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.
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.
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.
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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.
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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 TiO2 actually 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.
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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
Over the last few years, dermatology has become reliant on botany with regards to some of the newer therapies. These include:
Ingenol Mebutate “Petty Spurge”
Polypodium leucotomos
Sinecatechins (Veregin)
Ingenol Mebutate
Ingenol Mebutate is a topical gel derived from the Euphorbia peplus plant, and is approved for its effect on actinic keratosis. (Of note, Ingenol Mebutate is applied twice a day for the body, three times per day for the face)
Polypodium leucotomos
Polypodium leucotomos is an aquatic fern origination in Central America. For centuries it has been used by native Americans because of it anti-inflammatory effects. Polypodium leucotomos has significant antioxidant activity and can positively affect photodamaged skin. The product is marketed as Heliocare and can be purchased over-the-counter or through a physician for about $30.00. It does not have an FDA indication for chemoprevention or treatment of AK/NMSC.
Sinecatechins (Veregin)
Catechins have antioxidant, antiviral and immune-stimulatory effects. The graph below demonstrates the antioxidative activity of Veregen for the clearance of external genital warts.
This product is probably not an option for the treatment of AKs based on the studies conducted; however, it could be used for Molluscum, maybe even more so than genital warts.
Photodynamic therapy
What is the appropriate incubation time Levulan PDT Treatment? Using a noninvasive dosimeter, PpIX fluorescence 5 replicates were taken at 20-minute intervals for two hours following ALA application. Results demonstrated improvement of 48% of all lesions by 20 minutes, 92% of lesions by one hour, and 100% of lesions by two hours. PpIX accumulation correlated with changes in lesional erythema post-PDT and high levels PpIX are produced in AKs in two hours.
Regarding incubation and light strategies the label says to incubate for 14 hours, i.e., treat the day before and stay indoors to avoid activating the light. Reality tells us to incubate for two hours if possible, though one hour is more realistic. The light is on for 16 minutes and 40 seconds which is enough exposure to provide a 10 J/cm2 light dose.
But, are there better options??
A Phase II study of photodynamic therapy for Levulan topical solution plus blue light versus Levulan topical solution vehicle plus blue light using spot and broad area demonstrated that ALA was statistically superior to vehicle at 12 weeks for all treatment groups. The one-hour data seems to be slightly lower in efficacy indicating some dose response. There also appears to be some long-term benefit to Broad-Area versus Spot application, in that a much higher number of Broad Area patients who are clear at 12 weeks remain clear at 24 weeks compared to Spot treated patients.
Clinical Pearls
Assess available devices and practical applications
Understand rationale for therapy
Choose patients wisely and avoid over-exposure
Atrapro versus Aurstat: Battle of the Hydrogels
Microcyn is the active ingredient in Atrapro, it enhances wound healing by inducing vasodilation and it has an anti-inflammatory affect. Microcyn is also a biomodulator that denatures endotoxin and causes stabilization of mast cells; therefore, leading to a direct anti-itch effect. It’s important that dermatologists recognize that Microcyn is different than antibiotics in that it works via multiple mechanisms of action. Microyn causes damage to cell wall, membrane and intracellular components. In an open-label pilot study looking at the results of the use of Atrapro Antipruritic Hydrogel alone, data demonstrated a reduction in pruritus severity by day 14 in 88 percent of the patients (N = 17). There was a subjective reduction of itching by day three in 82 percent of the patients, and 76 percent of the patients improved at day 14 by investigator grade.
Aurstat Hydrogrel, which was cleared by the FDA as a medical device, contains hypochlorous acid and sodium hypochlorite. Hypochlorous acid and sodium hypochlorite function as preservatives; hence, providing an anti-itch effect. A study by Draelos, et al. demonstrated the ability of Aurstat Hydrogel to reduce pruritus in patients with mild to moderate atopic dermatitis over a seven-day period (N = 20).
What’s the difference between these products?
