MauiDerm News – Page 27

Botulinum Toxin 2013

January 8, 2014

Joel L. Cohen, MD

In this presentation, Dr Cohen, a leader in aesthetic dermatology, discusses where we are right now in terms of botulinum toxin. Currently, there are three FDA-approved botulinum toxins type A; these are Botox (Allergan), Dysport (Medicis/Galderma), and Xeomin/NT201 (Merz). Neuromodulators that are on the horizon include PurTox, Neuronox, and China ToxThe three approved botulinum type A products are approved for the use of glabellar lines; however, they are used off-label for other aesthetic purposes.

All three products contain a core neurotoxin protein (150 kD BoNT/A), this is where the mechanism of action lies. Botox and Dysport are wrapped in protein, which is part of the neurotoxin complex Xeomin, however, lacks these accessory proteins.All three products have demonstrated efficacy and have established good safety profiles.

Xeomin

Xeomin has both medical and aesthetic studies. In 2005, Benecke and colleagues published a double-blind non-inferiority trial of 463 patients comparing Xeomin to Botox and concluded that Xeomin is at least as effective and safe in treating cervical dystonia as compared to Botox. Of note, one of the criticisms of a non-inferiority trial is that it utilizes two timepoints, and you don’t know where the subsequent timepoint ends.

In 2006, Roggenkamper and colleagues published a double-blind, phase III trial comparing the efficacy and safety of Xeomin with Botox in patients with blepharospasm. No significant differences were found between the formulations and the non-inferiority of Xeomin compared to Botox was concluded.

It is critical to understand the changes and differences in the FDA requirements in the studies for neuromodulators. When Botox was approved, a one-grade improvement was required. With Xeomin, a two-grade improvement was required. This is an important concept to keep in mind when looking at responder rates over various studies.

Two recently published, identical randomized, double-blind, multi-center, placebo-controlled trials looked at 547 patients. 366 patients received 20µ Xeomin and 181 patients received placebo. Success was defined at a two-grade improvement on a four-point scale. The median onset of effect occurred within seven days after injection and the duration effect was typically up to three months. Single and repeat treatment was well-tolerated. The majority of adverse events were mild or moderate with headache being the most common. There was a 0.2 percent incidence of blepharoptosis following a single treatment.

Sattler, et al published a non-inferiority trial comparing Xeomin to Botox in the treatment of glabellar frown lines. The independent rater and patient assessment among both products were very similar at weeks four and 12. Because this was a non-inferiority study with two timepoints, you can miss the “duration of efficacy” and the “waning effect.” The authors concluded that Xeomin is equally as effective as Botox and both preparations were well tolerated.

A small study of 21 patients by Prager and colleagues compared Xeomin to Botox for the treatment of Crow’s feet. Both products demonstrated high efficacy and good tolerability at a dose ratio of 1:1 with no statistically significant differences between the two. Also of note, the high response rates observed after four months suggest a good effectiveness beyond this observation period.

Conversation Ratios

It is important to remember that the three neuromodulators approved for aesthetic use are separate products; therefore, there is no TRUE or EXACT “conversion ratio”. Dr Cohen emphasizes the importance of learning how to use each product differently in clinical practice. The injection techniques are similar; however, there are no direct specific conversion ratios. Regulatory agencies around the world have recognized that these are different products, and there is no interchangeability among botulinum toxin neuromodulators.

Controversies

It is also important to keep in mind that combination same-syringe delivery (e.g. botulinum toxin-A and hyaluronic acid filler ”mixed together”) can be imprecise on many levels from not uniformly mixed to potential unintended spread of one of the agents.

Another big controversy is that of zinc supplementation on botulinum toxin treatments. A publication in 2012 advocated a proprietary zinc formulation to “extend the durability of botulinum toxin” and “make non-responders, responders.” Dr Cohen found that there were HUGE problems with this study. Zinc deficiency does not seem to be an issue with healthy aesthetic patients, and the article assumes that basically everyone is zinc deficient. Another major issue with this study is that the only physician who injected the product has a financial interest in the product, identified all of the patients for the study, and was an active participant in the study design. In summary, the effect of zinc supplemation with a phytase has yet to be clearly elucidated.

Dosing

When looking specifically at dosing, aesthetic physicians have historically used high-dosages in the forehead, which often caused them to look completely “flat”. “It is important to understand the importance of achieving a relaxed and natural look. Over the years, Dr Cohen and many colleagues colleagues have found that they can basically cut the forehead dose in half. This helps in achieving a natural look, softens the musculature and maintains brow shape and positioning, which is very good for patients. There are published consensus statements and recommendations on how much product to use and how best to use it for each of the products available.

Botulinum Toxin has also shown to improve facial wound healing. Dr Cohen has incorporated its use when performing Mohs closure. This leads to less tension in the scar; therefore less scar spread and a better overall aesthetic look through “chemo-immobilizaton” (Mayo 2006, Flynn 2009)– similar to what has been described peri-procedure with peri-ocular resurfacing (Carruthers) and peri-oral resurfacing (Kadunc).

Dueling

There are many attempts in the literature to try to compare the various neuromodulators. This started from an article published in 2008 in the Journal of Cosmetic and Laser Therapy looking at patient satisfaction with different botulinum toxin type A formulations in the treatment of moderate to severe upper facial rhytids. The patients were switched from Botox to Dysport and, by and large, the patients wanted to go back to Botox. Unfortunately, when studies like this are introduced, Dr Cohen comments that there is a tremendous amount of bias. Often time we see “novelty bias.” Patients return after a second injection and they don’t see the “wow” effect, and there could be “recall bias” as well in trying to remember the effect of the first treatment versus subsequent treatments.

