New Drugs 2013: Part 2

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.

 newDrugs2013_fig02

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).

 newDrugs2013_fig03

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 3: New Insights

Hensin Tsao, MD, PhD

 

Mosaics

In the world of dermatology, we are filled with hamartomatous “overgrowth” syndromes. Many, however, are de novo so the genetic mechanism is unclear. Often times, segments or large quadrants of the body are affected clinically suggesting somatic mosaicism.

Two studies in 2012, that complimented some earlier studies, looked at somatic mosaic mutations of these various overgrowth syndromes. In the first study, megacephaly was a feature in all three cases. Patients may have nevus flammeus. The blood/saliva from all patients was subjected to total exome resequencing, which is a technology that is really hitting medicine right now. In effect, total exome resequencing is looking at all of the coding sequence of one’s genome (exome) and in doing so, trying to find the mutation that may be responsible for the phenotype that you see. In the first study, megacephaly was a feature in all three cases. Patients may have nevus flammeus.

The three genes that were found were the AKT3, PIK3R2, and PIK3CA.

Clinical Pearls
  • Germline and mosaic versions of cancer mutations lead to developmental and hamartomatous conditions
  • As sequencing technologies improve, the mechanism of new syndromes will emerge
  • Interesting that these patients may not be more susceptible to cancer overall
 Looking Ahead
  • Between biologics and small molecule inhibitors, we are in a new therapeutic renaissance
    • The mechanism-to-medicine bridge is finally open
  • NextGen sequencing will help define rare hereditary and mosaic genodermatoses
  • Health care economics, not science, is the wild card

 

Dermatology Year in Review Part 2: New Treatments

Hensin Tsao, MD, PhD

 

Dermatologists should remember that most basal cell carcinomas (BCCs) are removed by surgery or with radiation or topical therapies. This past year there has been much more data on hedgehog signaling, which is involved in most BCCs.

Hedgehog Pathway

Vismodegib, which targets the hedgehog pathway, has been studied in BCCs. Of note, the hedgehog pathway is also being studied in other cancers, including pancreatic and brain cancer.

Sekulic, et al. published a study in the New England Journal of Medicine looking at the efficacy and safety of Vismodegib in advanced basal-cell carcinoma looking at 33 patients with metastatic basal-cell carcinoma and 63 patients with locally advanced basal-cell carcinoma, the latter of which is more prevalent in the dermatology setting. The primary endpoint of the study was independent review by an outside dermatologist. The study concluded that Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma.

The most commonly reported adverse events (AEs) were muscle spasms, alopecia, and dysgeusia. Other AEs included decrease in weight, fatigue, nausea, decrease in appetite, and diarrhea.

Tang, et al. studied the results of inhibiting the hedgehog pathway in patients with basal-cell nevus syndrome. (New England Journal of Medicine) There were 41 patients in the study; 26 on Vismodegib vs 15 on placebo. The study looked at cessation of new BCC development while on Vismodegib and the decrease in the diameter of existing lesions while on Vismodegib.

The data from this study demonstrate that one can see no new BCCs form while on Vismodegib and a significant decrease in the diameter of existing lesions while on drug. (Of note, there was a significant attrition of use because of the side effects.) Also of importance is the fact that GLI1 levels diminished on patients taking Vismodegib; therefore, indicating that the drug is hitting its target.

Clinical Pearls
  • This small-molecule hedgehog pathway inhibitor is effective for metastatic, advanced and generalized BCCs
    • Represents nice bench-bedside development of a new cancer agent
  • Side effects, recurrences after drug discontinuation, and cost are limiting factors
    • Although FDA-approved, the role of Vismodegib for common BCC settings is unclear given limitations

 

Head Lice

The emergence of resistance to first line antipediculicides complicates the public health problem of head lice. Dermatologists should remember that second-line treatments, such as lindane and malathion, have limitations related to safety; therefore, newer approaches for the treatment of head lice are needed.

David Pariser and colleagues published a large prospective trial in 2012 in the New England Journal of Medicine looking at topical Ivermectin 0.5% for the treatment of head lice. The study found that Ivermectin has a higher success rate versus the control vehicle.