Both studies authored by Dr. Zoe Draelos
Both have small number of patients (17 vs. 20)
Both have short durations (14 d vs. 7 d)
Atrapro has two vehicles, Aurstat has a kit
Atrapro works to prevent mast cell degranulation to stabilize itch, Aurstat acts via hypochlorous acid
Both claim anti-microbial activity without antibiotic properties
Take Home Message:
Both of these products may reduce the need for steroids and antibiotics and that may be where we see their potential utility in clinical practice.
Nuvail- A New Approach to Damaged Nails
Nuvail, a new and unique patented polymer that leaves a breathable, elegant, invisible film when applied to nails, was recently approved for restoring the health of nails. Polyureaurethane is the active ingredient.
What’s the rationale for polyureaurethane?
Polymer adheres to nail plate
Solvents evaporate upon application
“Vapor permeable” waterproof seal formed with nail and periungual skin folds (provides a better feel for the patient)
Changes in nail from sealant effect impairs further growth of fungal elements
Drying effect of nail plate and bed from waterproof seal
Clinical data demonstrated a 60 percent improvement in nail color, nail plate involvement, onyycholysis, thickness, and hyperkeratosis after six months of treatment.
The recommended application of Nuvail is qHS, the product should be applied in even strokes to affected nail plate (in entirety), proximal and lateral folds, and the distal tip. It is important that patients allow the product to dry completely before applying pads or clothing. Patients should know that nail polish may worn on top of Nuvail; however, nail polish should not be applied until Nuvail is completely dry. Prior to the next application of Nuvail, nail polish should be removed. The affected nails should be cleaned with nail polish remover once a week.
Overall Conclusions
Assess history of dosages, onset of eruption, and patterns
Monitor systemic issues of patients
Carefully assess labels of “allergy” and do not hesitate to reconsider label
In the world of dermatology, we are filled with hamartomatous “overgrowth” syndromes. Many, however, are de novo so the genetic mechanism is unclear. Often times, segments or large quadrants of the body are affected clinically suggesting somatic mosaicism.
Two studies in 2012, that complimented some earlier studies, looked at somatic mosaic mutations of these various overgrowth syndromes. In the first study, megacephaly was a feature in all three cases. Patients may have nevus flammeus. The blood/saliva from all patients was subjected to total exome resequencing, which is a technology that is really hitting medicine right now. In effect, total exome resequencing is looking at all of the coding sequence of one’s genome (exome) and in doing so, trying to find the mutation that may be responsible for the phenotype that you see. In the first study, megacephaly was a feature in all three cases. Patients may have nevus flammeus.
The three genes that were found were the AKT3, PIK3R2, and PIK3CA.
Clinical Pearls
Germline and mosaic versions of cancer mutations lead to developmental and hamartomatous conditions
As sequencing technologies improve, the mechanism of new syndromes will emerge
Interesting that these patients may not be more susceptible to cancer overall
Looking Ahead
Between biologics and small molecule inhibitors, we are in a new therapeutic renaissance
The mechanism-to-medicine bridge is finally open
NextGen sequencing will help define rare hereditary and mosaic genodermatoses
Health care economics, not science, is the wild card
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Dermatologists should remember that most basal cell carcinomas (BCCs) are removed by surgery or with radiation or topical therapies. This past year there has been much more data on hedgehog signaling, which is involved in most BCCs.
Hedgehog Pathway
Vismodegib, which targets the hedgehog pathway, has been studied in BCCs. Of note, the hedgehog pathway is also being studied in other cancers, including pancreatic and brain cancer.
Sekulic, et al. published a study in the New England Journal of Medicine looking at the efficacy and safety of Vismodegib in advanced basal-cell carcinoma looking at 33 patients with metastatic basal-cell carcinoma and 63 patients with locally advanced basal-cell carcinoma, the latter of which is more prevalent in the dermatology setting. The primary endpoint of the study was independent review by an outside dermatologist. The study concluded that Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma.
The most commonly reported adverse events (AEs) were muscle spasms, alopecia, and dysgeusia. Other AEs included decrease in weight, fatigue, nausea, decrease in appetite, and diarrhea.
Tang, et al. studied the results of inhibiting the hedgehog pathway in patients with basal-cell nevus syndrome. (New England Journal of Medicine) There were 41 patients in the study; 26 on Vismodegib vs 15 on placebo. The study looked at cessation of new BCC development while on Vismodegib and the decrease in the diameter of existing lesions while on Vismodegib.
