New Drugs, New Devices

By Ted Rosen, MD

The year 2017 saw many new drugs and devices introduced that show considerable promise for dermatology patients. A fast round-up of what was approved in 2017 (including one December 2016 entry) appears in Table 1.

Table 1.

Drug Brand Approval Date Indication/Area What’s New
Crisaborole Eucrisa® 12/14/16 Atopic dermatitis Good safety data, no limit on therapy duration, safe for use on face and eyelids, etc.
Dupilumab Dupixent® 3/28/17 For moderate-to-severe atopic dermatitis, approved for adults only, minimal adverse events
Guselkumab Tremfya® 7/13/17 Psoriasis Superior to adalimumab for achieving PASI75, PASI90, and PASI100 (44% achieved PASI100 at 24 weeks)
Brodalumab Siliq® 2/15/17 Similar results as guselkumab
Blue Control Device

 

 7/13/17 Wearable blue light for psoriasis
Delafoxaciin Baxdela® 6/19/17 Antibiotic Fluorinated quinolone, wide spectrum
Ozenoxacin Xepi® 12/14/17 Non-fluorinated quinolone, cream for impetigo
Oxymetazoline Rhofade® 1/19/17 For persistent facial erythema of rosacea
Benznidazole Not branded 8/29/17 Chagas disease Oral agent to treat tropical disease
Avelumab Bavencio® 3/23/17 Merkel cell carcinoma New treatment for aggressive neuroendocrine cancer
Pembrolizumab Keytruda® 3/14/17 Hodgkin lymphoma Expanded indication for adult and pediatric Hodgkin lymphoma
H202 40% Eskata® 12/17/17 Seborrheic keratosis Topical solution, 40% solution most effective, 41.3% of lesions clear or near-clear
HZ/su Vaccine Shingrix® 10/20/17 Shingles vaccine May be more effective than current vaccine
Dignicap Cooling Cap 7/3/2017 Chemotherapy-induced alopecia 70% of chemotherapy patients expected to lose all of their hair retained at least 50% of scalp hair
DermaPACE device 12/28/17 Diabetic ulcers 48% of patients had >90% healing at 20 weeks

Note that trademarks and registered trademarks are the property of their respective owners.

 

The “libraries” of therapeutic options for many conditions are being expanded, such as the treatments for atopic dermatitis, psoriasis, and cutaneous cancers. With the wealth of new options comes the need to learn how to best deploy these new drugs and devices for use in our patients. A few highlights follow.

Crisaborole

Atopic dermatitis can be a lifelong condition and one that distresses patients by its appearance as well as by itching. Crisaborole, a nonsteroidal phosphodiesterase-4 (PDE-4) inhibitor, is indicated for patients with atopic dermatitis of at least two years duration. There is no skin atrophy, so it may be safely used on the face, eyelids, skin folds, and external genital areas. It is to be used twice a day and there is no limit on how long therapy may persist.1 See Figure 1 for atopic dermatitis patients treated with crisaborole by the author.

Atopic Dermatitis Crisaborole

Figure 1. Monotherapeutic regimen with crisaborole in an adult woman with atopic dermatitis.

 

Dupilumab

Dupilumab is indicated for moderate to severe atopic dermatitis in adults; it is a monoclonal antibody that works against subunit 4Rα of the interleukin (IL)-4 and IL-13 receptors. It reduced pruritus markedly compared to placebo and the once-weekly and twice-weekly regimens provided about equal effectiveness.2

Avelumab

Avelumab is an anti-programmed cell death (PD)-ligand (L)1 immunotherapeutic agent that has been approved for use in pediatric (≥ 12 years) and adult patients with metastatic Merkel cell carcinoma, an aggressive neuroendocrine cancer with high morbidity and mortality rates. Complete response occurred in 10/88 patients in a phase II trial and 19/88 had partial responses with median overall survival rates of 12.9 months.3

Cemiplimab

This anti-PD-L1 monoclonal antibody is used to treat unresectable locally advanced or metastatic cutaneous squamous cell carcinoma. It is not yet approved but early results hold great promise as the objective response rate in phase I was 46.1%. A phase II pivotal study is currently enrolling. The most commonly reported side effects are fatigue, arthralgia, and nausea.4

Important Trends in 2017

  • The armamentarium of agents is building up, giving us more choices and likely improving treatment for patients
  • Many drugs are now being tested against active comparators—these head-to-head studies provide relevant and valuable clinical information (such as the study that showed guselkumab was superior to adalimumab in achieving PASI75, PASI90, and PASI100)
  • Indications may expand, for example, guselkumab is being investigated now for its potential utility in treating psoriatic arthritis

 

References

  1. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology. 2016;75(3):494-503.e494.
  2. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. The New England journal of medicine. 2014;371(2):130-139.
  3. Joseph J, Zobniw C, Davis J, Anderson J, Trinh VA. Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma. The Annals of pharmacotherapy. 2018:1060028018768809.
  4. Kaplon H, Reichert JM. Antibodies to watch in 2018. mAbs. 2018;10(2):183-203.