Onset and Duration

The original Dysport trials demonstrated that median time to onset ranged from two to four days. This data; however, was not captured in the original Botox trials. A subsequent JDD trial did actually capture the effect of Botox starting to “kick-in” within the first few days as well.

It is imperative that clinicians be critical of study designs when they are comparing these various products. A meta-analysis looked at the Botox duration effect in the treatment of glabellar lines. Overall, the effect was about four months in 50 percent of patients.

Repeat injections in the same area tend to extend the duration of the product. This has been demonstrated in several studies among all three of the approved neuromodulators.

Summary

Overall, we have good safety and efficacy data among these three products demonstrating that people respond and seem to have better self-esteem (Dayan). Data suggest that, overall, patients look and feel better.

Fractionated Laser Technologies: Just the Fracts…

December 28, 2013

Sandy Tsao, MD

In this presentation, Dr Tsao discusses fractional resurfacing and its efficacy in clinical practice. A lot of information has become available to clinicians regarding improving the aging process for their patients. Fractionated resurfacing technologies have been designed to provide benefits for many aspects of aging by taking the best of the ablative and non-ablative technologies. In comparison to other non-ablative technologies, fractional non-ablataive resurfacing demonstrates greater efficacy. It is important to remember that fractional resurfacing is safer for non-facial areas.. It is also safer for darker skin phototypes. , Fractional resurfacing demonstrates a safer side effect profile when compared to traditional ablative devices.. The recovery time is markedly reduced and there are no permanent lines of demarcation to date.

There are a number of fractional technologies available; however, dermatologists should remember that there is not one particular laser that can target all of the concerns regarding photoaging. When you are thinking about these devices, you need to consider what you are actually trying to target. Dr Tsao comments that the ultimate goal in fractional resurfacing , is to create a localized thermal injury. Thermal injury is thought to be the key for tissue repair. Heat-induced inflammation results in immediate collagen shrinkage and tissue contraction and, subsequently, fibroblast stimulation and neocollagenesis. This concept, Dr Tsao mentions, is very similar to the ablative devices; however, the side effects and down time are much less. There is a zone of irreversible thermal damage and its associated inflammation which must heal before re-epithelialization begins. Prolonged inflammation due to infection, hypersensitivity, or extensive thermal damage due to vigorous treatment can result in complications.

How do fractional resurfacing devices work?

As previously mentioned, there are a number of fractional ablative and non-ablative technologies available,. It is important to match treatment depth and treatment parameters with the clinical indication(s), i.e., are you targeting pigment (superficial to mid dermis), mild rhytids (mid reticular dermis), moderate rhytids (deep reticular dermis) or surgical scars, burn scars and acne scars (deep remodeling). This is the real learning curve with these devices…you need to know what you are targeting and whether or not you may need a combination of these therapies to achieve your clinical goals.

Each of the devices has a different way of administering the microthermal zones. These devices include continuous motion scanning and traditional lens array stamp pattern, which can be a little bit harder to administer because of the potential of overlap or skip regions.

Non-Ablative Fractional Resurfacing

Every pulse creates a localized injury or, microthermal zone (MTZ). You are actually creating columnated areas of heat inflammation. The depth and diameter depend on the type of device that you are using, as well as the parameters selected for treatment. The fractional non-ablative devices create the columnated thermal injury while leaving the normal intact skin in between; therefore, retaining viable stem cells in between the microthermal zones of injury. This allows for the skin to repopulate much faster, resulting a limited healing period.

Fractional non-ablative laser treatment results in complete re-epithelialization in 24 hours. In human tissue, you can see clear collagen denaturization from papillary dermis into mid reticular dermis. The healing occurs from viable tissue and the zones of spared tissue which contain clusters of epidermal stem cells and Transit Amplifying (TA) cells. What is unique about the non-ablative technologies is that they leave the epidermis intact. The downtime for most of these technologies is about three days of some redness and swelling. This is a very manageable outcome for most patients.

Dr Tsao also comments that over the past two or three years, we have been very fortunate to have a new fractional non-ablataive device available at 1927 nanometers which matches one of the water absorption peaks in the mid infrared spectrum . This wavelength absorption is stronger than most non-ablative wavelengths and weaker than ablative wavelengths. This device fulfills the role to more selectively target lentigines, pigmentation, actinic keratoses and seborrheic keratoses

Ablative Fractional Resurfacing

These devices work exactly like the non-ablative devices in that they create microthermal zones; however, the big difference is that the epidermis is shed along with a portion of the dermis. This creates more thermal damage, requiring a longer recovery time. Replacement of the skin surface requires about one week. Patients must be aware of the longer downtime with the fractional ablative devices. Ultimately, what you are aiming to achieve is a healthier more youthful epidermis and dermis.

How does this translate clinically?

If a patient does not want surgery or ablative treatment, then fractional non-ablative or ablative resurfacing could be a viable option. It is important to set realistic expectations with your patients as far as achievable outcomes. Non-ablative fractional devices will provide improvement of superficial rhytids and dyspigmentation, but not likely provide significant benefit for deeper rhytides. The fractional non-ablative devices provide marked improvement of atrophic and acne scars. The fractional ablative devices provide greater benefit for moderate to deep rhytides and dyspigmentation, especially perioral rhytids.