The side effects for Ivermectin were rather tolerable. AEs included pruritus, excoriation, and erythema.

Clinical Pearls
  • Ivermectin targets glutamate channels whereas permethrin targets sodium channels
  • Topical ivermectin achieved a success rate of >90% with single application
    • Similar to oral ivermectin
  • Nit combing not necessary with ivermectin as opposed to permethrin
  • Nice option for permethrin-resistant louse or even as first line
 Targeted Therapy for Melanoma

Although molecular control of melanoma through targeted therapies has shown tremendous success, relapse is still the general rule; therefore, long-term remission will require immune participation in order to have recognition at the immune surveillance level. Often times, the tumor evades the immune system by circumventing immune checkpoints; yet, recent advances in the studies of targeted therapy for melanoma (Anti-PD-1 and Anti-PD-L1 antibodies) have demonstrated positive efficacy in tumor reduction.This new area of research is at the level of the tumor itself. These therapies, currently under trial, both have major potential in clinical practice and patient outcomes.

Data from Topalian et al, published in the New England Journal of Medicine show that the objective response rates are less than 30 percent as defined by the RESIST criteria. Many patients experienced a drop-off of greater than 30 percent tumor reduction using anti-PD-1.  The anti-PD-L1 shows similar results, but not to as great as an extent as that of anti-PD-1.

Clinical Pearls
  • Anti-CTLA4, anti-PD-1 and anti-PD-L1 represents the triumvirate of immune checkpoint therapies
    • Precise molecule and formulation may be important
    • Tremelimumab (another anti-CTLA4 antibody) did not show any significant survival benefit
  • Anti-PD-1 and anti-PD-L1 treatments appear to be less toxic than ipilimumab
  • Combination molecular therapies for acute control and checkpoint therapies for long-term control may be the wave of the future

 

Overcoming Rejection and Cancer

A small study in the New England Journal of Medicine looked at the role Sirolimus (rapamycin) in secondary skin cancer prevention in the transplant population. Rapamycin, which targets the mTOR pathway, blocks the transduction pathway. This action not only prevents the rejection, but can also prevent SCC from developing.

Patients in the study were randomized to either Sirolimus or cyclosporine, tacrolimus. All patients had at least one prior SCC and were stratified by the number of prior SCCs. Overall there was a significant improvement in the probability of survival-free with Sirolimus compared to the calcineurin inhibitor controls. However, when the data is broken down, one can see that the majority of this effect occurred in the sub-population, i.e., patients with only one prior SCC.

Clinical Pearls
  • Sirolimus is an effective suppressor of transplant rejection and has the added benefit of suppressing development of SCCs
  • The medicine’s positive effects must be balanced against a large number of adverse effects
  • It is less effective in patients who have already had more than one SCC
  • This is not the final word in prevention of skin cancer in transplant recipients

Psoriasis Update: Part 3

Comorbidities and Cardiovascular Status of Psoriasis Patients

Craig Leonardi, MD

In this final session of the psoriasis discussion, Dr Leonardi discussed co-morbidities and the cardiovascular status of patients with psoriasis.

Metabolic Syndrome and Psoriasis

Psoriasis patients are at an increased risk for the metabolic syndrome. There are meta-analyses that have been performed that have shown that these patients have an increased risk for type 2 diabetes, hyperlipidemia, hypertension, and obesity.

Myocardial Infarction (MI) in Patients with Psoriasis

Joel Gelfand and colleagues conducted a cohort study of 130,976 to determine the risk of MI in psoriasis patients. The results showed that patients with severe psoriasis had a marked increase of MI as compared to those patients with mild disease.

Why do psoriasis patients have increased cardiovascular risks?
  • The use of dyslipidemic therapies, such as corticosteroids, acitretin, and cyclosporine
  • The increased prevalence of associated and/or independent risk factors: smoking, obesity, hypertension, and alcohol misuse
  • Uncontrolled inflammation leading to endothelial dysfunction and dyslipidemia
Does the treatment of a chronic inflammatory disease reduce cardiovascular risk?

