Psoriasis 2015: Clinical Pearls

Bruce Strober, MD, PhD

Dr Strober provides us with some important takeaway points from his psoriasis lecture…

  • Apremilast achieves PASI 75 in approximately 30% of patients after 16 weeks of therapy.
  • Apremilast has FDA-approval for the treatment of both psoriasis and psoriatic arthritis.
  • Apremilast also has been shown to provide improvement for nail and scalp psoriasis, and the reduction of pruritus.
  • Apremilast is associated with a >5% weight loss in between 10-20% of treated patients.
  • Secukinumab is the FDA-approved biologic medication with currently the highest level of clinical efficacy of all the self-injectable medications.
  • A side effect of secukinumab is oral candidiasis, which is usually mild and occurs in up to 5% of patients.
  • IL-23 inhibition is a future mechanism of action for psoriasis therapy that shows very high efficacy in early clinical trials.
  • Tofacitinib inhibits JAK kinases and will be an oral drug approved for psoriasis.
  • Tofacitinib increases the risk for varicella-zoster.
  • Both secukinumab, apremilast and tofacitinib are all drugs that variably treat psoriatic arthritis.

Year In Review: Clinical Pearls

Ted Rosen, MD; James Treat, MD; Matthew Zirwas, MD

What’s new in dermatology? Here are some important clinical pearls that may help you in clinical practice…

  1. Younger patients with NMSC and melanoma at increased risk internal cancer
  1. Women with GU malignancies at increased risk of SCCA of the skin
  1. Four cups of coffee may contain enough caffeine to lower risk of new BCC in patient with prior occurrence of BCC
  1. Sildenafil use increases risk of melanoma?
  1. Freshwater injury: wound not improving with antibiotics, think algae!
  1. Acne: leads to stress, fatigue and reduced sexual activity
  1. Spironolactoneis an effective “add on” to retinoid in adult women with acne
  1. Dapsone gel reported to lead to methemoglobinemia (blue fingers, toes, lips, SOB): rare but serious potential adverse effect
  1. Adalimumab: acne conglobata (and hidradenitis supprativa)
  1. Lindioil (extract of Indigo naturalis plant) may help psoriatic nail dystrophy; AVAILABLE AT:
    1. etsy.com
    2. indigo-botanicals.com
  1. Vitamin D3 at high dose (~4000IU daily) may help refractory chronic idiopathic urticarial
  1. AFTER successful repigmentation of vitiligo: maintain on topical tacrolimus 0.1% BIW
  1. Vitiligo may be associated with auditory dysfunction
  1. Weekend only dosing of cyclosporine can be used as long term maintenance therapy in some atopics
  1. Oral Glucosamine increases efficacy of cyclosporine without increasing side effects, allowing lower doses to be effective
  1. Oral magnesium is worth trying in patients with difficult to control Hailey-Hailey
  1. Simvastatin helps venous stasis ulcers to heal
  1. Antihistamines make isotretinoin work better
  1. Nitroglycerin works for chondrodermatitis Nodularis Helicis
  1. It may be possible to prevent atopic dermatitis with emolliation started before 3 weeks of age
  2. Tonsillectomy should be considered in children with severe psoriasis that correlates with GRoup A Streptococcal infection
  3. Topical timolol can be very effective for early superficial hemangiomas.

 

10 Pearls from Dermatopathology

Whitney A. High, MD, JD, MEng

  1. Dermatopathology is one of two ABMS-recognized subspecialties in dermatology, and one may become fellowship-trained after first being a board-certified dermatogist or general pathologist.
  1. Biopsy use is increasing. In nine geographic areas of the USA, over the time period 1986-2001, the biopsy rate among those >65 years of age rose 5-fold and the melanoma rate rose 2.4-fold.
  1. There are mulitple steps involved in taking a specimen from a piece of “wet” tissue, in formalin, to an interpretable slide and to a typewritten report. These steps include:

Biopsy performed & fixed in formalin            Accessioned

Grossed                                                                Processed

Embedded                                                            Cut

Stained and coverslipped                                  Analyzed

Transcribed/typed/signed                                Transmitted back to the provider

  1. The dermatopathologist is examining but a small portion of your original sampling, and this must always be considered when one assesses the “representative nature” of the results.
  1. There is an old mantra in pathology: crap in = crap out. No dermatopathologist, regardless of skill or expertise, can weave a poor sample into an outstanding result.
  1. It is the clinician responsibility to secure a “representative biopsy,” and if this is not done, eventually this inadequacy will be discovered. Over the period of 1998-2005, the number of shaves increased, but the volume of a typical shaves decreased.
  1. The technique employed (shave, punch, excision) must be adapted to the clinical situation – there are no fixed rules that may be applied to every situation. This is why the clinician is being paid an “evaluation/management” code; to select a biopsy that is appropriate for the circumstances.
  1. A recent study of pigmented lesions showed the odds of misdiagnosis (overall and that associated with adverse outcome) were higher with a punch biopsy than with an excisional biopsy, whereas a shave biopsy was only weakly associated with misdiagnosis. (Ng et al. 2010)
  1. Situations where the biopsy technique should be carefully considered include suspected:

Verrucous carcinoma              Mycosis fungoides

bullous pemphigoid                 Immunofluorescence studies

Panniculitis                               Alopecia

Lymphoid proliferations        Pigmented lesions

  1. The pathology report itself should be carefully read and scrutinized to understand precisely what the dermatopathologist is trying to convey. Demographic data should be confirmed. The technique and specimen size should be verified. Data used by the dermatopathologist to formulate the diagnosis should be noted (i.e. step levels, immunostains, special stains, etc.). If questions still exist, a phone call should be placed to the dermatopathologist for expanded dialog.