Downtime

It makes a tremendous difference to patients if you can have photos available to show them the expected downtime so that they can make a more informed decision regarding their treatment.

Microlaser peel- 7 days of peeling, 2 weeks of pink hue
Fractionated non-ablative
- 1410nm- 1 day mild erythema and edema
- 1550nm- 2-3 days erythema and edema
- 1927nm- 4-5 days erythema and edema and pinpoint crusting; 1 week of pink hue
- 2940nm- 7 days erythema and edema, 2 weeks of pink hue
Fractionated ablative- 1-2 days pinpoint bleeding, 7 days erythema and edema; 4-6 weeks of pink hue
- Ablative-14 days erythema and edema; 2-3 months of pink hue

Clinical Pearls

When treating the eyes, you have to be extremely careful to prevent ocular damage. Less aggressive treatment is necessary to prevent ectropion formation. It is also important to use metal protective eyeshields when treating the eyelids. Proparacaine anesthesia and erythromycin ointment to coat the eyeshields can be used for lens placement. It is also important to use particular caution in patients with prior surgical procedure history, such as a prior facelift or blepharoplasty, as the facial anatomy may be altered .

With regards to darker skin phototypes, less is more (fluence, density, passes). You may want to consider a laser test site. You should also stress the need for strict photoprotection and discuss the increased risk for PIH. , You may consider pre-treatment use of retin-a or hydroquinones. You should also use greater cautionwhen using ablative fractional devices, as the risk of side effects is greater.

Remember that when you apply these treatments to non-facial regions you have to be very cautious as there are not as many pilosebaceous units to assist in re-epithelialization, resulting in an increased risk of scar formation when treating these areas with both fractional non-ablative and fractional ablative devices.

Blasting Away Pigment: Targeting Hair, Tattoos, Brown Spots

December 23, 2013

Michael H. Gold, MD

The tattoo removal market is projected to grow significantly in North America. In 2004, there were 19,900 tattoo removal procedures at an estimated cost of $5.9 million and by 2009 there were 33,900 procedures estimating $14 million demonstrating a 21 percent increase in the market. There are two major market drivers for the procedure, the first being tattoo popularity. A study at Northwestern University published in the JAAD in 2006 reported that 23 percent of people in the United States have at least one tattoo (69,000,000 people). This was a 30.4 percent increase over the 2003 Harris Interactive study that reported that 16 percent of the US population had at least one tattoo. The second market driver is “buyers remorse” coming from “tattoo regret”-driven by changes in life and/or circumstances. “Tattoo regret” ranges from a reported 15 to an estimated 50 percent of tattoo wearers.

There are multiple, low-cost treatment options for tattoo removal. These include:

Cryogenics, i.e., cryotherapy
Acids of various kinds
Topical retinoids
Hyfercation
Continuous Wave Lasers
Bleaching agents
Surgical excision
Abrasives with or without chemicals
Dermabrasion or salabrasion

However, these methodologies come with many complications such as scars, permanent pigmentation changes, residual tattoo pigment, wound infection, ineffective overall treatment, and can be a painful and slow process.

Laser Tattoo Treatment

There are several advantages to laser tattoo treatment. It is a non-invasive procedure with less pain that produces optimal clearing. With laser treatment, there is a lower risk of scarring and reduced hypo-pigmentation. There is also no change in skin texture, minimal post-operative care and the healing usually takes about one to two weeks. However, there are disadvantages to laser treatment. Pain is the number one issue (it hurts a lot more to remove a tattoo than to get one), but topical and injected analgesia can be used in conjunction with the laser. Realistically, it is important to let customers know that as many as 10-15-20 treatments may be required to “satisfactorily” remove a single tattoo (the tattoo will lighten 30-50 percent with each treatment). It is extremely important to set appropriate expectations with you customers and their patients. The treatments can result in hypo-pigmentation, routinely resulting in redness and swelling and punctate bleeding is also a possible (but “normal”) side effect.

As with ANY laser treatment, other more serious side effects are also possible, including–hypo-pigmentation, burns, blisters & scarring.

Pigmented Lesions

The market for pigmented lesion removal is also projected to grow significantly in the coming years. These lesions include epidermal lesions (sun spots, age spots, and melasma) as well as dermal lesions (nevus of Ota/Ito and blue nevi).

Treating Pigmented Lesions with Lasers

Dr Gold comments that both the alexandrite 755 nm lasers and the Nd: YAG 1064 nm lasers are both effective lasers for pigmented lesions. There are several advantages to treating pigmented lesions with lasers, these include the fact that it is a fast procedure; it is a simple treatment technique with minimal discomfort. DCD may or may not be required, depending on the device being used. It usually requires one to four treatments and the lesions darken for five to ten days before they exfoliate. There is improved efficacy with laser treatment because of the thermal effect and the photoacoustical effect.

Several lasers exist for the treatment of both tattoos and pigmented lesions. For pigment, long-pulsed alexandrite lasers are good; Q-Switched lasers are the treatment of choice for tattoos and most pigmented lesions. It is important to remember that tattoos should NOT be treated with IPLs. Recently picosecond lasers have become available which show, in clinical studies, reduces the treatment time for the overall improvement of tattoos.