A retrospective cohort study demonstrated that the use of methotrexate reduces the incidence of cardiovascular disease in patients with psoriasis. It is also shown that treatment with TNF blockers decreases the mortality risk in patients with rheumatoid arthritis. In psoriasis, TNF-inhibitor treated patients had a 48 percent reduction of MI risk.

What about CV risk in the setting of IL 12/23 inhibition?

Briakinumab’s Phase III demonstrated an increased number of CV events ( 5 compared to 0 in placebo) and MACE signals were also seen in the ustekinumab phase III trial as well.

Association between biologic therapies for chronic plaque psoriasis and cardiovascular events- a meta-analysis

This study looked at 19 high quality studies. In the TNF studies, only two MACE events were reported (one in treated/one in untreated). In the 12/23 inhibitors, there were 10 events compared to 1 in placebo. Statistics show that the TNF antagonists are not associated with MACE.

In the JAMA article that was published, the conclusions (above) had to be tempered. Tzellos et al re-looked at the data and published a re-analysis of the data using different statistical modeling (they used the PETO method), they found no increased risk of MACE events.

Risk of MACE in IL 12/23 Psoriasis Trials
  • Background rate of MACE 0.0012/pt-yr, which was based on the aggregated rate in the placebo group for all 22 studies.
  • Rate in the IL-12/23 studies was 0.012 (10 times the background rate)
What are some of the next steps that need to be taken?
  1. Pay attention to the issue
  2. Emerging therapies-need to wait for phase III data (blocking 12/23 downstream)
  3. Pay attention to Amgen’s development efforts on brodalumab in which brodalumab and ustekinumab are involved in a comparator trial
  4. PSOLAR (Janssen registry) may provide data
Final Comments

American Academy of Dermatology Guidelines Recommends Monitoring; Basic CV screening includes:

Laboratory evaluation

  • Fasting comprehensive metabolic panel
  • Fasting lipids
  • Blood pressure
  • Assessment of overweight/obese status

Inquiry

  • Alcohol
  • Smoking
  • Depression
  • Arthritis

Ustekinumab: recommendations for use

  • Consider all options when selecting a biologic
  • Know that psoriasis pts typically have multiple cardiac risk factors
  • Consider starting with low (45mg) dose regardless of patient weight
  • Consider adding ASA 81mg QD
  • Await further analysis (FDA, EMA, Abbott, Janssen, Amgen)
  • Remember that all new drugs are ‘new’

Consider additional specialty care for psoriasis patients

 

Psoriasis Update: Part 2

Pipeline Psoriatic Arthritis Therapies that Have Efficacy in Psoriasis

Arthur Kavanaugh, MD

There are many potential therapies currently under development for the treatment of psoriatic arthritis (PsA) and appear to fall under two categories: biologic agents and oral agents (kinase/enzyme inhibitors).

Th Cell Development

Th17 cells are elevated in PsA patients. One of the exciting areas of research now is that of additional subsets of Th cells. This is leading to the development of new products in the pipeline for inflammatory diseases such as PsA.

Ustekinumab in PsA

This data was just presented a few months ago at the American College of Rheumatology looking at ACR scores and PASI scores both of which demonstrated improved response versus placebo.  It is important to keep in mind the effect of weight therapeutic response as heavier patients experience a lower response in therapy. Obesity seems to be very pro-inflammatory and it effects how people are responding to their current therapies.

What do we do with patients who have been on TNF inhibitors already and are not responding?

This group of patients is tough and demonstrates the need for more research.

Emerging Molecules Under Development for Psoriatic Arthritis
  • Secukinumab (IL-17a receptor)
  • Abatacept- (T cell inhibitor)-in PsA, you don’t see a great response, particularly in those who have been previously exposed to a TNF inhibitor
  • Tofacitinib-quite effective and lots of data for the RA patients; Safety issues are of concern
  • Apremilast-physicians want patients to do the best that they can on the drug; there are rather respectable results with apremilast; skin response was significantly better (about 20% at PASI 75); few discontinuations due to mild AEs (laboratory parameters appeared rather normally. Lab tests probably won’t have to be done as a part of reevaluation)
CZP in PsA

Data on certolizumab was presented at ACR and it appears to work well in PsA patients who have previously been on a TNF inhibitor.