Contact Dermatitis and Eczema Clinical Pearls

Matthew Zirwas, MD

Dr Zirwas provides us with important clinical pearls from his presentation on contact dermatitis and eczema…

  1. If a patient with facial dermatitis is patch tested with the TRUE Test, the likelihood that patch testing will get them better is 1%. (30% chance they have contact dermatitis x 20% chance it will accurately diagnose them x 50% chance they will remember their allergies x 50% chance they will be able to avoid them if they remember them = 1.5% chance they will get better).
  1. TRUE Test is great for diagnosing allergic contact dermatitis to common metals, rubber, and active ingredients in OTC and Rx products. It is very bad at diagnosing ACD to personal care products.
  1. If there isn’t somebody in your area who does comprehensive patch testing, at the very least you should add these ten allergens to the TRUE Test: Methylisothiazolinone 2000 ppm, Formaldehyde 2%, Propylene Glycol 100%, Fragrance Mix 2, Cocamidopropyl Betaine, Amidoaminde, Dimethylaminopropylamine, Hydroxyethyl methacrylate, Mixed dialkyl thioureas, Chloroxylenol.
  1. Patients can be accurately patch tested while on 10 mg of prednisone.
  1. Every allergen you tell someone they are allergic to decreases they chances they will remember what they’re allergic to by 50%. (Allergic to 0 allergens à100% chance of remembering, Allergic to 1 à50% likelihood of remembering, Allergic to 2 à 25% likelihood of remembering, Allergic to 3 à 12% chance of remembering what they are allergic to).

Neuromodulators for Skin of Color: Maui Derm 2015

Valerie D. Callender, MD

In this presentation at Maui Derm 2015, Dr Callender reviews the use of neuromodulators in skin of color. When we think about neuromodulators in skin of color, we need to think about how these aesthetic patients present in our office.

The concept of global beauty is the desire to maintain a beautiful, youthful appearance. This concept crosses all racial, cultural, and economic barriers. It’s more than just symmetry, size, and shape of facial features. So what is global beauty? It’s the appearance of smooth, even skin complexion, as well as the absence of rhytids, volume loss, and skin laxity. Remember that the amount and type of melanin determines one’s skin color. When estimating a person’s age, skin color uniformity was amongst the most important feature.

When we think about race, ethnicity and culture the definitions are very important.

  • Race: an objective term that includes people of the same heritage who may or may not share genetic similarities but possess similar physical qualities.
  • Ethnicity: a subjective term, that is self-assigned, each person determines the group that they most readily identify with & feel most connected to.
  • Culture: refers to a set of patterned beliefs, values, conventions, or social practices of a group & may or may not take into account the concepts of race or ethnicity.

Often times we interchange these terms and it’s important for us to understand that the “Face of America” is changing. Our current population is over 301 million with people of color being the fastest growing segment. Skin lightness is a global concern. Skin color is a sign of health, attractiveness and youthfulness; it also affects job and marital prospects as well as earning potential.

What really changes things is the media as it depicts beauty and youth almost simultaneously. Dr Callender feels that it important for all of our patients, among a variety of ages and skin types, that beauty is really skin deep.

Cosmetic Concerns Among Women of Color

A survey was conducted regarding cosmetic concerns in 100 women (81 African American, 16 Hispanic, and 3 Asian). The mean age was 41 years old. 86% of the women were concerned with hyperpigmentation or dark spots; 80% were concerned with blotchy, uneven skin; 77% found combination oily or oily skin was of concern; 49% claimed sensitive skin; and 40% found that rough skin was an issue. (Grimes PE, Dermatol Clinics. 2000)

Cosmetic Procedures in 2013

Screen Shot 2015-06-16 at 5.13.59 AM

Reference: ASAPS.Cosmetic surgery national data bank statistics. http://www.surgery.org/professionals/index. Accessed Sept 2014.

Facial skin again is common across all ethnic and racial groups and varies in severity, age of onset and cultural impact. Skin of color patients demonstrate signs of rhytids at a later age than do individuals with fair skin and signs of facial aging in darker skin occurs 10 to 20 years later than in Caucasians. This is due to the photoprotective properties of epidermal melanin. The mean protective factor from UVB in skin of color is 13.4 versus 3.4 for white skin. Remember that mid-facial volume loss and prominent tear troughs are striking features of skin aging in African Americans and perioral rhytids are less common. Photo-aging differences in Hispanics and Latinos are less characterized, but vary considerably due to the broad range of skin types in this population. As dermatologists, we must be aware of nuances surrounding facial rejuvenation for patients with diverse racial and ethnic backgrounds.