 

Pediatric Acne: Putting Best Practices into Actual Practice

By Lawrence F. Eichenfield, MD

Restaurants do it all of the time—something changes and the restaurant must understand the change, adapt to it, and make changes to its system. Changes may seem unimportant—a decrease in local foot traffic, changes in customer preferences for certain foods—but they can impact business. When the change is well managed, the restaurant recognizes it and responds accordingly. If it does this well, the consumer experience remains optimal, the restaurant retains or expands its business, costs are controlled, and outcomes remain favorable.

Why don’t we do this in healthcare? Specifically, why don’t we do this in the field of pediatric acne?

 

Here’s what has changed:

A great deal has been elucidated recently about the preadolescent acne microbiome. Preadolescents with acne tend to be colonized with a greater diversity of cutaneous bacteria than control patients; in particular, Streptococcus species are more prevalent. See Figure 1.

 

Pediatric-Acne

Figure 1. Preadolescent microbiome for acne for healthy controls, acne patients treated with benzoyl peroxide (BP), and those treated with tretinoin. Note that 1 and 2 indicate first visit and pretreatment while 2 indicates the second visit.1

 

In a study of girls between the ages of 7 and 12 with at least six acneiform lesions performed by Ahluwalia et al, patients were treated with benzoyl peroxide (BP) 4% for six weeks (range four to 8 weeks). They were administered a swab to assess the microbiome at week 0 and then at the end of their treatment. This study found that patients with more acneiform lesions were significantly more likely to have more P. acnes bacteria and there were trends toward decreased S. mitis and increased S. epidermis.  This has led to the intriguing observation that P. acnes seems to create a hostile environment for certain pathogens—but allows Staphylococcal strains like S. epidermis to flourish.1 This seems to suggest that early preadolescent acne may involve a shift from a dominant S. mitis in the microbiome to a dominant P. acnes, which is then accompanied by more acne lesions.

Another change has been the switch of BP from a prescription medication to an over-the-counter (OTC) product, as well as the introduction of OTC retinoids (adapalene). OTC products are a cornerstone of acne treatment, but patients seem somewhat less consistent at acquiring OTC products as compared to prescriptions.. In a cohort study of 84 patients (ages 12 to 45) seen in a dermatology clinic for acne, patients were contacted by phone two weeks after their appointment. All patients had been counseled by the dermatologist to purchase an OTC BP product as part of their treatment. Only 20% of the patients remembered what OTC product was recommended and about a third (36%) did not purchase any OTC products, although 93% picked up their prescriptions. Of the 64% of patients who reported that they did buy an OTC acne product as recommended, only 32% of these products contained BP.2

 

Here’s what we can do:

Knowing more about the microbiome, better and more targeted medications can be developed. The antimicrobial effects of BP have been shown to be equivocal.1 Nevertheless, BP is a key part of acne treatment.  BP is now available OTC and patients must be educated that it is an important element in acne treatment and that they must read labels or follow instructions to be sure to get the right OTC product. Some ideas to improve this situation are samples for patients to take home and handouts or other printed materials with product images so the patient purchases the right OTC product.

Pediatric acne guidelines are in place.3 There is a large body of evidence in the medical literature about how to treat pediatric acne. However, in medicine, there is often a time lag between the validation of medical evidence (including published clinical trials and updated guidelines) and their implementation. For example, it took over 15 years for the use of beta-blockade following myocardial infarction to translate into practice as a standard of care for the average heart attack survivor.

Pediatricians are on the frontlines of caring for pediatric acne. While patients can be referred to a dermatologist, it may be more efficient and convenient for patients if the pediatrician could manage these cases efficiently. To that end, these pearls are offered.

  • Pediatricians and the clinicians who work with them should be trained with respect to the guidelines on pediatric acne
  • Training materials for patients should be developed—it would be ideal if these could be ordered via electronic medical records
  • In particular, training materials should offer images of OTC products, if recommended, to assure patients select the right medications

References

  1. Coughlin CC, Swink SM, Horwinski J, et al. The preadolescent acne microbiome: A prospective, randomized, pilot study investigating characterization and effects of acne therapy. Pediatric dermatology. 2017;34(6):661-664.
  2. Huyler AH, Zaenglein AL. Adherence to over-the-counter benzoyl peroxide in patients with acne. Journal of the American Academy of Dermatology. 2017;77(4):763-764.
  3. Eichenfield LF, Krakowski AC, Piggott C, et al. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013;131 Suppl 3:S163-186.

Atopic Dermatitis: Epidemiology & Beyond

By Jonathan I. Silverberg, MD, PhD, MPH

The global prevalence of atopic dermatitis (AD) has been estimated at about 15% to 20% in pediatric and 1% to 10% of adult populations. The prevalence has increased in the past few decades in many regions.

Atopic Dermatitis Prevalence

Figure 1. Reported prevalence rates of AD vary between adults and children and, for pediatric patients, are higher in developing nations than the industrialized world

It was thought that AD prevalence has increased primarily in the developed world, but it is not possible to draw clear lines of demarcation.1 Sometimes national variations can be striking and seem to defy explanation.