Final Thoughts
  • Obesity is a major issue in PsA patients and encouraging patients to lose weight is important to therapeutic response
  • Biosimilars (CT-P13) will be coming soon and seem to demonstrate similar efficacy, safety, and PK similar to infliximab

 

Psoriasis Update: Part 1

Emerging Therapies

Craig Leonardi, MD

Dr Leonardi began this session with an update on what’s new in the first quarter of 2013 with regards to biologic therapy. So, where have we been? Our first set of drugs was T-cell inhibitors. 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 (PML) and was taken off the market in 2009.  Our attention then drifted over to cytokines and cytokine inhibitors for the treatment of chronic inflammation. Our 2nd generation biologics are what Dr Leonardi characterizes as the TNF-alpha inhibitors.

Etanercept, in its usually approved dose, achieves a 45-50% PASI 75 response and you can get even more improvement with the double dose. Infliximab, three infusions in the first six weeks, will carry patients up to about 82% PASI 75, and then you will see a slow loss of response over time; however, still about 65% PASI 75 responders over the long term. Adalimumab achieves a 71% PASI 75 at week 16.

Third generation drugs include ustekinumab and briakinumab (withdrawn). 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 over 80% as compared to placebo. Ustekinumab also has a nice, durable effect.

What about breakthrough early on with ustekinumab? It’s very common to see patients who have some return of disease, but just encourage patients to continue and hold on to see the positive effects.

Ustekinumab Safety Data

The 5 year safety data show that over time, adverse events on ustekinumab such 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 safety signal monitoring study like this, patients are coming out of the trial because they either are not responding or are not tolerating the drug well.

New Development Efforts

There are several new drugs currently in development of the treatment of psoriasis. These therapies target IL-12, IL-23, 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 score, 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 is  difficult to explain as the studies are rather disjointed, in that, as a dermatologist, you have to look past the published data. The higher dose of secukinumab (150mg) was selected for the phase III trials because of its PASI response of approximately 81%. There were no serious adverse events with secukinumab.

Conclusions
  • We have seen an explosion of biologic drugs that are mostly targeting the 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 exist for therapy
  • Assess benefit/risk ratios when deciding on appropriate treatment strategies

Small Molecules For Psoriasis

Kenneth Gordon, MD

Small molecules were the mainstay for systemic psoriasis therapy for about forty years. Many patients would say that they prefer small molecules to a shot and, in fact, sometimes physicians feel more comfortable with a pill as well. In the last decade; however, all attention with regards to the treatment of psoriasis has been given to the biologics.

How will these small molecules impact our practice?

Methotrexate (MTX) is the small molecule standard and, for the most part, well tolerated. Unfortunately, some of the first studies for MTX were conducted poorly. Overall, we can expect to achieve a PASI 75 of about 40 percent with relatively aggressive MTX dosing when compared to biologics.

Apremilast

Apremilast, an inhibitor of PDE4, is currently under development for the treatment of psoriasis. In Phase II studies, apremilast (30 mg  PO BID) has achieved a PASI 75 score of about 41 percent. More than 96 percent of adverse events (AEs) were not serious. The early phase III results have not yet been released, yet a recent press release said that the studies met their clinical endpoints. Overall, apremilast seems to be well tolerated, but we don’t have the results to date.

The JAK/STAT Pathway

Tofacitinib is a novel, oral JAK inhibitor currently being investigated as a treatment for psoriasis among other indications. Although tofacitinib is a small molecule that binds to a specific area, it may have a wide range of effects; therefore, targeting various phases of the inflammatory process.

The phase II data on tofacitinib (15mg BID and 5 mg BID) demonstrate a PASI 75 response of 67 percent and 40 percent at week twelve, respectively; therefore, showing that this could be quite effective for the management of psoriasis. The issue that we have with this therapy is the overall tolerance of this medication.

When looking at some of the data that we have in rheumatoid arthritis, we see changes in baseline in hemoglobin and also lymphocyte changes. An FDA briefing document states that as the dose of tofacitinib increases, as does the risk of malignancies, this also seems to be true for lymphoma and infection. While this medication has a broader immunosuppressive effect, there may be more issues with side effects and that is something, as dermatologists, that needs to be considered.