Botulinum Toxin-A in African Americans

There are several published studies looking at neuromodulators in skin of color. One of the early studies of onobotulinum toxin by Grimes and colleagues found that there was really no difference in terms of adverse events in skin of color patients and maximal response was observed on day 30 with 92.4% and 100% response, respectively. (Grimes, Shabazz.Derm Surg 2009;35(3):429-436) Kane and colleagues studied abobotulinum toxin with different dosing and also found no significant racial or ethnic differences in safety. African American subjects had a slightly higher rate ocular adverse events and a lower rate of injection site reactions. The response rates and duration were slightly higher in African American subjects (177 days in AA versus 109 in overall population), the reason for this is unknown. (Kane, et al. Plastic & Reconstructive Surg 2009;124(5):1619-1629.)

When we look at neuromodulators in Asian patients, we see differences in response rates with 10 units versus 20 units; however, there were no differences in adverse events. (Harii & Kawashima. Aesth PS 2008;32(5):724-730.) What are we really looking for among all of these studies is safety issues and that’s what’s important across all of these studies. A study of onobotulinum toxin in Brazilian patients, followed by TCA 35% peel and manual dermabrasion 7 days post-injection resulted in transient PIH in 33% of the subjects. Additionally, significantly less wrinkles were seen from 90 days to three years in subjects treated with onobotulinum toxin versus placebo. (Kadunc et al. Dermatol Surg 2007;33(9):1066-1072.)

Clinical Pearls for Skin of Color Patients

  • Appropriate lighting and close examination is needed in identifying and avoiding blood vessels in darker skin
  • Post-inflammatory hyperpigmentation (PIH) is uncommon but may occur from needle injection points
  • Many Eastern Asian patients desire to have wider & rounded appearance of the eyes. BTX-A treatment using 2u lower eyelid & 12u crows feet is a nonsurgical option for these patients (Flynn, et al. Derm Surg 2001;27(8):703-708.)
  • In Eastern Asian patients, the dose should be a six-point injection to the masseter (three-points per side for a total of 50-60 units). (Ahn BK, Kim YS, Kim HJ, Rho NK, Kim HS. Consensus recommendations on the aesthetic usage of botulinum toxin type A in Asians. Dermatol Surg 2013 Dec;39(12):1843-60.)

Conclusions

In general, there are no racial or ethnic differences in the treatment of facial lines with botulinum toxin-A. Safety and efficacy in all skin types has been demonstrated in many published clinical studies. As with any aesthetic procedure, understanding and consideration of cultural diversity must be given to each patient’s individual aesthetic ideals.

Judy L. Seraphine, MSc-Maui Derm News Editor

 

 

 

 

 

 

TNF-a Inhibition and the Treatment of Hidradenitis Suppurativa

Bruce Strober, MD, PhD

In this presentation, Dr Strober provides us with new data on TNF alpha inhibition in the treatment of hidradenitis suppurativa (HS). HS is sometimes referred to as acne inversa; however, Dr Strober feels it is a different disease based upon a lot of lines of evidence.

Based on recent insights into the pathogenesis of this disease, TNF inhibition has found to be an effective treatment. Essentially, it’s phenomenological, because if you look at lesional skin, there is more TNF alpha as compared to peri-lesional as compared to control skin. This isn’t to say that TNF is the only relevant cytokine; in fact, it may be the first of many which will be targeted over the next decade. Just like in psoriasis, TNF will be the first cytokine studied for targeting in HS.

Screen Shot 2015-06-01 at 9.12.04 AM

Etanercept

Overall, etanercept (ETN), at the doses that have been studied, does not appear to be effective treatment for HS. The prospective, double-blind, placebo-controlled trial of 20 subjects were randomized 1:1 for ETN 50mg BIW versus placebo for 24 weeks. The primary efficacy endpoint assessed the Physician Global Assessment (clear or mild). Secondary endpoints included change in Patient Global Assessment and quality of life (DLQI). The results demonstrated that there was no statistically significant difference in benefit between ETN and placebo. There are some case reports that also verify this phenomenon.

Infliximab

The case reports for infliximab, which were published several years ago, showed efficacy in the treatment of HS; however, many patients had concomitant IBD, which is not uncommon among patients with HS.

A prospective, double-blind, placebo-controlled trial of infliximab IFX) included 38 subjects randomized to either IFX or placebo. The study’s primary endpoint was a 50 percent reduction in HS Severity Index (HSSI) at week 8 and secondary endpoints included change in Visual Analog Scale (VAS) and DLQI.

Screen Shot 2015-06-01 at 9.12.16 AM

As noted in the table above, the HSSI score takes into account a variety of features, including dressing changes and pain—which are aspects of the HS experience that should be queried with each patient.

Screen Shot 2015-06-01 at 9.12.38 AM

As we can see, about 25%-30% of patients on IFX have a reduction in HSSI score versus the placebo group. If you look at the 25%-50% reduction range, you can still see a bias towards IFX. Dr Strober feels that these are good data substantiating the value of IFX for the treatment of HS.

The VAS score as well as DLQI also show that IFX did better than placebo.

Dr Strober has used IFX on at least forty patients and feels that it really is the best drug out there, if you can access it. He also recommends using it with methotrexate to sustain the effect of IFX.

Adalimumab

Adalimumab (ADA) represents the best set of studies done to date for the treatment of HS. The PIONEER II study looked at the safety and efficacy of ADA versus placebo in patients with moderate-to-severe HS after treatment for the first 12 weeks. The endpoint involved counting abscesses and inflammatory nodules. The HiSCR score, which Dr Strober feels is a valid score, is not dissimilar from other endpoints, in that it measures relevant issues in HS.

