Medical Dermatology – Page 7

Debunking the Myths of Sunscreen

December 10, 2013

Curtis Cole, PhD

Curtis Cole, PhD, from Johnson & Johnson Consumer Products, is a leading expert on sunscreens and has spent his life’s work on sunscreen technology and formulation. In this presentation, Dr Cole leads a discussion on what every dermatologist needs to know about the current status of sunscreens.

If sunscreens are so good for you, why is there so much noise about it?

Dr Cole mentions the fact that the press and media tend to comment on sunscreen use prior to sunscreen season(s). Many of these comments are read and misinterpreted by consumers and provoke questions around the safety of sunscreens. So what is the truth about sunscreens? Dr Cole states that fundamentally, ultraviolet radiation from sunlight is the major cause of skin cancer. Sunscreens can diminish the amount of ultraviolet radiation entering the skin; therefore, protecting and helping to prevent skin cancer.

Over the last ten years, several papers have been published demonstrating the proof that sunscreen does prevent and reduce skin cancer risk in humans if they are used on a regular basis. (Green A, et al. Lancet. 1999;354:723-729., Heather, L et al. Pigment Cell Melanoma Res. 2010;23:835-837., Adele C, et al. J Clin Oncol. 2011;29:257-263.)

What about estrogenicity and sunscreens?

The SCCNFP is a European “watchdog” group that oversees the safety of UV filters. In a 2001 meeting, the SCCNFP states that “it is of the opinion that the organic UV filters used in cosmetic sunscreen products, allowed in the EU market today, have no estrogenic effects that could potentially affect human health.” There really is no significant estrogenic effect from these UV filters. Studies have shown that estrogenic activity detected in in vitro binding assays did not correlate with in vivo activity. In addition, in vitro binding activity of UV filters are on the order of 1 to 3 million times less potent than estradiol, the standard estrogen compound. Research has also found that UV filters are several hundred times less potent than nutritional sources of estrogen, such as soy or natural supplements.

Does Retinyl Palmitate (RP) in sunscreens increase susceptibility to skin cancer?

The National Toxicology Program (NTP) conducted a nine-year study of RP in albino hairless mouse model. They utilized four concentrations of RP and two of Retinoic Acid and were evaluated against vehicle and untreated controls-solar simulator V source as well as BL and FS lamps. The endpoints were latency period to tumor appearance and tumor yield. Unfortunately this study was flawed; therefore, making the ability to draw a conclusion difficult if not impossible. The study was flawed for several reasons including:

Vehicle utilized 15% isopropyl adipate, a potent penetration enhancer
The top two concentrations of RP were toxic and had to be eliminated from the study
The “enhancing effect” of the vehicle over the untreated but irradiated mice was equivalent to 200% increase in the UV dose
The effect of RP was only evident in one gender of the mouse model and not the other

The results are contrary to human evidence that retinoids are chemoprotective to skin cancers. The NTP is considering redoing this study in order to achieve results that are more accurate.

Nano Materials in Cosmetic Materials

Nano materials are much more efficient in blocking UV and they are much more cosmetically acceptable. There are hundreds of papers that are published looking at the “nano sizes” questioning the penetration of TiO² and ZnO particles. A recent paper by the FDA demonstrated that they could not find penetration from these nano-sized particles. A paper from Sayre R, et al. looked at whether “physical blockers” really act differently than “chemical” UV filters. They found that ZnO and TiO²actually have a semiconductor energy band gap and absorb UV with the same mechanism as “chemical” UV filters. The “transparent” micronized inorganic filters have little scattering effect, if they did, they would be very visible on the skin. (Sayre R, Kollias N, Roberts R. Physical sunscreens. J. Soc. Cosmet Chem; 41:103-109)

What about inorganic (mineral filters)?

Are they better than organic (chemical) filter-based sunscreen? Dr Cole states that there is a much higher level of absorbance among the organic filters because the chemical filters are much more potent. Dr Cole is not saying that the physical filters are not useful, they do; however, have a place for patients who cannot tolerate the organic filters. Also of note, the organic filters are much more aesthetically pleasing.

Do you really have to wait 15-20 minutes for sunscreen protection?