R20 Tattoo Removal

R20 involves performing three to four laser treatments in one session. The result of the R20 method is 50 to 85 percent clearing in a single session without any additional side effects. Laser Tattoo removal treatments form tiny vapor bubbles in the skin (frosting) that looks like fine white powder. Ordinarily, this frost refracts the laser beam preventing it from penetrating the skin. After 15 to 20 minutes, the frost disappears making it possible to do another treatment or “pass”. Dr Gold states that the R20 Tattoo Removal method simply waits for this to happen and lets us treat clients three to four times in one visit. Combining three to four laser tattoo removal treatments during one office visit lets the laser reach deeper than with a traditional single-pass treatment. One R20 treatment would be sufficient to completely remove an amateur black tattoo or for lightening a tattoo for a new one. For professionally applied black tattoos however, about 50 to 75 percent fading will occur. This is significantly more fading than expected from three to four conventional treatments. Using the R20 method will cut the total time for removal by half or more.

Conclusions

In conclusion, we know that 25 million people in the US have a tattoo. There are 250,000 women being tattooed each year. Approximately 50 percent of people who have a tattoo look to have them either removed or augmented. The average age of procuring a tattoo is eighteen, often leaving the tattoo as a permanent reminder of their poor decision to get one in the first place. A clinical pearl that Dr Gold tells all of his patients is that it costs more money to remove a tattoo and it hurts more to remove a tattoo then it does to get one.

Pediatric Dermatology: Nail Diseases

December 17, 2013

Ilona Frieden, MD

Sheila Friedlander, MD

In this section, Drs Frieden and Friedlander reviewed coxsackie onychomadesis, the treatment of onychomycosis in children and a how to best obtain nail specimens in kids.

Healthcare providers should be aware that onychomadesis is a sequela of HFMD and fairly commonly seen after coxsackie A-6 infection. With onychomadesis, you typically see shedding of the fingernails and toenails within one to two months after HFMD. Onychomadesis can appear in the form of exaggerated Beau’s lines. It is not surprising that this happens with infection, but why can it occur with mild disease? Osterback R et al obtained shed nails from two siblings with onychomadesis who had HFMD eight weeks before the nail shedding. The nail clippings were enterovirus positive by RT-PCR and one case was identified as CVA6. Dr Frieden believes that this may, in fact, be an infection of the nail matrix and not merely a physiological response of stopping nail growth.

Onychomycosis

Fungal nail infections are more common in adults; however, they DO affect children (0.16%). The incidence of fungal nail infections in children may be increasing due to occlusive foot lifestyle. While families want their children to be “perfect”, they are reluctant to put their children on prolonged systemic therapy, and do they want their children to undergo lab studies. It is important to keep in mind that children have thinner nails and; therefore, grow faster.

How do we best approach fungal nail infections in children? A study by Lawry MA, et al. showed that the best approach to diagnosing fungal nail infections is through PAS and culture and the second best approach is PAS.

Clinical Pearl: Dr Frieden comments that one of the best ways to get a diagnosis of onychomycosis in a small child is by using a disposable curette. Kids are not as afraid of this versus a scalpel because this instrument is blunt and looks more like a spoon. This is a great technique for a KOH or culture specimen.

How do we treat children?

Benign neglect (this is certainly still a reasonable approach)
Ciclopirox, amorolfine lacquer, bifonazole-urea
Griseofulvin 20/kg for at least 6 months; don’t exceed 1 gram (compliance can be difficult as well as side effects)
Terbinafine 5mg/kg/d don’t exceed 250mg; FN 6 wks; TN 12 wks (Families can get a month supply for $3-$6)
Fluconazole 6mg/kg/week once a week; FN 12 weeks; TN 26 wks
Itraconazole caps 5mg/kg/d pulse therapy; FN 2 pulses; TN 3 pulses

Dermatologists should know that onychomycosis does not always require systemic treatment for a cure. Dr Friedlander and her colleagues conducted a prospective trial of forty children with non-matrix nail disease. 30 patients (25 male and 15 female with a median age of 9.8) were placed on active topical ciclopirox lacquer and 10 patients on vehicle. The lacquer was applied daily and nails were trimmed weekly for 32 weeks. If the patients had a poor response, they were rolled over to active treatment at week 12. The only known AE was a transient discoloration of the nail.

The graph above shows that 77 percent of these patients had mycologic cure, 71 percent had effective treatment and 34 percent had a complete cure. These numbers are much higher than what we see in adults. These patients were followed over one year and the vast majority of them did not relapse. When asked about quality of life and whether or not the patients would undergo this treatment again, over 90 percent responded “definitely yes” or “probably yes.” (Friedlander SF et al. Ped Dermatology. 2012;Dec28)

This trial was just a a small pilot study, and thus needs to be repeated. Non-lunula nail disease can remit without medication (n =2); and topical therapy appears to work better in young nails than in adult nails. This data suggests that topical therapy may be a reasonable option as first-line therapy for some children with fungal nail disease.

There are new products currently being studied for the treatment of nail disease. Nuvail, for example, is an innovative approach in that it is a poly-urethane vapor permeable substance. It is currently marketed for dystrophic/brittle nails. A small prospective study of Nuvail in 62 patients demonstrated 60 percent improvement in six months and a 62 percent mycologic cure in six months. Stay tuned for more information….

