritants when managing these patients. Topical treatment includes tacrolimus/pimecrolimus and ciclopirox. Oral therapy includes the tetracyclines and cyclosporine followed by a topical treatment.

Defective Barrier in Rosacea

The fact that rosacea patients sting and burn is not just because they are blushy, but also because of the microscopic ruptures in their skin barrier, i.e., their stratum corneum is not in tact. There are areas that are extremely “leaky”. Sun damage can also affect the barrier. We also know that irritants can provoke rosacea by provoking inflammation and proteases. Moisturizing improves rosacea TEWL and the associated symptoms.

The graph below demonstrates barrier improvement as rosacea gets better with Metronidazole, which is designed to take the inflammation away.

Summary

What do we know about the pathogenesis and treatment of rosacea? We know that it is very complex. Improving the barrier,  can improve rosacea and it is important to remember that rosacea skin is extremely sensitive, such as that of atopic skin.

 

The Role of HPV in Skin Cancer

Eggert Stockfleth, MD

In this presentation, Dr Stockfleth reviews the latest data and the role of the human papillomavirus (HPV) in skin cancer.

We know that HPV is very stable. The virus is host specific and has a very special DNA from the oncogenic type (E6 and E7). HPV is approximately 45-55 nm in size and its genome size is 8kb.

Currently, there are 200 different types of HPV.

HPV is one of the most frequently transmitted STDs.

HPV Prevention Strategies
  • Reduce duration of infectiousness through treatment
  • Decrease transmission efficiency with consistent condom use
  • Reduce/limit  number of sex partners
  • Quadrivalent HPV vaccine
    • Gardasil® : protects against HPV types 6, 11 (responsible for >90% EGWs) 16, 18 (responsible for 70% cervical cancer)
    • Administered as 3 injections over 6 month period (0,2,6 mo’s)
    • ACIP recommended: females 9-26 yrs of age


Human Immunity

Therapeutic Modalities for External Genital Warts (EGWs)

Various therapeutic modalities exist for the treatment of EGWs. These can be both patient-applied or provider-administered. Patient applied therapies include Imiquimod cream, Podofilox gel/solution, and Sinecatechins ointment. Provider-administered therapy includes Trichloracetic acid, Bichloroacetic acid, Cryotherapy, Podophyllin resin, laser therapy, excision/electrosurgery and interferon.

The Role of Cutaneous HPV in Skin Carcinogenesis

The association between HPV and non-melamona skin cell was first described in patients with epidermodysplasia verruciformis (EV). Cutaneous HPV types include HPV 5, 8, 9, 12, 14, 15, 17, 19-25, and many more. 30-60% of HPV patients develop multiple cutaneous squamous cell carcinomas (SCCs) on sun-exposed sites after 10-30 years. These SCCs harbor the ongenic types of HPV 5 and HPV 8 in more than 90% of cases.

Cutaneous HPV and SCC

SCC is prevalent on 80% of sun-exposed areas in cutaneous SCC and the main risk factor is UV radiation (UVA and UVB).  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.

The p53 gene is involved in almost 75% of all skin cancer. HPV positive cells can block p53; therefore, blocking apoptosis.

Criteria to Define a Causal Role in Disease by Infectious Agents (HPV and Skin Cancer (SCC))

Biology of HPV:

  • Presence of HPV in (pre)cancer cells
  • Expression of viral genes in (pre)cancer cells (E6, E7)
  • Transforming properties (in vitro and in vivo models)

Epidemiology:

  • Relative risk (RR) and Odds Ratio (OR)

HPV 23 was the most prevalent type of virus in immunocompetent and immunosuppressed OTR. The accumulation of the HPV23 E6 protein is caused by HIPK2.  HPV23 E6 interacts with HIPK2 upon UV-induced DNA-damage; therefore, inhibiting HIPK2.p53 complex formation which is the key event in the induction of UV-induced apoptosis.

Cutaneous HPV infected cells may overcome UV-induced apoptosis and be causal in the early onset of skin carcinogenesis.

Conclusions

Current data suggests that cutaneous HPV may play a role in the development of cutaneous SCC.  HPV induced anti-apoptotic effects in UV-damaged cells may lead to persistence and accumulation of further mutations.

Research is still ongoing regarding vaccination and treatment.

Belotero

Derek Jones, MD

In this presentation, Dr Jones reviews the data on Belotero, a novel therapeutic approach to dermal fillers.

CPM Technology

Belotero utilizes CPM Technology. This is the most important difference with regards to Belotero and other dermal fillers. Belotero utilizes CPM Technology, a key differentiator between  Belotero and other hyaluronic acid  dermal fillers. CPM Gel provides further cross-linking steps resulting in a coherent molecule with different density zones, resulting in a coherent molecule with unique density zones.

What does this mean clinically?

While particulate biphasic fillers may lift and enlarge dermal spaces leaving lumps, Belotero integrates into dermal spaces allowing for smooth transition between treated and untreated areas.

This is important clinically as it is hypothesized that using Belotero may reduce the Tyndall effect.

Belotero US Clinical Study

The Primary Phase was a 24 week initial study in comparison to Zyplast. 118 patients were enrolled and the researchers looked at the treatment of nasolabial folds (NLFs). The open-label extension phase (OLEX) was an extension of the evaluation from 24 weeks to 96 weeks that included 85 patients.