The study design was rigorous, in that they did a randomized, placebo-controlled approach. They key point here is that ADA will be dosed weekly, not every other week as it is when treating psoriasis. The phase II studies showed that ADA every other week did not perform as well.

Screen Shot 2015-06-01 at 9.13.00 AM

Interestingly, many more women were enrolled in this study than men. Also of note, is that two thirds of the patients in the study were smokers. Remember that HS is a systemic, inflammatory disease. Much like psoriasis, we should think of it as a systemic syndrome of inflammation.

When we look at the data (below), we can see the numerical improvement in the rating scale of skin pain is biased towards ADA versus placebo and we can see more people achieving a HiSCR on ADA versus patients on placebo.

Screen Shot 2015-06-01 at 9.13.12 AM

The ADA group also does better with regard to inflammatory lesion count reduction as well as the Sartorius Score reduction.

The safety data are remarkably clean in these studies, particularly focusing on infection, serious infection and malignancy. If anything, there were more events in the placebo group.

Clinical Pearls

What do we need to remember about HS?

  • HS is a chronic, negatively life-impacting disease.
    • Associated with metabolic syndrome (obesity, DM, HTN, dyslipidemia)
  • Pathogenesis multifactorial; primarily inflammatory and not infectious, and our understanding is evolving
  • Phase II/III studies with adalimumab are the best studies, to date, and convincing of efficacy and good safety
  • Infliximab also is very effective

 

MauiDerm News Editor-Judy L. Seraphine, MSc

 

Antibiotic Stewardship and Isotretinoin

Presented by Guy Webster, MD, PhD

Written by Judy Seraphine, MSc

In this presentation at Maui Derm 2015, Dr Webster discusses the proper use of antibiotics, i.e., “antibiotic stewardship” and how the use of isotretinoin can help us avoid the use of antibiotics.

Dr Webster states that the philosophy of antibiotic use used to be “bacteria are bad, kill them all.” The yang of that philosophy, which we are beginning to appreciate more, is that bacteria are really a part of our personal ecosystem, whether on the skin or in the gut, and that if we mess with our own personal ecosystem, we may cause problems. There’s reasonable data showing that antibiotic use among children at a young age can lead to increased weight gain as they get older due to changes in their flora that become stable.

Remember that antimicrobials are in many soaps and personal products. In fact, 75% of adults have detectable levels of antimicrobials. Topical antibiotics are available over-the-counter and are not regulated (e.g., polymyxin, neomycin, bacitracin). Dr Webster feels that the big problem with antibiotic usage is in farming. The concept here is that antibiotics promote animal growth. The United States uses 29 tons of agricultural antibiotics per year. Resistant strains, as well as antibiotics themselves, can get into wastewater from livestock and poultry farms leading to a potentially altered microbial ecosystem as well as causing disease.

MRSA has also been seen in animals. Strain ST398 was a sensitive Euro human strain that crossed into animals. The use of tetracycline to increase hog weight gave birth to resistant ST398 variants, including MRSA. This strain is now recovered from human infection as well as supermarket beef and pork (30%) and shopping cart handles (10%). There is a clear crossover from the farm to the community. (Nature 499:398, 2013) Data suggest that 30% of farm workers using tetracycline feed have tetracycline-resistant MRSA nasal colonization. On the contrary, only 2% of workers from antibiotic-free farms carry nasal MRSA.

Dr Webster asks us to think about this question—in the face of ongoing agricultural abuses, will what we do with the use of antibiotics make a difference?

The dermatology specialty has a long history of profligate antibiotic usage and until recently, most dermatologists were not study-driven as many diseases are too rare to easily study. We also know that many diseases are said to respond to antibiotics; however, they are not infections (e.g. acne, rosacea, eczema, hidradinitis, bullous pemphigoid).

How do we decide how/when to use a long-term antibiotic?

Long-term antibiotic use is defensible when you are treating a real disease that could harm the patient and clearly responds to antibiotics, and there is nothing more sensible, safe, and/or affordable.

Granuloma annulare (GA) is a great example. There are case reports published in several journals supporting the long-term use of antibiotics for GA; however, recent studies have shown little benefit and this is probably something that we, as dermatologists, should stop doing.

Doxycycline is clearly effective for the treatment of mild-to-moderate bullous pemphigoid. It has demonstrated superior safety as compared to prednisone and may be given for years.

Reasonable evidence and randomized controlled trials support the use of doxycycline and minocycline for the treatment of acne. The use of cephalexin, azithromycin, penicillin, ampicillin, ciprofloxacin, and TMP/SXT is only supported by anecdote or smaller studies. While many dermatologists prefer personal experience over data, Dr Webster believes that we need to shift away from this and use what has shown to be effective in studies.

The duration of oral antibiotics for the treatment of acne has not been widely studied. Recent guidelines suggest that it should be limited to three to six months. A retrospective cohort study, published in 2014, found that the mean duration of use was 129 days and among the 31,634 courses, 57.8% did not use concomitant retinoid therapy. Although the duration of antibiotic usage is decreasing compared with previous data, some patients are still receiving them for longer periods than they probably need; thus increasing exposure and cost.

Data show that the use of topical retinoid plus an antibiotic is effective for the treatment of acne and after three months, if patients are on the topical retinoid alone, they tend to do as well as those patients who are on combination therapy or an antibiotic alone. The key is to utilize the retinoid from the beginning.