Sunscreen testing protocols mandate drying times of 15-20 minutes before SPF testing can begin; the mandatory labeling reflects this instruction. Actually, UV protection is instantaneous. However, it is important to remember that water resistance may require more drying time. All of the sunscreens that claim water resistance have a type of polymer that is set up to be a barrier against the water. Reapplication (every two hours) of sunscreen is another key component of preventing/reducing sunburns, in fact this is mandatory labeling by the FDA. A paper in 2001 surveyed 57 people on a beach in Texas. Out of these subjects, there were at least 50 people who got sunburned on the beach; those who do not get sunburned re-applied their sunscreen every two hours. (1Wright M, Wright S, Wagner F. Mechanisms of sunscreen failure. J Amer Acad Dermatol. 2001;44:781-784)

Current Misconceptions on High SPF

Dr Cole asks the question of whether SPF 100 is really better than SPF 50. Here are the facts: SPF 100 blocks 99% of damaging UVR and SPF 50 blocks 98% of damaging UVR. Therefore, 1% of SPF 100 is getting through the filter and 2% of SPF 50 is getting through the filter. This means that it is the amount getting through the filter that matters. It’s not so much what you block, it is how much gets through. It would take twice as long to get the damage with SPF 100 than what you get with SPF 50.

Numerous studies have demonstrated that consumers typically under apply sunscreens. Higher SPFs can help compensate for under-application as SPF protection is directly proportional to the amount applied.

How does all of this information affect the products and labeling?

Most sunscreen products were unchanged
- High SPF products (>SPF 50) still allowed
What did change?
- All products now labeled with drug facts box
- Test method for broad spectrum claims final – CW
  - Broad spectrum claims not allowed for products with SPF<15
Statement recognizing use of sunscreens for skin cancer prevention and skin aging is permitted (with an SPF of at least 15 and/or Broad Spectrum)

Broad Spectrum

Broad Spectrum is determined based on “critical wavelength” in vitro absorbance calculation, i.e., wavelength below which 90% of the absorbance is present. 370nm is the “pass/fail” critical wavelength for “Broad Spectrum Protection.” It is important to remember that critical wavelength measures the breadth of protection, yet it does not measure the magnitude; therefore, critical wavelength does not always correlate with UVA protection. The ability to achieve a critical wavelength of 370 becomes more and more difficult as SPFs increase above 30. Dr Cole recommends looking for products with an SPF:UVA-PF ratio of less than 3:1 (which is a requirement for European sunscreen products).

Individuals Particularly Sensitive

Patients/Consumers who are need of the best available protection are those who are highly sensitive (Phototypes I and II, photosensitive conditions and patients on immune suppressive drugs and those who have skin cancers. Others who are also in need of good protection are those who want to limit further photodamge, fine lines, wrinkling and pigmentation.

Why use a high SPF?

Extreme conditions of exposure warrant a higher SPF. These are conditions such as high altitude and those of high reflectivity such as ocean surface, sand and snow. In a controlled consumer trial (split-face, double-blind design) of 56 people at 8500 feet with all day sun exposure demonstrated that more individuals had sunburn using an SPF 50 versus an SPF 85 product. (Rigel et al. 2009. J Am Acad Dermatol;62, I:2:348-349)

Testing of high SPF products has been validated up to SPF 90. A controlled, randomized, multi-center trial was conducted using SPFs 16, 70 and 90 and four test laboratories using multiport and singleport solar stimulators. The results showed that all of the SPF levels could be distinguished from each other in the four labs; yet, no significant differences in SPF values of each product between laboratories. The testing demonstrated the ability of the laboratories to determine high SPF values with accuracy and reproducibility. (Stanfield, Ou-Yang, Chen, Cole, & Appa. 2011. Photodermatology, Photoimmunology & Photomedicine ;27:1,30-35)

Sunscreens and Squamous Cell Carcinoma and Malignant Melanoma

A randomized controlled study in Australia looked at sunscreen use (daily versus discretionary), risk of BCC and SCC (and melanoma). Use of an SPF 16 product and weight of the product brought in was measured every three months. The researchers found a significant reduction in the risk of SCC (RR 0.61; 95% CI 0.46 to 0.81). This suggests that melanoma may be preventable in adults with the regular use of sunscreen. (Green AC, et al. J Clin Oncol. 2011;29(3):257-263.)

Conclusions

Skin protection from damaging sunlight requires a multi-layer defense. Sunscreen should be part of the overall plan for protecting from sun damage. It is important to avoid unnecessary sunlight and you should avoid highest UVB intensities of sunlight (10am-4pm). Skin should be covered with clothing and a hat and high SPF should be used for skin that remains exposed.