Pediatric Dermatology: Hand-Foot-Mouth and Beyond

December 17, 2013

Ilona Frieden, MD

Sheila Freidlander, MD

Dr Frieden discusses the new manifestations of an old disease. Classic HFMD presents with exanthem (skin) and (enanthem) mouth symptoms. Skin symptoms include grey-white vesicles on the palms and soles and occasionally on the buttocks, diaper area, knees and elbows. Mouth symptoms include vesicles and erosions on anterior oral mucosa and are very painful.

From November of 2010 to February 2011, 63 cases of atypical HFMD were reported to the CDC. 34 cases had vesicle, stool, blood, and/or respiratory samples. 74 percent of these cases were PCR positive for coxsackie A6, whereas in the past in North American most cases were due to coxsackie A16. These patients differ from those with classic HFMD in that there was a wider age range, greater than ten percent of the body surface area was involved, these patients had fevers and a rash that appeared “severe”, and they had findings of “locus minoris resistentiae.”

Mathes E and colleagues published a report on coxsackie exanthems characterizing the 2011 outbreak of the emerging viral type, A6. There were 64 children and 18 and ot 19 were positive for PCR enterovirus. 58 percent of the children had atopic dermatitis, 56 percent had ecema herpeticum-like eruptions which were termed “eczema coxsackium”. Additionally 22 percent had findings of locus minoris, 35 perecent had Gianotti-Crosti-like eruptions and 18 percent had hemorrhagic purpuric or petechial skin lesions. (Mathes E, et al. Pediatrics. 2013;132(1):e149-157.) This virus can also affect adults. An important sequellae is onychomadesis which can develop two to four weeks after infection.

New Ways to Diagnose Viruses

Traditionally, it was difficult and expensive to find out which/whether a specific virus was pathogen. Viral cultures are expensive and the question remained as to what to look for. Acute and convalescent titers were the “gold standard”, but follow-up studies were required so you didn’t receive the answers you were looking for right away. Dr Friedlander comments that we are now lucky enough to have commercially available multiplex PCR diagnostic panels for viruses. These panels are available in some labs or hospitals. They can typically detect influenza A and B, adenovirus, parainfluenza 1-3, respiratory syncytial virus A and B, human metapneomovirus and human rhinovirus. Other panels can detect coronavirus, coxsackie/echo virus, bocavirus, adenoviruses, parainfluenza and seasonal influenzas. This is a positive step as it provides clinicians with the ability to have answers more rapidly than previously.

Pediatric Dermatology: Infantile Hemangiomas

December 17, 2013

Sheila Freidlander, MD

Ilona Frieden, MD

In this presentation, Drs Frieden and Friedlander discuss infantile hemagiomas, coxsackie and beyond, and nail disease.

Infantile Hemangiomas (IH): What We’ve Learned

At USC, Dr Friedlander and her colleagues followed 500 babies in a prospective study looking at the incidence and risk factors for IH. They found that overall 4.5 percent of infants were affected. The risk factors included placental anomalies (35 percent of IH deliveries) and gestational age (extreme prematurity). One of the unexpected findings was that of location (53 percent were located on trunk, only 12 percent on the head and neck), this would make sense with what one would expect as the trunk is a larger body surface area. They also found that 91 percent of the hemangiomas were focal and 23 percent were abortive/telangiectatic. The most important thing that was discovered was that only one of the 34 lesions discovered on the 500 babies needed intervention. This is reassuring information and can help guide clinicians to “worry less” about small truncal lesions: however facial and larger lesions should be evaluated early to determine if intervention would be appropriate. .

IH: Where do they come?

Dr Friedlander comments that the worrisome cases are those where the potential for functional deformity or cosmetic disfigurement exist. There are three major theories that most experts are comfortable with regarding the pathogenesis of IH. The first is placental embolization; supporting evidence for this includes the following: IH share surface characteristics with placental tissue (glut-1, HPL). In addition, placental markers (hCG and hPL) are expressed on endothelium of proliferating, but not involuting IH tissue. Other similarities between placental and IH tissue have been identified through DNA profile clustering analysis.

The second theory concerns a somatic mutation in a gene mediating endothelial cell proliferation (VEGF receptor). VGEF (vascular endothelial growth factor) can be likened to a stimulus package for endothelial cells. Most of the time VEGF will complex with an inhibitory receptor. If there is not enough of the inhibitory receptor (VEGF 1) around, then VEGF will complex with other “more stimulatory type” VEGF receptors and proliferation then results. Angiogenesis is a tightly regulated balance of promoting and inhibitory factors. In the simplified model below, complexing of VEGFR2 with VEGF activates EC proliferation.

The third theory, which is the most popular right now, is that IH may result from a combination of factors, including the presence of an area of localized hypoxia Vascular cells in this area of low oxygen tension produce hypoxia inducible factor (HIF). HIF sends a message to endothelial progenitor cells in the bone marrow, which then “home” to the hypoxic area and proliferate there.

Why do the endothelial progenitor cells (EPCs) misbehave in the first place? Perhaps they possess a mutation such as mentioned in theory 2, perhaps it is just the hypoxic endothelial cells, in a particular area, expressing “recruitment” factor for EPCs. . It has been found that infants with IH have an increased number of circulating EPCs, supporting this latter theory.

The general belief is that all of these theories could be involved with IH.