Conclusions
  • Small molecules are again being developed for systemic psoriasis therapy
  • While they have exciting mechanisms of action, it remains to be seen if efficacy will be superior to methotrexate
  • Small molecules, since they work on multiple areas of the immune system, can have a very significant effect on the immune system

 

 

Pediatric Acne

Lawrence Eichenfield, MD

Lots of new studies have been conducted with regards to pediatric acne along with some updates to The American Acne and Rosacea Society’s Pediatric Guidelines, which have also been recently endorsed by The American Academy of Pediatrics.

For dermatologists, mid-childhood (age 1 – 7) acne is most worrisome. It can be associated with premature adrenarche, Cushings Syndrome, CAH, gonadal/adrenal tumors, and precocious puberty. 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. Dermatologists should also consider a referral to an endocrinologist.

Pre-adolescent (7 ≤ 12 years) acne is common and may precede other signs of pubertal maturation. A complete work-up beyond history and physical is generally unnecessary unless there are signs of androgen excess, polycystic ovarian syndrome, or other systemic abnormalities

How should we manage preadolescent acne?

It’s important to remember that comedones are often early common on the forehead and mid-face and the truncal area is much less common. This may precede other signs of puberty. For the most part, it correlates with sebum output and sebaceous follicle numbers. P. acnes colonization is a key thing to keep in mind. **The prevalence of severity of acne of acne correlates with advanced pubertal maturation.

Acne Guidelines: Recommendations and Highlights

Acne Categorization by Age

  • Acne in neonates- 0-6 wk
  • Infantile – 0-1
  • mid-childhood 1-7
  • preadolescent 7-12
  • adolescent 12-19

 

Initial Therapy: recommendations regarding initial therapy

OTC products such as benzoyl peroxide as a single agent, topical retinoids, or combinations of topical retinoids, antibiotics, and benzoyl peroxide as individual agents or fixed-dose combinations

Topical retinoids (tretinoin, adapalene, tazarotene) 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 age

Topical Antibiotics

  • Topical antibiotics (clindamycin, erythromycin) are not recommended as monotherapy
  • If topical antibiotic treatment is to be prolonged for more than a few weeks, topical benzoyl peroxide should be added, or utilized in combination products

Oral Antibiotics

  • Oral antibiotics are appropriate for moderate to severe inflammatory acne at any age
  • Second generation tetracyclines (doxycycline, minocycline) are sometimes preferred to tetracycline because of ease of use, fewer problems with absorption, and less frequent dosing

Fixed Dose Combination Treatment

  • May be useful in regimens of care for all types and severities of acne

Hormonal Therapy

  • Second-line therapy in regimens of care in pubertal females with moderate to severe acne. Tobacco use and family history of thrombotic events should be assessed.
  • Due to concerns about growth and bone density, many experts recommend withholding OCs for acne unassociated with endocrinologic pathology until one year after onset of menstruation

Isotretinoin


  • Isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents and may be utilized in younger patients
  • Extensive counseling particularly regarding the avoidance of pregnancy, as well as careful monitoring of potential side effects and toxicities, is recommended

What about off-label treatment?

Below is a summary of some recent studies that look at off-label therapy for pediatric acne.

Tretinoin 0.04% micro-gel

  •  8-12 mild to moderate acne
  • Mean 59 lesions (9 inflammatory)
  • 12 weeks: 48% lesion count decrease
  • Tretinoin 0.04% vehicle controlled 8-11 yrs
  • Ada 0.1/BP2.5% vehicle-controlled 9-11 yrs

Retinoids

111 pt 9-11 yr olds, Retin A 0.04% micro db, vehicle controlled study, 12 wks

  • 66% prepubertal; 65 lesions (9.5 inflammatory)
  • 44% Non-inflam lesion count (vs 30%)

285 pt 9-11 yr olds, Ada .1-BP 2.5, db vc 12wks

  • 54 lesions (15 inflammatory)
  • 47% clear/almost clear (vs 15%)
  • App 50% Total lesion count decrease (vs<10%)

Oral Antibiotics

Short-term combination therapy and long-term relapse prevention in the treatment of severe acne vulgaris.