The data from this study demonstrate that one can see no new BCCs form while on Vismodegib and a significant decrease in the diameter of existing lesions while on drug. (Of note, there was a significant attrition of use because of the side effects.) Also of importance is the fact that GLI1 levels diminished on patients taking Vismodegib; therefore, indicating that the drug is hitting its target.
Clinical Pearls
This small-molecule hedgehog pathway inhibitor is effective for metastatic, advanced and generalized BCCs
Represents nice bench-bedside development of a new cancer agent
Side effects, recurrences after drug discontinuation, and cost are limiting factors
Although FDA-approved, the role of Vismodegib for common BCC settings is unclear given limitations
Head Lice
The emergence of resistance to first line antipediculicides complicates the public health problem of head lice. Dermatologists should remember that second-line treatments, such as lindane and malathion, have limitations related to safety; therefore, newer approaches for the treatment of head lice are needed.
David Pariser and colleagues published a large prospective trial in 2012 in the New England Journal of Medicine looking at topical Ivermectin 0.5% for the treatment of head lice. The study found that Ivermectin has a higher success rate versus the control vehicle.
The side effects for Ivermectin were rather tolerable. AEs included pruritus, excoriation, and erythema.
Topical ivermectin achieved a success rate of >90% with single application
Similar to oral ivermectin
Nit combing not necessary with ivermectin as opposed to permethrin
Nice option for permethrin-resistant louse or even as first line
Targeted Therapy for Melanoma
Although molecular control of melanoma through targeted therapies has shown tremendous success, relapse is still the general rule; therefore, long-term remission will require immune participation in order to have recognition at the immune surveillance level. Often times, the tumor evades the immune system by circumventing immune checkpoints; yet, recent advances in the studies of targeted therapy for melanoma (Anti-PD-1 and Anti-PD-L1 antibodies) have demonstrated positive efficacy in tumor reduction.This new area of research is at the level of the tumor itself. These therapies, currently under trial, both have major potential in clinical practice and patient outcomes.
Data from Topalian et al, published in the New England Journal of Medicine show that the objective response rates are less than 30 percent as defined by the RESIST criteria. Many patients experienced a drop-off of greater than 30 percent tumor reduction using anti-PD-1. The anti-PD-L1 shows similar results, but not to as great as an extent as that of anti-PD-1.
Clinical Pearls
Anti-CTLA4, anti-PD-1 and anti-PD-L1 represents the triumvirate of immune checkpoint therapies
Precise molecule and formulation may be important
Tremelimumab (another anti-CTLA4 antibody) did not show any significant survival benefit
Anti-PD-1 and anti-PD-L1 treatments appear to be less toxic than ipilimumab
Combination molecular therapies for acute control and checkpoint therapies for long-term control may be the wave of the future
Overcoming Rejection and Cancer
A small study in the New England Journal of Medicine looked at the role Sirolimus (rapamycin) in secondary skin cancer prevention in the transplant population. Rapamycin, which targets the mTOR pathway, blocks the transduction pathway. This action not only prevents the rejection, but can also prevent SCC from developing.
Patients in the study were randomized to either Sirolimus or cyclosporine, tacrolimus. All patients had at least one prior SCC and were stratified by the number of prior SCCs. Overall there was a significant improvement in the probability of survival-free with Sirolimus compared to the calcineurin inhibitor controls. However, when the data is broken down, one can see that the majority of this effect occurred in the sub-population, i.e., patients with only one prior SCC.
Clinical Pearls
Sirolimus is an effective suppressor of transplant rejection and has the added benefit of suppressing development of SCCs
The medicine’s positive effects must be balanced against a large number of adverse effects
It is less effective in patients who have already had more than one SCC
This is not the final word in prevention of skin cancer in transplant recipients
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Dr Hensin Tsao, Director of the Melanoma Clinic at Massachusetts General Hospital, lead off the 2013 Maui Derm meeting by providing the audience with an overview of some of the top stories in dermatology in 2012-2013.