One concern for all clinicians is the development of resistant strains with the use of long-term antibiotics. Unlike the current beliefs about the long-term use of antimicrobial agents, one study found that the prolonged use of tetracycline antibiotics commonly used for acne treatment lowered the prevalence of colonization by S aureus and did not increase resistance to the tetracycline antibiotics. (Antibiotics, Acne, and Staphylococcus aureus Colonization Matthew Fanelli, MD, Eli Kupperman, BA, Ebbing Lautenbach, MD, MPH, Paul H. Edelstein, MD, and David J. Margolis, MD, PhD)

Minimizing Antibiotic Use

Besides giving an antibiotic with a retinoid, you need to consider patient fears, common sense, cost and adverse events. The UK is very concerned about resistance and they tend to use isotretinoin much faster.

Clinical Pearls

  • No topical monotherapy
    • Add benzoyl peroxide to minimize resistance
  • Oral antibiotics should be given with a topical retinoid
    • Allows for discontinuation of antibiotic after three months in most
  • Earlier switch to isotretinoin or spironolactone when antibiotic + retinoid fails

Isotretinoin Issues

Isotretinoin has been used for many years and, in fact, the longer we use it, the safer we have deemed it to be. Isotretinoin resistance can develop from inadequate dosing, virilization, being taken on an empty stomach, young patients with bad disease, and competing medications. Data show that a meal high in fat increases the absorption of isotretinoin.

Screen Shot 2015-05-14 at 6.28.20 AM

Common adverse events (AEs) among patients taking isotretinoin include dry skin, dry lips, high triglycerides and acne flares. Uncommon AEs include elevated CK and elevated AST and ALT. Patients may also experience dry eyes, decreased night vision, depression, and acne fulminans, i.e., an eruption of bad acne in a patient who may have had relatively trivial acne.

Isotretinoin-induced acne fulminans is uncommon, but devastating. It is most often seen early in the treatment of patients, usually on too high of a dose, with moderate-to-severe chest acne. If someone presents with a few nodules on their chest, Dr Webster will often start them at 20mg/day of isotretinoin along with one month of prednisone 20mg/day.

Isotretinoin and bowel disease has become a worry. There have been scattered reports of patients flaring as well as scattered reports of safe usage. Retrospective studies have shown no link or a very weak link between IBD flares and isotretinoin usage. There may; however, be a link between acne and IBD and antibiotics and IBD. (J. Invest Derm 2012, doi:10.1038/jid.2012.387)

 Many small studies, although not all adequate, have been conducted looking at the association between isotretinoin and bone mineral density (BMD). A recent study using DEXA found that there was no change from the beginning to the end of isotretinoin treatment in patients’ BMD.

Regarding depression, studies have shown that there are no differences in depression among teens taking isotretinoin versus antibiotics and that there is no greater risk of suicide in isotretinoin versus non-isotretinoin. But, there are always case reports where someone is on the drug and gets depressed, goes off the drug and gets better, then goes back on and gets depressed again. Those outliers probably have something real going on. Studies have been conducted looking at patients with bipolar disease. If you have a known bipolar teen whom you are looking to put on isotretinoin, you may want to consult with the psychiatrist.

 

 

 

 

 

 

 

Social Media

Jeff Benabio, MD

In this presentation at Maui Derm 2015, Dr Benabio reviews some important issues around social media and medicine. Dr Benabio reminds us that there’s a general feeling of malaise among physicians. Why do we suppose there is such angst in healthcare? One reason to consider is that doctors are uncomfortable with the idea that they are being rated on the Internet.

There are several factors that have contributed to the changes we see in healthcare; these include the digitalization of healthcare, consumerism and healthcare reform. Social media is one of the main digital aspects of medicine. When we think about social media, try not to think just “FaceBook.” Social media a lot more—it is all of the tools that allow us to connect and share with other people.

It is important to remember is that it’s not just about the numbers. What we need to understand is why the numbers [of views/hits] can be so astronomically high and why that can be important in healthcare. The numbers are high because a. the information has essentially become free; b. we are wired to connect; and c. smartphones are ubiquitous. When we put all of this together, we see very different behaviors. We can see this in business and in healthcare. Consumers/Patients are acting differently because information is free and everyone can connect to everyone.

Economists have discussed the idea that we are reaching a state whereby consumers, i.e., patients have what’s referred to as “perfect information.” Patients now have almost “perfect information” about their disease, their hospital, their health plan, their doctor, etc. They can choose what they do about it. For us, as healthcare providers, we need to understand that this is where our patients are going to get their information. We need to know the information that’s out there, particularly the information about our practices and ourselves.

There are whole fields of study around what’s called ‘behavioral economics.’ Studies are looking at how consumers behave in certain situations. This is the same thing in healthcare, i.e., how patients behave when they have information that they didn’t have before. Consumers used to choose products based on a. prior information; b. other opinions; and c. marketing. Today, things are fundamentally different. Prior experience is no longer perfect; in fact, consumers are nowhere near as loyal to brands as they used to be. Your prior experience is not nearly as informative as other people’s opinions. We can begin to question whether we know what’s right or whether the crowd knows what’s right. We, as consumers, truly believe that other people have good information. Marketing, today, is much easier to ignore.