Doxycycline (DCN) and (Adapalene 0.1% – benzoyl peroxide 2.5%) = (A/BPO) or vehicle qd x 12 weeks, then A/BPO vs vehicle

  • 76% lesion count decrease

What about Isotretinoin-induced flares?

  • Appears to be a dose-related phenomenon, so start at a low dose to avoid this problem

What about prevention?

  • Systemic cyclines for anti-inflammatory effects (e.g. Mino or Doxy q day x 2 weeks)
  • Patient monitoring

 

Acne and Rosacea: Part 1

Our panel of experts in the field of Acne and Rosacea presented interesting case studies and new data that may help the practicing dermatologist improve the overall outcomes of patients in their practice.

Isotretinoin Issues

Guy Webster, MD, PhD

What are the reasons that 20% of patients do not respond to isotretinoin?

  • Inadequate dosing
  • Virilization
  • Taken on an empty stomach
  •  Young patient with bad disease

Dr Webster feels that the most common cause of isotretinoin resistance is due to patients taking the drug on an empty stomach. Data exist that demonstrate that high-fat meals enhance the absorption of the drug. A new isotretinoin, 4-oxo-isotretinoin, (brand name Absorica) demonstrated 2 times greater absorption on an empty stomach (83%) that that of the standard isotretinoin in the absence of food.

Adverse Events

Common AEs include dry skin, dry lips, high TGs, acne flare. Uncommon AEs include elevated CK, elevated AST and ALT, dry eyes, decreased night vision, depression and acne fulminans.   Acne fulminans is uncommon yet, devastating. This is most often seen early in treatment in patients with moderate to severe chest acne. To avoid this you can start with low dose, (e.g. 10mg/day or 20 mg/day) and give prednisone 20 mg/day for the first month.

Bowel disease has also been talked about in association with isotretinoin for the last thirty years. Studies found that the bowel disease was as common in the isotretinoin group as in the antibiotic group, yet both groups were higher than placebo. This could be related to the acne itself, not necessarily the medication.

Data shows that twenty-week acne therapy with isotretinoin does not affect bone. Regarding depression, there was identical risk for suicide and depression on isotretinoin as seen in that of patients on antibiotics in a very large well-powered study.

Rosacea

Hillary Baldwin, MD

We know that facial diseases cause a great deal of emotional distress. Rosacea is linked to depression and suicide and an improvement in rosacea is linked to improvement in quality of life (QOL). While teaching camouflaging/make-up techniques takes time, it does result positive effects. Many brands are available and also are accessible and affordable and in reality, minimal training is required.

Why then is it that some patients do not use makeup?

  • 53% don’t know how to use makeup
  • 29% fear it will get worse
  •  9% didn’t feel they needed it

After the use of makeup:

  •  99% made noticeable improvement
  •  99% continued to use it
  • 75% felt that it contributed to relationship with others
  • Overall improvement of QOL

Dr. Baldwin’s take home point….get familiar with a someone who knows how to do makeup and send your patients to them. It will certainly improve their QOL.

Why isotretinoin in rosacea?

It’s efficacy was first noted in 1981. There are numerous doses from 0.1-1.0 mg/kg/day. Isotretinoin improves papules, pustules, ocular disease, halts the progression of developing rhinophymas, and can lead to a reduction in erythema.

Continuous low-dose isotretinoin (10-20mg/day)

This may provide long-term control and is an alternative to antibiotics; however, appropriate monitoring necessary. Patients still have to follow iPLEDGE rules which can be difficult because they have to return monthly.

In a study with 573 patients with moderate PPR or rosacea that compared isotretinoin to doxycycline, the isotretinoin 0.3mg/kg/day dosing was found not to be inferior to doxycycline (100mg) and both were found to be superior to placebo.

Conclusions
  • In severe, refractory or recalcitrant patients, dermatologists should consider the use of isotretinoin
  • Cosmetic camouflage/makeup does work and has shown to improve patient QOL

Interesting Cases

Alan Shalita, MD

In this presentation, Dr Shalita reviewed interesting cases of acne and possible management strategies to overcome these challenging patients.