Therapy for IH

Dr Frieden comments that extrapolating from the data from Dr. Friedlander’s study, about one in every thousand infants will need an intervention for a hemangioma. For several years, beta-blockers have been studied as a treatment for IH. There are more than 240 articles published. Dr Frieden and her colleagues conducted a systematic review of 41 case series, with greater than ten patients, looked at a total of 1264 patients. 28 percent of the patients received prior treatment, most commonly oral prednisolone. Propranolol was initiated at the mean age of 6.6 months at a mean dose of 2.1 mg/kg/day. The mean duration of treatment was 6.4 months. The results of this systematic review demonstrated a response rate of 98 percent (range 82-100 percent). The response rates were comparable irrespective of anatomic sites. There was rebound growth in 17 percent. Adverse events occurred in about three to five percent, with sleep changes and acrocyanosis being the most common. Serious AEs were rare. (Marqueling et al. Pediatr Dermatol. 2013; 30(2):182-91.

In Dr Frieden’s experience, this response rate really parallels that of isotretinoin, i.e. it works so well that you don’t really need statistics to prove that it works. Dr Frieden also comments that in her practice, they have been treating IH with propranolol for several years and have seen remarkable results.

Steroids versus Propranolol

Another systematic review compared steroids to propranolol. The review of literature was conducted from studies from 1965-2012; 16 studies (2,629 patients) versus 25 studies (795 patients). The overall efficacy rate for systemic steroids was 71 percent compared to 97 percent for propranolol. AEs for steroids were 17.6 percent versus 13.7 percent in propranolol. This review concluded that propranolol has greater efficacy and acceptable AEs for the treatment of IH. (Izadpanah A, et al. Plast Reconstr Surg. 2013;131(3):601-613.)

Propranolol Consensus Guidelines

Dr Frieden and her colleagues developed guidelines in order to come up with best practices for treating these patients. It is important that dermatologists understand whether patients should be treated inpatient or outpatient. Inpatient hospitalization is suggested for infants younger than eight weeks of age including gestationally-corrected age for preterm infants, any infant with inadequate social support, and any age infant with comorbid conditions affecting the cardiovascular or respiratory systems. Outpatient treatment with monitoring can be considered for infants/toddlers over eight weeks of age with adequate social support and no significant comorbid conditions.

Regarding monitoring, the peak effect of oral propranolol on HR and BP is one to three hours after administration. Patients should be monitored with HR and BP measurement at baseline and at one and two hours after receiving the initial dose. This should be repeated with significant dose increases, i.e., greater than 0.5 mg/kg/day, including at least one set of measurements after the target dose has been achieved. If HR and BP are abnormal, then the child should be monitored until the vitals signs normalize and if necessary the dosage adjusted. The cardiovascular effects are usually most pronounced after the first dose so there is no need to repeat monitoring for the same dose again unless the patient is very young or has comorbid conditions. Of note, HR is usually easier to accurately obtain than BP.

With regards to hypoglycemia, routine glucose testing is not recommended. The risk of hypoglycemia is age-dependent and is related to the effects of propranolol on gluconeogenesis and glycogenolysis. Hypoglycemia ia more likely to occur if a child has had a prolonged period of time without oral intake and is age dependent. Infants less than six weeks of age should be fed at least every four hours, infants six weeks to four months should be fed every five hours and infants greater than four months every six to eight hours. Propranolol should be temporarily discontinued during intercurrent illness, especially in the setting of restricted oral intake.

Providers must remember that these guidelines are based on current knowledge and should be considered provisional. Martin. et al have written an article providing written instructions re: propranolol therapyr for parents and caregivers. It is a useful educational tool and resource for these parents and includes extremely helpful information. (Martin K, et al. Pediatr Dermatol. 2013;30(1):155-159.

How do beta blockers work?

Both speakers agree that we don’t fully understand how this class of medications works for IH. One of the theories is that they decrease rennin production. The second theory is the regression via HIF-1-alpha-mediated inhibitor of VEGF-A and the third theory is the inhibition of “homing” of endothelieal progenitor cells to hemangioma sites, as Dr Friedlander previously discussed.

Topical Beta Blockers

Sometimes the risk-benefit ratio of propranolol is of concern. We now have an option with the topical beta blocker, timolol, which has been previously approved for adult and pediatric glaucoma. There have been at least twenty articles since February 2010 with approximately 175 patients evaluated. Nearly all of these studies were retrospective with the largest series being of 73 patients. Most of the studies utilized timolol ophthalmic solution but two reports used compounded propranolol. There were varied concentrations and frequency, however timolol 0.5% gel-forming solution is most commonly used, typically with a – duration of three months or more.

Collectively, reports in the past two and a half years have shown encouraging results with topical beta blockers. Lesions on the eyelid tend to do particularly well, as do hemangiomas which are more superficial and smaller in size. Preliminary reports suggest that timolol is well tolerated, in that there have been no significant toxicity reports to date. The drug is also relatively inexpensive. It is important; however, to remember that timolol has a relatively higher potency and there is a risk of achieving significant blood levels, particularly in small premature infants. The quantity used should be limited; some healthcare providers use a maximum of one drop two times per day.

Multimodal Therapy

We have seen beneficial effects of early pulsed dye laser (PDL) therapy in individuals with infantile hemangiomas. (Admani S et al. Dermatologic Surgery. 2012;1-7) Multiple cases have demonstrated that in some cases you can do better with combination therapy, such as steroid use and PDL or beta blockers and PDL. Mixing and matching with regards to treating IH is a reasonable approach.