Immunodermatology: Part 2: Practical Immunology

November 30, 2013

Andrew Blauvelt, MD, MBA

Practical immunology is important for dermatologists to understand as it relates to a wide variety of pipeline drugs currently under investigation. In Dr Blauvelt’s view, there are three major cell types involved in psoriasis pathogenesis: 1) dendritic cells (upstream/initiating immune responses); 2) T cells (making pro-inflammatory cytokines); and 3) keratinocytes. Targeting IL-23, which is made by dendritic cells, leads to reductions in Th17 cells, since IL-23 is the major survival and growth factor for this type of T cell. Thus, ustekinumab is an indirect T-cell targeting agent. The main cytokine that is being made by the Th17 cells is IL-17A, which leads to activation and growth of keratinocytes. IL-17A is now considered the main effector cytokine of psoriasis. So, by targeting IL-17, downstream function of keratinocytes can be normalized.

A recent study looked at patients on either etanercept or ixekizumab (an anti IL-17A antibody currently under investigation for the treatment of psoriasis). Within two weeks of initiation of therapy, ixekizumab led to the down-modulation of psoriasis-related gene expression to a much greater extent when compared to etanercept. Of the 959 genes up-regulated with psoriasis, 559 were turned off within two weeks of ixekizumab therapy versus 84 with etanercept therapy. This proof-of-concept translational study supports the idea that IL-17A is a key cytokine involved in the pathogenesis of psoriasis.

Pipeline products that specifically block IL-23

These products are unlike ustekinumab in that they do not block IL-12.

MK-3222, an anti-p19 monoclonal antibody (mAb), from Merck
- Phase 3 studies underway
CNTO1959, an anti-p19 mAb, from Janssen
- Phase 2 studies completed
AMG139, an anti-p19 mAb, from Amgen
- Phase 1 studies completed

Pipeline products that block IL-17A function

Secukinumab, a fully human anti-IL-17A mAb, from Novartis
- In Phase 3 studies, phase 2 studies published in 2012 (Br J Dermatol)
Ixekizumab, a humanized anti-IL-17A mAb, from Lilly
- In Phase 3 studies, phase 2 studies published in 2012 (N Engl J Med)
Brodalumab, a fully human anti-IL-17RA receptor mAb, from Amgen
- In Phase 3, phase 2 studies published in 2012 (N Engl J Med)

According to Dr. Blauvelt, all three of the IL-17 blockers look incredibly good from published results and the safety signals, thus far, also look good. If Phase 3 studies confirm these initial results, clinicians will soon have a variety of new promising agents to treat psoriasis patients.

Acquired T-cell Immunity

Regarding the normal function of Th17 cells, individuals who have impaired Th17 responses develop chronic mucocutaneous infections, especially with Candida albicans and Staphylococcus aureus (e.g., Job’s syndrome); these patients also do not develop psoriasis. Normal Th17 responses lead to healing of acute infections with these organisms and no psoriasis (e.g., healthy individuals). Exaggerated Th17 responses lead to healing of acute infections, but eventual development of psoriasis. Of importance, the IL-23/Th17 pathway seems to be less important to systemic immunity when compared to skin and mucosal immunity.

Interestingly, there is also emerging literature regarding the role of IL-17A in the pathogenesis of atherosclerosis. This may mean that targeting of IL-17A may not only treat psoriasis, but also improve atherosclerosis. This, in turn, may decrease the risk of cardiovascular disease associated with psoriasis.

Looking into the Future

As dermatologists, it is important to consider whether drugs that inhibit IL-23 or IL-17 cause or worsen skin or mucosal infections, such as those caused by S. aureus and Candida. Based upon the normal function of this immune pathway, it is unlikely that these drugs will cause or worsen systemic infections. Lastly, it remains to be determined whether they will impact systemic anti-inflammatory activity, including atherosclerosis. Obviously, this latter point will be very important when choosing the proper therapy for patients with moderate-to-severe psoriasis.

Immunodermatology: Part 1

November 30, 2013

Andrew Blauvelt, MD, MBA

Immunodermatology is an important content area for dermatologists to consider when managing patients with psoriasis. The genetics of psoriasis has been an exciting and complex area of research over the last few years, especially in terms of how genetics relate to the immunology of psoriasis. A recent paper highlighted how psoriasis genetics and pathogenesis are much more complicated than was formerly believed. Previously, there were 26 identified genetic susceptibility loci associated with psoriasis risk, and now there have been an additional 15 loci identified. Dr. Blauvelt, when discussing psoriasis with his patients, describes it as a complex polygenic disease; yet, according to Dr. Blauvelt, up to 60% of psoriasis patients will have no other family members with the disease. According to the paper, investigators are “just scratching the surface” and these 41 genetic signals account for approximately 22 percent of estimated psoriasis heritability and further genetic studies, including fine-mapping studies and searches for uncommon susceptibility variants, are in order (Tsoi LC, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44(12):1341-1348).