The Patient with Sandpaper Comedones

This is a rare condition that is often times difficult to treat. Dermatologists can try compounded tretinoin solution (0.05%), which can be very, very irritating but effective and possibly TCA peels, with the right concentration. Laser abrasion may be effective if you have access to a CO2 laser. Another technique that can provide some relief is what Dr Shalita refers to as “vacuum suction.”

What about chin acne?

Chin acne is typically found in young adult women and may involve the mandible and adjacent neck. Chin acne may or may not be hormonal, but frequently improves with the use of a combination of  both oral contraception and spironolactone. Oral antibiotics can also be helpful. Topical therapy is often times too irritating for patients.

Patients with Nodulopustular Acne

Many dermatologists withhold isotretinoin treatment for too long. If this is the case, you may occasionally need I&D. It is recommended to start on low isotretinoin (target: total dose 120-150 mg/kg) and you may need to culture if the patient is not responding.

Primary Irritant Reaction

This is more common in fair skin, but can occur in all skin types. In many cases, it was a common reaction to topical retinoids; however, it can also result from peels and cryotherapy. Dr Shalita finds that topical tretinoin is effective.

Summary
  • Take time with your patients
  • Topical retinoids should be used in all but he most severe forms of acne
  • Benzoyl peroxide reduces or eliminates less sensitive organisms
  • Antibiotics: Minocycline>Doxycycline>Tetracycline- (forget erythromycin)
  • Isotretinoin: Start low; consider adding steroids to avoid acne fulminans
  • Don’t be afraid to use hormonal therapy

Infectious Disease Update: Year in Review

Andrew Blauvelt, MD

Dr Blauvelt presented an update on important information and data on infectious diseases that were published in some of the top tier medical journals in 2012 and their clinical implications for the practicing dermatologist.

 Clinical Pearls
  • Look for Staph. Aureus infection in and around implantable electronic devices-these were associated with hematomas and wound healing; recommended treatment was complete removal of the device and antibiotic therapy
  • Be aware of possible bacterial contamination in antiseptic products in the office; of note, antiseptic products are NOT required to be manufactured under sterile conditions (currently under review by the FDA)
  • Erythema migrans in persons with a history of Lyme Disease most likely represents reinfection and not recurrent disease
  • Tattoos may be infected with mycobacteria contaminating the tattoo ink. Tattoo ink does not have to be manufactured in sterile conditions. M. Chelonae was found recently in a batch of tattoo ink. Diagnose, treat, and report accordingly
  • Travel history is important for a sick patient with cutaneous abscesses.  Meloidiosis, a disease caused by environmental (in soil) gram-negative bacillus Burkholderia pseudomallei, presents with multiple cutaneous abscesses and pneumonia. It has a 40% mortality rate.
What about viruses?
  • Adults born from 1945-1965 should receive one time testing for the hepatitis C virus without prior assessment of HCV risk (recommendation from the CDC)
  • All persons identified with HCV infection should receive brief alcohol screening/intervention as indicated followed by an appropriate referral to a specialist
  • Clinical data and ex vivo experiments that show pre-exposure prophylaxis with anti-HIV drugs can block subsequent infection; however, controversy exists over ethics, practicality, and cost
  • Genital herpes simplex virus 2 (HSV-2) enhances sexual transmission of HIV
  • Antiviral medication for the treatment of HSV-2 using short courses of high-dose acyclovir and valacyclovir (1 gram TID) may decrease outbreaks, but does not prevent  subclinical HSV-2 genital shedding of the virus.  The therapy does decrease shedding by about 50% but the rate of breakthrough shedding was 16-20 episodes/year. Novel therapies need to be developed to block shedding
More Clinical Pearls
  • Live vaccines may be safer in the setting of biologic therapy than previously believed.  In a study of MCR patients receiving biologics, 633 patients were inadvertently vaccinated with the herpes zoster vaccine. None developed varicella or zoster.
  • In addition to previously identified in EVER1 and EVER2 genes, epidemodysplasia verruciformia may be caused by a genetic defect in RHOH which leads to T cell defects
  • Injectable corticosteroid products may be contaminated during the compounding or manufacturing process
  • Natural disasters can lead to unusual medical conditions.  Mucormycosis, caused by infection with ubiquitous molds in soil and decaying wood, resulted in 13 cases of mucormycosis resulting in 5 deaths in storm affected areas. The median number of wounds through which the mold penetrated was 5.
  • Bilateral leg lymphedema, which can lead to elephantiasis verrucosa nostra, is associated with obesity (and not filariasis in non-endemic areas).  The average BME was 51.4.
  • Topical 0.5% Ivermectin lotion is a promising new therapy for head lice. In two large studies, a single application of 0.5% ivermectin applied to dry hair, left for 10 minutes, and then washed off resulted in nearly 75% of patients being louse free at day 15.  Nit combing in not necessary because ivermectin if both pediculocidal and ovacidal.
Aditya Gupta, MD, PhD