Gluten: What is all the fuss about? Part 2

December 10, 2013

John J. Zone, MD

Dr Zone has treated over one thousand patients with Dermatitis Herpetiformis (DH). It usually presents as itchy, red bumps in the elbows and knees. DH should be diagnosed through a biopsy and Dr Zone recommends biopsying in the area close to redness, but not directly on the red bumps.

There have been several studies looking at the prevalence of DH. The numbers in Europe are very similar to those of the United States. It is a genetic disease but it is distributed throughout life. We don’t know what the factors are that set off the onset of disease. We do, however, know that people with DH express the entire range of intestinal abnormalities. Some people will have Grade IV and others will only have Grade I.

Dr Zone stresses another important point that people with DH develop antibodies to epidermal transglutaminase (TG3). Dr Zone states that roughly one in six celiac patients will develop DH.

What about people who have intestinal inflammation, but don’t have DH or symptomatic CD?

It is important to consider that celiacs may have:

Only aphthous stomatitis
Only eczema
Only alopecia areata
Only psoriasis
Diabetes
Only fatigue or anemia

What this means is that all of the diseases mentioned above might be associated with celiac disease, it is pretty rare, but those people who have it might get better on a gluten free diet.

A 1998 paper studied oral ulcers and celiac disease. They found that approximately five percent of patients with “idiopathic” apthous stomatitis have been found to have positive endomysial antibody tests and then CD on small bowel biopsy. Stomatitis will clear with a gluten free diet. (Jokinen J et al: Celiac sprue in patients with chronic oral mucosal symptoms. J Clin Gastroenterol.1998; 26:23-26) In a 2008 study, the researchers looked at 269 kids ages 3 to 17 with CD and 575 otherwise healthy subjects. They found apthae in 61 of the 269 kids (22.7%) and 41 of the 575 normals (6%). 33 out of 46 CD kids on a strict gluten-free diet reported significant improvement or clearing of apthae. (Campisi et al. Dig Liver Disease. 2008 40:104-107)

Alopecia Areata (AA)

Alopecia areata is a T-cell mediated disorder that produces hair loss. Some studies have shown that patients with AA and CD have regrown hair with a gluten free diet (GFD) others have seen no effect of GFD. Also of note, chronic diseases can make the response to a GFD less likely. Dr Zone states that there is probably about one in 100 chance of having celiac disease. The questionable association between CD and AA and hair regrowth will only be answered by a prospective trial of testing new onset AA kids for total serum igA and tTG, establishing CD rate, and then comparing the outcome on GFP compared to non CD kids on a normal diet.

CD and Psoriasis

Take Home Point—CD occurs at a slightly increased frequency in psoriasis patients and response to a GFD has been reported.

A 2002 study of patients with long standing psoriasis who were found to have CD all had marked improvement on a GFD. Psoriasis patients with positive anti-gliadin antibodies have improved on a GFD. The prevalence of positive EMA and tTG antibodies is no greater than the rest of the population (1:133). The question is “is gluten a source of chronic antigen stimulation in psoriasis?” (Cardinali et al. Br J Derm. 2002.147:187-188)

CD and Atopic Dermatitis

There is no increased incidence of atopy in CD patients but patients with dermatitis who are shown to have CD will improve on a GFD. This was a large case controlled study of 82 CD patients and 180 matched controls and their first-degree relatives. The researchers found increased prevalence of asthma, eczema, rhinitis, or elevated IgE levels. However, patients with eczema and Cd did improve their eczema on a GFD. (Greco L, et al. Paediatr Scand. 1990 79:670-74)

Take Home Points

Screening in patients with these disorders (serum IgA and IgA tTG(TG2)) will result in 1-2% positivity (low yield)
But: Patients with a (+) result who are then treated with a Gluten Free Diet will likely likely have response of their skin disorder to dietary restriction of gluten

What about people who are “gluten sensitive?”

There is a group of people who have gone on gluten free diets and say that they feel better. These are people with normal IgA tTG and normal small bowel biopsies. Up to 50 percent of these people do have the high-risk genotype (higher than the 25 percent in normals). A 2012 studied demonstrated that certain symptoms can improve with dietary gluten restriction including GI symptoms, neurological symptoms, skin symptoms and “brain fog” (the most common symptom). These were all patients with a normal intestinal biopsy. (Lundin EA and Alaedini A:Non-gluten sensitivity. Gastrointest Endosopy Clin N Am. 2012. 22: 723-734) A study at the University of Maryland documented that symptoms could be induced by gluten through a blinded challenge that they performed at the university.

In patients with non-celiac gluten sensitivity, adaptive immune response (IgA, tTG, IgE anti wheat and cellular response to gliadin, etc.) cannot be identified. These patients have normal intestinal biopsies and multiple symptoms in response to gluten ingestion that do not occur with placebo. These people may have an innate immune response that can occur in the absence of HLA DQ2. There are also no serologic markers.

Dapsone Treatment

This is the most common question that Dr Zone hears from colleagues. Dapsone is a major oxidant stress to red blood cells. It is important to make patients aware of hemolytic anemia and the blue/gray color associated with methemoglobinemia. Clinical management should stress the maintenance of the smallest dose necessary to control the disease. Occasional new DH lesions (2-3/week) are to be expected, and are not an indication for raising the dose. Before initiating Dapsone treatment, you should perform a baseline CBC and Chem profile; G-6-PD in asians, blacks or those of southern mediteranean descent. You should start your patients at 25 mg. daily and increase 25 mg. weekly until the symptoms are controlled. CBC should be performed weekly for four weeks, then monthly for six months, then semi-annually. Chem profile should be performed at six months and then annually.