If we consider healthcare, a recent study showed that 62% of consumers/patients have used online reviews to learn about doctors and this number is continuing to grow. There are websites, such as healthgrades, that provide very good information. The whole purpose of healthgrades is to provide accurate information to consumers about their healthcare choices. Healthgrades retrieves their information from quality metrics and national service metrics. In a few years, your data may be publicly reported as they are already doing that now with hospitals and consumers love it.

While consumers like healthgrades, they trust Yelp more than any other review site. As physicians, that may be a hard pill to swallow. Consumers use Yelp for other decisions with very good accuracy. A 2014 paper by Hanauer and colleagues surveyed patients regarding physician-rating sites. They found that 40% of patients say online reviews are very important and 35% of patients selected a physician based on a positive review. Additionally, 37% of patients avoided a physician with negative reviews.

Doctors are very concerned with how these reviews are filtered. Do you have to pay for advertising in order to obtain positive reviews? Dr Benabio has done some research on this question. A recent study, using regression analyses, looked at correlations between whether physicians had paid for advertising or not and whether that had any impact on if Yelp filtered the review. It turns out that the factors that were significant were having either a one-star or five-star review. Whether or not you were a Yelp advertiser or not did not make a difference.

For the most part, our patients love us. The average score for a doctor is 9.3 out of 10. Patients are interested in wait times, billing/payment, staff friendliness, ease of scheduling, and office environment/cleanliness.

Consumers of all types use Google. Eighty-six percent of patients Google their symptoms before they see a doctor. Google is running “pilot” physician consultations with patients when they search for healthcare-related topics. Consumers are realizing that they can get point-of-question care live from platforms like Google. HealthTap is another site that is aggressively recruiting physicians to participate in point-of-question care. HealthTap is connecting these questions with patients to enable them to do live video visits with a doctor. Doctors are now doing house calls again…they are meeting patients wherever they are. This is a normal expectation for consumers.

Another site, Iodine, allows patients to input their medications and then provides them with perfect information from other patients’ ratings on that prescription/product. Real Self is a similar platform for cosmetics. Today’s patients want transparency. A Deloitte study found three out of four consumers believe providers should publish quality of care information on the Internet. Two out of three patients believe that providers should publish their prices online.

Other Social Media Sites

Twitter is technically a microblog. It’s a way to say “what are you doing?” It’s a powerful tool to share information and report news. About one in four physicians use social media daily, mostly for keeping up with healthcare news. Plastic surgeons tend to lead with 50% of them using Twitter. Virtually all surveys of physicians who use social media say that it has a positive effect, i.e., it increases patient engagement, improves care delivery and patients are more satisfied. Doctors also feel more connected to patients and peers and it is a great tool for education.

Doximity is a social networking site for doctors. It allows you to take topics from a journal and engage in a conversation with your colleagues. Doximity also has very interesting crowd-source data.

What about Instagram? Instagram is a photo application that tends to be very much in the moment. There are 150 million active users and it’s the most popular social media site for teenagers.

How does social media affect healthcare usage? The American Academy of Facial Plastic and Reconstructive Surgery conducted a poll and found that one in three respondents in a survey pool of 2700 of its members said that they had seen an increase of procedure requests as a result of patients’ social media awareness.

In the last few years, FaceBook has gone public and as a result, they are now filtering posts. This is trying to drive you towards paying for advertising. As it turns out, people respond better to ads than they do random posts.

Summary

In conclusion, we need to recognize that the future of dermatology and healthcare is digital. As physicians, we needn’t use all of the existing social media sites but we must understand social media as it is changing what it means to be a patient. Sincerity and commitment to our patients is “always in.”

 

MauiDerm News Editor-Judy L. Seraphine, MSc

 

 

 

 

 

 

 

 

 

Growth Factors in Photodamaged Skin: Clinical Pearls

Zoe Diana Draelos, MD

Dr Draelos provides us with her clinical pearls on growth factors (GF):

  • GF are multifunctional peptides active in the picogram range
  • GF act as signaling molecules between cells by binding to cell surface receptors
  • GF modes of targeting:
    • GF release into the blood stream to reach distant targets (endocrine mode)
    • GF diffuse over short distances to affect other cells (juxtacrine mode)
    • GF influence neighboring cells (paracrine)
    • GF act on the cells in which they are produced (autocrine mode)
  • GF relevant to cosmeceuticals are epidermal growth factor, keratinocyte growth factor, fibroblast growth factor, platelet-derived growth factor
  • Epidermal growth factor is produced from macrophages and monocytes, it affects epithelium and endothelial cells stimulating the proliferation of keratinocytes, fibroblasts, and endothelial cells
  • Keratinocyte growth factor is a small signaling molecule that binds to fibroblast growth factor receptor 2b found in the epithelialization-phase of wound healing
  • Fibroblast growth factor is a very potent angiogenic factor derived from monocytes, macrophages, and endothelial cells (22 human FGFs identified) that induces proliferation of endothelial cells, keratinocytes, and fibroblasts
  • Platelet derived growth factor is produced by platelets, macrophages, neutrophils, smooth muscle cells and induces proliferation of smooth muscle cells and fibroblasts
  • Current controversy exists as to whether growth factors are drugs or cosmetics

Immunotherapy Update

Keith T. Flaherty, MD

At Maui Derm 2015, Dr Flaherty, a medical oncologist at Massachusetts General Hospital, reviewed updates in melanoma therapy for advanced disease and how these drugs have impacted clinical care. As we try to build on targeted therapy based on our current knowledge of pathways, we ask ourselves what will be the role of combinations and/or precision medicine-type immune therapy matching strategies. Of note, the therapies discussed are investigated in the metastatic setting first, and as dermatologists, we are considering their use in the adjuvant setting.