Dr Gupta, one of the leading authorities in the world on fungal infections, provided the audience with an update onychomycosis and how dermatologists can improve upon the management of this condition.  Dermatologists should be aware of the prevalence of onychomycosis and this may help practitioners understand why patients may fail certain therapies. There are various therapies available for onychomycosis including oral therapy, topical therapy, and devices.

Oral Therapy

Terbinafine is probably the gold standard for the management of onychomycosis. Dr Gupta and his colleagues studied various terbinafine dose regimens and found that 2 pulses 250mg/day 4 weeks on/4 wks off/4 wks on appeared to have the best outcomes; however, there was not a significant difference between continuous and pulsed regimens.  It is important that dermatologists understand the existing data on the various antifungal medications currently available in order to apply this information into clinical practice.

Topical Therapies

The nail plate is the greatest barrier when treating fungal infections. Currently, ciclopirox is the only topical therapy approved in the United States. However, there are emerging therapies currently under investigation.

Device Therapy

There are lots of questions about laser therapy. Podiatrists seem to use laser therapy quite often; yet, dermatologists continue to raise questions about their effects and how they actually work. Laser therapy poses the same challenges as those of topical therapies. To date, there is only one published trial (n=13) and the study demonstrates an efficacy rate of 51%. More studies are needed to determine if laser treatment is effective.

In conclusion, dermatologists need to recognize the importance of the choice of agent for onychomycosis and identify other important management strategies that may help to improve the outcomes of their patients.

 

 

 

Emerging Technologies in Dermatology

Rox Anderson, MD

In this presentation, Dr Anderson reviewed some of the emerging technologies in the field of dermatology. Topics discussed included:

  • Microscopy
  • Epidermal blister transfer blasting
  • Restoring elastic recoil
  • “Targeting” sebaceous glands

“Optical tools are used quite often in diagnostics in the field of dermatology and the ability to get true microscopic cross-sectional imaging is coming our way.” For example, Optical Coherence Tomography (OCT), an exciting clinical advancement, will soon be hands of dermatologists providing practitioners with the ability to conduct true microscopic tomography of the skin.

How can one practically conduct epidermal blister grafting?  Dr Anderson’s group has been researching a process for replacing radiation-damaged skin with non-damaged epidermis of the same patient. This process has shown to be both cost-effective and timely, in that, significant improvement was seen in six months. This process could potentially be applied to conditions such as vitiligo, radiation injury, field cancerization, wounds, ulcers and other dermatologic disorders.

“One of the problems with aging is that we lose our elastic recoil.” This year, there has been some interesting information on the role of fractional lasers and the loss of elastic dysfunction. Can you artificially restore the elastic of the skin? These processes are in the pipeline and may one day be available.

Whatever benefit we get from sebaceous glands is outweighed by acne. What would happen if we move sebaceous glands? In the 1990s, research thought that most likely, there would be no acne and the process would be analogous to laser hair removal. Could lasers used at a certain wavelength selectively kill sebaceous glands? The answer is yes, if you have access to a laser at 1720 nm.  The histological results are good and perhaps in the future scientists will develop a laser that will be capable of treating acne.