It is also important to consider the overlap between psoriasis genes and susceptibility genes identified for other autoimmune diseases, such as Crohn’s disease, ulcerative colitis, celiac disease, ankylosing spondylitis, rheumatoid arthritis, systemic lupus, multiple sclerosis, and types 1 and 2 diabetes. All of these diseases are polygenic (numerous genes are contributing to the susceptibility), which is a common theme of many common diseases. Of particular interest is the fact that 11 out of 41 susceptibility genes overlap between psoriasis and Crohn’s disease; in fact, six of the 11 genes are related to the IL-23/Th17 cell signaling pathway, suggesting that Crohn’s disease may respond to IL-23/Th17 blockade.

Psoriasis genes fall into five major functional categories and are either related to the innate or acquired immune system. These categories include genes linked with IL-23/Th17 cell activation (acquired); antigen presentation (acquired); type 1 interferon induction (innate); NF-kB signaling (innate); and skin barrier function (innate). Genes that are psoriasis-specific, i.e., no other disease associations, are mostly associated with innate immunity.

Examples

IL-36

The genetic basis for generalized pustular psoriasis has been identified. Mutations occur in the gene that encodes for the IL-36 receptor antagonist. This is an example of classic Mendelian inheritance, in that patients who have mutations in this gene develop disease; if they do not have defects, then they do not have the disease. Therapeutically, there is no IL-36 antagonist drug yet, however, this may be developed in the future for patients with generalized pustular psoriasis. IL-36 normally stimulates keratinocytes to produce IL- 8, which is a major neutrophil chemotactic factor. IL-36 will drive neutrophils into the skin, and patients who have this defect in their IL-36 antagonist will have uncontrolled levels of IL-36, leading to elevations in other more downstream pro-inflammatory cytokines (TNF, IL-8, IL-6, IL-1).

CARD14

CARD14 is another example of Mendelian inheritance, being that patients who have critical mutations in this gene develop chronic plaque psoriasis. On chromosome 17, a mutation in Card14 (G to A) at position 349 was seen in certain familial cases of psoriasis. CARD14 mutation is involved in the innate immune system. Dysfunction in this gene leads to increased NF-kB activity; this, in turn, leads to increased pro-inflammatory cytokine production by keratinocytes.

Numerous other CARD14 variations are associated with non-familial cases of psoriasis as well. These variations however, are not Mendelian. The genetic variations translate into increased NF-kB activity in keratinocytes and increased risk to develop psoriasis.

IL23R

Dr. Blauvelt notes that this gene is very clinically relevant as it relates to the mechanism of action of ustekinumab. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. If patients don’t have fully functional IL-23 receptor, then IL-23 does not function well as a stimulator of Th17 cells; thus, this gene defect protects against psoriasis development. This is a genetic “hit” to the system, whereas ustekinumab would be a pharmacologic “hit” to the system.

Other genes associated with the IL-23/Th17 pathway include the p19 subunit and the p40 subunit of IL-23 itself.

Summary

There is a tremendous amount of new information regarding genes and psoriasis. Psoriasis pathogenesis represents a complex interplay between innate (how the skin initially reacts) and acquired immunity (mostly related to the IL-23/Th17 pathway). There is certainly a lot more detailed research to come in this area. Regarding translating this information to the bedside, the hope is that genetic profiling will help clinicians predict severity and course of disease as well as to help determine the response to specific therapeutic agents.

Small Molecules for Psoriasis: A New Frontier?

November 27, 2013

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, i.e., a pill 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 the dermatology practice?

Methotrexate (MTX) is the small molecule standard and, for the most part, well-tolerated. Most countries require the use of MTX before trying a more expensive medication. Unfortunately, some of the first studies for MTX were conducted poorly. Overall, you 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 III studies, apremilast (30 mg BID) has achieved a PASI 75 achievement rate of 33%. The majority of adverse events (AEs) were not serious. The phase III results (ESTEEM I and II) demonstrate greater improvements from baseline Dermatology Quality of Life Index versus placebo and a greater proportion of patients reported improvements in the MCID versus placebo. Apremilast seems to be well tolerated in patients with moderate to severe psoriasis, with mild and infrequent gastrointestinal side effects (nausea and diarrhea).