Ipilimumab

Ipilimumab was the first entry into the field in terms of a positive phase III trial. Ipilimimab at 3mg/kg, with or without gp100, was given every three weeks for four treatments. Based on the data, there’s no question that ipilimumab outperformed the gp100 vaccine alone. This outcome, at the level of overall survival, demonstrated the efficacy needed to warrant the approval of ipilimumab.

Screen Shot 2015-04-07 at 10.36.22 AM

Click to Enlarge

 

Ipilimumab was already a ten-year old therapy for which metastatic melonama patients were taking the drug for a few months course of treatment and who are still alive and well. Dr Flaherty states that we knew, when these results emerged, that there may be a truly, durable, lasting effect.

There is a cost to this type of treatment in terms of adverse events (AEs). All of the toxicities associated with this drug come from autoimmune attack(s) affecting the skin, large intestine, endocrine glands, or hepatic autoimmune injury. Why these tissues and not others? There are several theories, but not a firm understanding. If you focus on the ipilimumab monotherapy group, you can look at those who had severe autoimmune toxicity, i.e., you have to stop giving the drug and/or give high-dose corticosteroids to stop the autoimmune reaction. This occurs about 10 percent of the time. Everything short of this autoimmune toxicity appears, in short, in mild or moderate form and basically goes away without any immunologic intervention.

Phase III MDX010-20 Study:  Most Common irAEs (Grades 3-5) Over Entire Study

Click to Enlarge

 

The idea is that we think we’re unmasking normal tissue tolerance, but in a largely reversible way. About two thirds of patients who receive ipilimumab have some form of autoimmune toxicity, only about 10 percent have enough of it that it creates a truly life-threatening scenario for which we need to intervene. Not all of the toxicities manifest at the same time. Dr Flaherty feels that in major melanoma programs, we have become quite comfortable with regards to counseling patients as far as what to look out for and when to call with suspected reaction(s). Dr Flaherty believes that ipilimumab is a therapy that can absolutely be safely administered.

The other phase III trial that corroborated the effects of ipilimumab looked at patients taking ipilimumab (10mg/kg) plus decarbazine (850 mg/m2) or dacarbazine (850 mg/m2) plus placebo at weeks one, four, seven, and ten, followed by dacarbazine alone every three weeks through week 22. This trial was similarly positive with the addition of ipilimumab. The difference, as shown below, was really not very different from that of the ipilimumab versus vaccine trial.

First-line Ipilimumamb/DTIC vs DTIC: OS

Click to Enlarge

 

The toxicities of the two-drug approach were modestly worse. When the FDA looked across the two data sets, they didn’t feel that the addition of chemotherapy was synergistic; therefore, they went with the previous study and approved ipilimumab as a monotherapy for metastatic melanoma.

In clinical practice, you can look at the pooled data set (below) and feel comfortable counseling patients that they have about a 20 percent chance of walking away with the diagnosis of metastatic melanoma by receiving this treatment (four doses over three months) with time-limited risk of toxicity.

Ipilimumab Analysis:  Pooled OS Analysis

Click to Enlarge

 

We have learned that if you “cherry-pick” patients and only treat those with lower disease burden, the rate may be as high as 30 percent.

The PD-1 Pathway

What is the role of the PD-1 pathway in suppressing anti-tumor immunity? How might we think about deploying antibodies that try to intercept this negative immune regulator? We can target on either the PD-1 side or the PD-L1 side [with antibodies]. Scientifically, we would anticipate that this would alleviate the negative influence that the expression of this immune marker on tumor cells can produce in terms of silencing T-cells directly. There was a belief that PD-L1 target is actually safer than PD-1 targeting because you don’t disrupt PD-L2/PD-L1 interactions that a PD-1-blocking antibody would and there is some clinical evidence that this may be true.

Pembrolizumab

Pembrolizumab was FDA-approved in the late summer of 2014. In the pivotal, randomized study, patients who had received ipilimumab and/or a BRAF inhibitor, if they were BRAF mutant, were randomized to receive pembrolizumab 2mg/kg IV every three weeks (ongoing), pembrolizumab 10mg/kg IV every three weeks (ongoing) or chemotherapy. This was a trial that was aiming to show that patients who had exhausted the available therapies could benefit from treatment with pembrolizumab. This data set addresses the unmet need of patients who don’t get a benefit from ipilimumab.

Primary End Point:  PFS (RECIST v1.1 Central Review)

Click to Enlarge

 

The data (above) is impressive when looking at pembrolizumab compared to chemotherapy at the level of progression-free survival. This is clearly a positive study and very important data for patients who had exhausted all of the other treatment options. It is true; however, that this therapy does not work for all patients and about half of patients will still experience disease progression. The number of patients who have objective responses, again these are patients who have not exhausted all other options, appears to be about 20-25 percent.