Gluten: What is all the fuss about? Part 1

December 10, 2013

John J. Zone, MD

Dr Zone has been studying gluten since the 1970s. He comments that recently, all we hear about is gluten sensitivity and gluten free diets. In fact, there are entire sections in the supermarket that are dedicated to gluten sensitivity. This used to be considered rare and now, it appears, that everyone has it. There are now improved methods for diagnosing celiac disease and so the number of people diagnosed has increased. However, there is also a population of people who have self diagnosed gluten sensitivity.

What is gluten?

Gluten is a group of proteins from grains that are insoluble in water. It is made up of prolamins and glutelin. Prolamins are high in proline, alcohol soluble, and monomeric. Glutelin, which we know less about, is soluble in dilute acid or alkali and is comprised of aggregated polymers. Dr Zone mentions that the initial studies feeding people various fractions of gluten were conducted during the 1950s and 1960s, prior to IRBs, “we could feed people a lot of things that we can’t feed people now” and they found that a particular fraction of gluten, the prolamins, were toxic. (The glutelin fraction was never studied) Existing prolamins include gliadin (wheat), hordein (barley), and secalin (rye), all of which may induce celiac disease. Glutenin (wheat), which is a glutelin, may be pathogenic in celiac disease, but this has not yet been confirmed.

Wheat Allergy

In dermatology, we don’t always think about food-induced allergies. Wheat allergy is IgE mediated, i.e., crosslinking of IgE molecules bound to basophils and mast cells. It is repeat sequences in gluten peptides, e.g., serine-glutamine-glutamine-glutamine-glutamine-proline-proline-phenylalanine—not necessarily gliadin. This subsequently releases chemical mediators such as histamine.

The reason why patients with urticaria don’t always respond to anti-histamines is because they are also releasing TNF, proteases, heparin, and IL-5. This is why some people with urticaria will get better with TNF inhibitors.

Wheat Dependent Exercise Induced Anaphylaxis

Dr Zone has seen this on two occasions and it can be quite dramatic. One of his patients had a severe reaction after exercising and they deduced that it occurred because he had eaten gluten; as he didn’t eat gluten before execising, he could continue playing squash. This is caused by omega gliadin and the way to test for this is through a skin test or challenge.

Celiac Disease

Celiac disease is also known as gluten sensitive enteropathy, celiac sprue, and non-tropical sprue. One in 100 Caucasian Americans do have celiac disease. This is an HLA-associated disease. 90 percent of celiac disease and DH patients express HLA DQ2; 9 percent express DQ8. 20-25 percent of Caucasians have DQ2 or DQ8. The receptors coded by the HLA genes are essential for the processing of the gliadin antigen in celiac disease. So if you think about the people out there buying gluten-free foods, 20-25 percent of them have the gene makeup to process the gliadin antigen and develop an immune response. So, essentially, lsss than 5% of the people with the correct HLA genes will develop clinical celiac disease, others may have silent or latent celiac disease and some healthy individuals have all of the genetic makeup to develop celiac disease, yet they will never get it.

It’s important to remember that celiac disease clusters with other autoimmune disorders such as Addison’s disease, autoimmune thyroiditis, atrophic gastritis, SLE, RA, myasthenia gravis, and vitiligo. The interesting thing about this is that we know the antigen that precipitates the autoimmunity. Celiac disease is also common in Down’s syndrome.

Dr Zone comments that it is a “huge mistake” to go on a gluten free diet without first being tested for celiac disease. There is range of pathology in celiac disease that can be seen by proximal small intestinal mucosal immunopathology. Dr Zone also states that he and many of his colleagues were taught that to have celiac disease, you have to have a bloated abdomen, be malnourished and short and skinny…this is how it was described in the past.

What is celiac disease?

Celiac disease is an inflammatory injury of the small intestinal mucosa after ingestion of gluten in wheat, rye, or barley. We can see improvement once gluten is withdrawn from the diet. It is important to remember that many patients with histological inflammation have atypical intestinal symptoms or no symptoms at all. Clinical studies have shown that only 15-20 percent of CD and DH patients identified by serology and confirmed by biopsy have classical symptoms of diarrhea and malabsorption.

So how do you diagnose celiac disease? IgA tissue transglutminase (TG2) is the hallmark of celiac disease and correlates with the severity of intestinal inflammation. A 2003 study looked at the prevalence of CD in the United States based on IgA tTG testing of serum found the following ratios:

1:133 in not at risk individuals
1:56 in symptomatic patients
1:39 in second degree relatives
1:22 in first degree relatives

This demonstrates that CD is common, and not rare. (Fasano et al: Prevalence of Celiac Disease in at Risk and Not at Risk Groups in the United States. Arch Intern Med. 2003; 163: 286 – 292)

Conclusions

Celiac disease is as common as psoriasis and can be found in one to two percent of the Caucasian population. CD profoundly affects the immune system, which is the modulator for inflammatory skin disease.

It is important to remember that most celiac patients have few or no symptoms at all. There is a wide range of intestinal abnormality and the high risk genotype is essential for pathogenesis.

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.