This is important as it was an FDA pivotal trial and Dr Jones encourages everyone to review the pivotal trials on Restylane and Juvederm as well to look at similarities and differences among the fillers.

The mean age on these studies was 52.4 and the subjects were predominantly female.

In order to be eligible for this study, patients had to be a two or a three on the Wrinkle Severity Rating Score (WSRS) and to be deemed a “responder” that had to have at least a one-point improvement on this scale that was persistent.

The results demonstrated that both Belotero and Zyplast performed similarly at week 2, but by week 24 the results greatly improved with the use of Belotero.

Regarding the responder analysis, well over 50% of the subjects had at least a one- point change on the WSRS by week 24 and the percentage of subjects maintaining correction from week two to week 24 was greatly superior for Belotero.

Efficacy measured in GAIS was significantly better with Belotero versus Zyplast. In looking at the Physician’s Preference Assessment, 100% of the physicians preferred Belotero to Zyplast with regards to storage and handling, 67% preferred Belotero regarding the comfort and design of the syringe, and 33% preferred Belotero regarding ease of injection “flow”. Overall, 83% of the physicians preferred Belotero to Zyplast.

Adverse events were very similar to what one would expect with a hyaluronic acid such as erythema, bruising, and swelling. The AEs observed were not statistically significant.

The results of the Primary Phase study conclude that Belotero is superior to Zyplast in the correction of the nasolabial fold when evaluated 12 weeks after treatment. More patients preferred Belotero and the treatments were safe and well tolerated.

Belotero Balance (OLEX)

This was an open-label extension trial consisting of treatment with Belotero on both sides at completion of the 24-week visit (visits at week 32, 48, 72, 96, after the last main study treatment). Patients received touch-up treatments with Belotero in both nasolabial folds at week 24 and could receive an optimal touch-up treatment at week 32 to balance an observed unevenness between the two sides. At each of the visits, adverse events and relevant medication use was noted. The subjects could also receive optimal touch-up injections at week 48 or week 72 if the WSRS on that side is two or three. Subjects who did not receive an optimal touch-up injection at weeks 48 or 72 had the option of receiving a touch-up at week 96.

After repeat treatment, the filler starts to hold and dermatologists can see that with the other fillers as well.

The mean GAIS score, as assessed by the treating physician, was between two (improved) and three (much improved) at all timepoints. The GAIS was greater on the side of the face previously injected with HA in the double-blind trial, indicating greater improvement on that side.

During the OLEX study, there was an injection-free phase of 48 weeks in 80.2% of the patients.

At all time points during the open-label extension the treating investigator assessed improvement by both the WSRS and GAIS on both NLF.

In conclusion, Belotero appears to be a safe and well-tolerated, novel dermal filler.

 

 

 

 

 

 

Filler Complications

Joel Cohen, MD

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

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

 

Filler complications include:

  • Superficial injection
  • Vascular compromise
  • Bruising
  • Sensitivity
  • Granuloma
  • Infection (or possible ” biofilm”)
Superficial Injection

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

Approach to Infra-Orbital Hollow injection

This is a much less common injection than the actual tear trough. Dr Cohen uses anesthetic eye drops, a jaeger retractor to protect the globe, and a 32 gauge needle above the level of the muscle. He discusses the importance of the 32 gauge needle as he believes it slows down the injection, or alternatively a 30g cannula can be used as well to try to decrease the incidence of bruising. This is an off-label area of injection and should be done very superficially, but it is very important to avoid superficial nodules—so inject slowly and avoid depositing clumps.

Injecting the Tear Trough

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

Persistent Swelling

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

When injecting the glabella, you would want to see a little bleeding, you absolutely do not want to see it blanche.  Bototulinum toxin immobilization prior to filler (sometimes a week or two prior), may provide a better, more durable response with the filler (Carruthers, Derm Surg, 2003).

Vascular Compromise and Necrosis

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

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

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

Understanding the vessels and patterns is important not only to dermatologists, but to patients and office staff as well. Hyaluronidase with multiple stabs and perhaps into the adjacent artery has been demonstrated as a novel treatment for impending necrosis. It is very important as a healthcare provider to intervene immediately and not “wait and see what happens” in the cases of impending necrosis. A new article in Derm Surg suggests prostaglandin E may be helpful, and many experts also recommend hyperbaric oxygen be considered in some cases as well.

Scars

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

Bruising

Bruising may occur regardless of the injection site. The injection pattern is extremely important and it is critical that dermatologists understand the various approaches to injection. There are some things that patients can do to reduce bruising, such as avoiding non-therapeutic anticoagulant over-the-counter agents.. There are vitamins that can potentially interfere with bleeding; so again, something to keep in mind.  Clinicians need to be realistic with their patients, so they can expect some bruising and/or swelling which may last up to ten days. It is important to communicate this as a reality with patients prior to the procedure.

Cannulas

There are a few cannulas available in the US. Dr Cohen uses cannulas most often in the hands, cheeks, infra-orbital, and décolleté. They seem to decrease bruising along with potentially decreasing pain in some areas, and this has been seen in two preliminary studies (Hexsel and Barrone).

 

Summary

In conclusion, there are a variety of fillers available for patients. It is important that dermatologists understand the anatomy of the face in order to optimize injection results and minimize potential complications.