Two different doses were investigated in this study (2 mg/kg Q3W and 10mg/kg Q3W). Because there was no difference in efficacy, the lower dose, which is modestly safer, was the regimen that was approved. The toxicity is identical in type with ipilimumab. This type of immune therapy produces the same autoimmune reactions in terms of the affected organs and tissues. The issue is that the severity is clearly lower than that of iplimumab.

AEs of Clinical Interest for Pembrolizumab

Click to Enlarge

 

If you look at the Grade 3 and Grade 4 AEs (above), notice how there are only a few autoimmune toxicities in the approved pembrolizumab group (2mg/kg).

For our patients, this is a drug that can be effective and a bit less dangerous in terms of autoimmune toxicities.

Nivolumab

Nivolumab, another PD-1 antibody that was approved in December 2014, was studied in patients who had not received prior therapy. Patients were randomized to nivolumab (3 mg/kg IV every two weeks) plus placebo or placebo plus dacarbazine (1000 mg/m2 IV every three weeks). The thought here was that if you were going to conduct a clinical trial that was chemotherapy controlled, you couldn’t include BRAF-mutant patients because you wouldn’t offer them decarbazine as a front-line “cytotoxic” therapy. Patients in this study were stratified based on PD-L1 status.

This drug has a huge impact in terms of overall survival.

Primary Endpoint:  Overall Survival

Click to Enlarge

 

The data demonstrate a one-year overall survival rate of 73 percent. Many practitioners look at the evidence and would like to get PD-1 antibodies in the front-line. Currently, these drugs are approved for second- or third-line.

Progression-free survival clearly improved as well with nivolumab. These are immune therapies, but they have a clear impact on tumor burden as well. About sixty percent of patients have some demonstrable tumor effect.

When you see a response, the likelihood that the response is going to be durable through six and twelve months of follow-up is very likely.

PD-L1 status is an interesting biomarker to which we should pay attention. The overall survival outcome for patients whose tumors express PD-L1 on their surface does better than the control group and the overall population. (see below)

OS by PD-L1 Status*

Click to Enlarge

 

It is fairly clear that we can do some enrichment by using PD-L1 on the tumor as a biomarker.

Combination Therapy

In the medical oncology metastatic melanoma field, there is a lot of research around the concept of combining PD-1 and CTLA-4-blocking antibodies. Tumor responses in patients receiving nivolumab plus ipilimumab demonstrated that approximately 90 percent of patients responded after a follow-up of about 13 months.

Cli

There is still a group of patients who remain refractory, even to two-drug therapy. This phase I data ultimately launched a large phase III trial and we expect to see the data in June of this year (2015). The combination regimen cannot be given at the full dose of each drug; at least one of the therapies has to be attenuated. The data in the phase III trial is not quite as robust; however, we look forward to hearing the results in June.

When you look at the best available data with PD-1 monotherapy (pembrolizumab), this is actually not bad (below). Dr Flaherty feels that it is still unclear as to whether combination therapy is lifting us to a new plateau. We need more evidence to support that. Regarding safety, in patients who were taking combination therapy at the doses that were taken into the phase III trial, there was a sixty percent rate of severe (Grades 3 and 4) autoimmune toxicity. The results from the phase III data will help us to determine whether or not this combination therapy can be clinically useful.

Pembrolizumab Change in Tumor Size

Click to Enlarge

 

Adjuvant Therapy

There is some preliminary evidence on adjuvant therapy as we only have an interim result from a trial looking at ipilimumab monotherapy versus placebo in 951 patients with high-risk, stage III, completely resected melanoma. The primary endpoint was recurrence-free survival. If you focus on hazard ratio, there is about a 25 percent improvement. The question is whether or not this drug is really doing something more effective in the adjuvant setting than it would otherwise do in the overt metastatic setting. This is not clear—we need to see more data, more follow-up, and more overall survival evidence to know if this is a therapy that should be moved to the high-risk, resected setting. This therapy can have significant toxicity consequences, so we do have reason to be concerned.

Toxicities are substantial in the adjuvant setting. Notice the rate of Grade 3 and 4 toxicities. (below) This is the same drug that has a ten to twelve percent toxicity rate in the overt metastatic setting, but more in the adjuvant setting—partly because of the higher dose.

Safety:  Immune-related Adverse Events

Click to Enlarge

 

There were treatment-related deaths in this trial. This is not something that we can take lightly.

Vaccines

From 2010 to 2015, in the metastatic melanoma field, we have run about twelve phase III trials and they have all been positive, except for the most recent of the vaccine trials, a MAGE-3 peptide. Prior to this, we have had three peptide vaccine trials suggesting a detriment in overall survival. We still have not found a way to deploy these therapies. Dr Flaherty states that many of us are hopeful that either by using some biomarker selection strategy or, more likely, using these agents with immune checkpoint antibodies, we may be able to find utility in steering immune responses towards specific epitopes. Currently, there are no ongoing phase III trials.

Conclusions

Ipilimumab was the first-in-class immune checkpoint inhibitor and has demonstrated survival advantage. Long-term follow-up clearly supports survival impact with only three months of therapy. PD-1/PD-L1 is considered “best-in-class” based on higher response rates and better disease control; however, the percentage rate of long-term survivors is unknown. The combination of ipilimumab/nivolumab suggests synergistic toxicity and the question remains regarding synergistic efficacy. The adjuvant role of therapy is still not defined as we only have interim data for ipilimumab at the higher dose.