The JAK/STAT Pathway

Tofacitinib, a novel, oral JAK inhibitor recently approved for the treatment of rheumatoid arthritis, is 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 achievement rate 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 safety 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.

In conclusion, you can see that small molecules are again being developed for systemic psoriasis therapy. While they have exciting mechanisms of action, it remains to be seen if they will be superior to methotrexate in both efficacy and safety, especially with regards to the immune system. Pricing and prior authorization requirements will be critical when it comes to treating patients.

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 3

July 11, 2013

High Risk Squamous Cell Carcinoma

Marc Brown, MD

In this presentation, Dr Brown discusses high risk squamous cell carcinomas. Dr Brown comments that this is the tumor than worries him more than any others.

Introduction

Squamous cell carcinoma (SCC) is the second most common type of cancer and more than 250,000 new cases are reported every year. The estimated lifetime risk is between 10 to 15 percent. The incidence of SCC increases dramatically with age and in older patients (80+), there are more skin cancer deaths from SCC than melanoma. The ratio of SCC is 2:1 in males versus females.

Risk Factors

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 metastasis.

Dr Brown feels that the size and the depth of the tumor are probably the two biggest risk factors. There is evidence that any tumor greater than 2 cm in size if it is an invasive SCC increases the risk for both recurrence and metastatic disease. Depth is also very important. Literature suggests that tumors in the 4-6mm, Clark IV-V, or a deep subQ/muscle depth of invasion would be considered to be a high risk squamous cell cancer.

Regarding location, areas of high risk include the ear, lip, and genitalia.

Histology is extremely important. Risk factors include:

Perineural invasion
Poorly differentiated
Acantholytic, adenoid squamous
Desmoplastic

Clinical features of high risk SCC include rapid growth, pain, paresthesias, and cranial nerve involvement. Any of these clinical features should raise a red flag.

Immunosuppression is another important risk factor for SCC. These consist of:

Organ transplant recipients
HIV
Cancer: CLL
Immunosuppressive drugs

Mortality from SCC

A 2005 publication from Clayman et al conducted a prospective analysis of 210 patients for a median of 22 months. The disease specific survival was 85%. The significant risk factors included recurrent SCC, tumor size greater than 4 cm, tumor depth greater than 7mm, subQ invasion and perineural invasion. The patients with no risk factors have 100 percent survival.

A similar article published in the Lancet looked at 615 patients over 12 years. 26 patients (4%) developed metastatic disease. Patients with tumors less than 2 mm in size did not develop metastatic disease. 16 percent of the patients with tumors greater than 6mm in size did develop metastatic cancer. Other prognostic factors included immunosuppression, tumor in the ear and an increased horizontal size.

National Comprehensive Cancer Network (NCCN) Guidelines

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

Treatment of SCC and Metastatic Cancer

High risk SCC accounts for approximately 2500 deaths per year. When clinically detectable nodal metastatic disease has occurred, the prognosis is poor ( 5 year survival less than 30%).

Treatment for these patients can consist of:

“Watchful waiting”
Adjuvant radiation
ELND
Role of sentinel role biopsy in high risk SCC

SCC in Organ Transplant Patients

In the United States, there are approximately 28,000 transplants per year. There are over 110,000 people waiting for transplants and over 170,000 people living with an organ transplant.

What does this mean for dermatologists? This is an area to which we should pay particular attention. Because of the extended long-term survival of organ transplant recipients, dermatologists will be caring for them. Of importance, 70 percent of organ transplant recipients will eventually develop skin cancer and five to seven percent will die of their skin cancers.

Pipeline Psoriatic Arthritis Therapies that Have Efficacy in Psoriasis

July 11, 2013

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 on therapeutic response as heavier patients experience a lower response in therapy. Obesity seems to be very proinflammatory 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
  - The skin response was significantly better than placebo, but not robust (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 (CZP) (RAPID-PsA) was presented at ACR and rapid improvements in the signs and symptoms of PsA, as well as skin manifestations and nail disease of psoriasis, were observed among both CZP doses (200mg q2W/400 mg q2W). Similar ACR response rates with CZP were also seen in patients with and without prior anti-TNF exposure.

Final Thoughts

Obesity is a major issue in PsA patients and encouraging patients to lose weight is important to therapeutic response
The biosimilar (CT-P13) will be coming soon and it seems to demonstrate similar efficacy, safety, and a PK similar to that of infliximab

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