Melanoma
Dermatologists should know that melanoma is the 5th most common cancer in males and the 6th most common cancer in females affecting one in 36 men and one in 55 women. Most of these numbers are not including melanomas in situ, which would then most likely make the numbers higher. (American Cancer Society 2012)
Unfortunately, melanoma incidence and mortality continue to increase. There is also a disparity in survival among races, i.e., African Americans tend to have a survival disadvantage compared to whites and other races, especially in Stage III.
Another interesting fact is that there are twice as many deaths from melanoma for men than for women; therefore, there is a thought that there is a female survival advantage. Based on the graph below, one can see that the mortality for rate for males, after age 65, really begins to take off. There appears to be some sort of lethal phenotype associated with melanoma in elderly men, especially in the head and neck. This is a group to whom one should pay particular attention.
A study in the Journal of Clinical Oncology demonstrated a superior outcome of women versus men with Stage I/II cutaneous melanoma. This was based upon a pooled analysis of four European Organization for Research and Treatment of Cancer Phase III trials.
The bulk of the effect appears to come from the tumor thickness (especially in tumors greater than 2 mm). Overall, males seemed to do worse than females.
When the studies are aggregated, almost every study conducted around the world shows a hazard ratio of approximately 0.6 to 0.7. This is consistent across many studies; therefore, this does not show a detection or reporting bias.
Clinical Pearls
Melanoma incidence and mortality rates continue to increase
There may be a disparity in survival between races
There appears to be stronger evidence for a “female advantage” in survival although biologic basis is unclear
Unlikely reporting bias since it has been observed worldwide
Injection Infection
Another hot topic is that of blood-borne viral infections linked to tattooing. Most of the time it is due to the tattoo artist being substandard in hygiene. Recent studies have demonstrated that M. chelonae infection has been associated with tattoos. Molecular analysis showed M. chelonae was found in 11 clinical isolates and in an unopened bottle of ink. 18 out of 19 patients responded to macrolides and or doxycycline depending on sensitivities. It should be noted that contamination likely occurred before distribution.
For Dermatologists, there appears to be a need for better oversight and record keeping.
Sun Avoidance
Sun avoidance is a crucial component of all skin cancer prevention campaigns. Scientists have begun to study the effects of direct light, diffuse light, and reflected light. Modeling revealed that a large amount of diffuse UV radiation occurs. Recent studies indicate that direct UV occurs mostly on exposed sites during summer months; reflected irradiation occurs during winter months.
SimuVEX software was utilized to estimate UV from various ambient sources. Diffuse radiation accounted for 75-85% of the annual sun exposure. It is not clear whether or not shading can protect against diffuse light.
Tanning Beds
The WHO has classified sun lamps as a carcinogenic agent. The true morbidity of tanning bed use is an area of intense scrutiny and better estimates are emerging.
The British Medical Journal published a meta-analysis (27 studies) in 2012 looking at cutaneous melanoma and its association with sunbed use. This study found that there is about an 87% increased risk of melanoma if tanning [beds] are first used before age 35. There is an element of dose-dependence associated with the use. This is becoming a significant public health problem as tanning bed use now contributes to about 10% of melanomas. As expected, the risk of melanoma with tanning bed use is independent of latitude. Public health response is more aggressive these days, but we’re not there yet.
Natural Disaster Dermatology
Murcormycosis is a rare infection caused by molds that are ubiquitous in soil, decaying wood and organic material and if left untreated, it can lead to massive tissue necrosis. Although it usually occurs in immunocompromised patients, the fungus can develop after trauma in the immunocompetent patient.
A 2011 study looked at necrotizing cutaneous murcormycosis after a tornado in Joplin, Missouri. The study found that of the 13 patients with murcormycosis, five patients died; four out of the six patients were not treated with Amphotericin B and one out of seven patients treated with Amphotericin B died.
What are the risk factors that lead to mortality after infection?
Number of wounds that were punctured
Rhabdomyolysis
Clinical Pearls
Outbreaks of rare saprophytic infections after catastrophes have been reported
All 13 cases had DNA evidence of Apophysomycestrapeziformis
Infection needs to be considered early so proper treatment with AmphoB can be instituted
Increased number of puncture wounds, early signs of rhabdomyolysis
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