For example, among pediatric patients in the age range of 6 to 7 years, the prevalence of AD was, from lowest to highest, 0.9% in India and 22.5% in Ecuador.2 Among older children (aged 13 to 14), prevalence was lower in China, Asia-Pacific, the Middle East, India, and parts of Latin America but higher in some parts of Africa, Northern and Eastern Europe, and Oceania.2 The prevalence rates for AD vary broadly by developed versus developing nation and are higher for children than adults, see Figure 1.

Factors that may help to explain the global variations in AD prevalence:

  • Genetic factors
  • Environmental factors
  • Microbial exposures
  • Immune dysfunction
  • Definitions of AD, eczema, diagnostic criteria3

Most cases of childhood AD start in in the first five years of life. Approximately, 20-50% of childhood AD persists into adulthood.4 However, adult onset AD is quite common, with one in four adults with AD report adult-onset of their disease.5

Emerging data suggest that family structure may play a role in AD rates. Using multivariable logistic regression and adjusting for socio-demographic factors, it was found that US children from single-adult households, families with a mother but no father present, families with unmarried mothers, and families with non-biological fathers had increased odds of developing AD.6 Other risk factors for AD include cigarette smoking and exposure to second-hand smoke.7 Moreover, both adults and children with AD have higher rates of mental health symptoms, such as depression and anxiety.8,9

AD is characterized by a dysregulation of the immune system and a disruption in the skin’s barrier function. These conditions may set the stage for AD-associated comorbidities. Some of these comorbidities may be interrelated and their exact association with AD may not be yet entirely elucidated.10

  • Cutaneous infections, including extra-cutaneous infections (such as sepsis)
  • Disturbed sleep, sleep inefficiency, fatigue
  • Cardiovascular conditions, such as atherosclerosis, myocardial infarction, congestive heart failure
  • Cerebrovascular disorders, including stroke
  • Obesity
  • Hypertension
  • Hyperlipidemia
  • Diabetes type II

The burden of AD is not trivial. Patients experience severe and sometimes relentless pruritus, may have skin pain11 experience sleep and mental health disturbances, and suffer from an unsightly rash that may cause embarrassment and social isolation. Most AD patients (88%) report the daily presence of itchy skin and 69% report that the itchiness lasts at least 12 hours a day. Fifty percent of AD patients report pain accompanies pruritus and 69% describe the itchiness as being severe or unbearable. Most AD patients (90%) report that their AD disrupts sleep at least one night per week.12-14

AD is a highly prevalent condition associated with serious comorbidities, a high disease burden, and great costs to the healthcare system.

 

References

 

  1. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Annals of nutrition & metabolism. 2015;66 Suppl 1:8-16.
  2. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. The journal of allergy and clinical immunology. 2009;124(6):1251-1258.e1223.
  3. Dizon MP, Yu AM, Singh RK, et al. Systematic review of atopic dermatitis disease definition in studies using routinely collected health data. The British journal of dermatology. 2018;178(6):1280-1287.
  4. Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): A systematic review and meta-analysis Journal of the American Academy of Dermatology, Vol. 75, Issue 4, p681–687.e11. Published online: August 18, 2016
  5. Lee HH, Patel KR, Singam V, et al. A systematic review and meta-analysis of the prevalence and phenotype of adult-onset atopic dermatitis. Journal of the American Academy of Dermatology. Published online: June 1, 2018
  6. McKenzie C, Silverberg JI. Association of family structure with atopic dermatitis in United States children. Journal of the American Academy of Dermatology. 2018.
  7. Kantor R, Dalal P, Cella D, Silverberg JI. Research letter: Impact of pruritus on quality of life—A systematic review. Journal of the American Academy of Dermatology, Vol. 75, Issue 5, p885–886.e4. Published online: August 28, 2016
  8. Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic dermatitis. The Journal of allergy and clinical immunology. 2013;131(2):428-433.
  9. Yu SH, Silverberg JI. Association between Atopic Dermatitis and Depression in US Adults. The Journal of investigative dermatology. 2015;135(12):3183-3186.
  10. Silverberg JI. Associations between atopic dermatitis and other disorders. F1000Research. 2018;7:303.
  11. Vakharia PP, Chopra R, Sacotte R, et al. Burden of skin pain in atopic dermatitis Annals of Allergy, Asthma & Immunology, Vol. 119, Issue 6, p548–552.e3. Published in issue: December 2017
  12. Simpson EL, Bieber T, Eckert L, et al. Patient burden of moderate to severe atopic dermatitis (AD): Insights from a phase 2b clinical trial of dupilumab in adults. Journal of the American Academy of Dermatology. 2016;74(3):491-498.
  13. Dawn A, Papoiu AD, Chan YH, Rapp SR, Rassette N, Yosipovitch G. Itch characteristics in atopic dermatitis: results of a web-based questionnaire. The British journal of dermatology. 2009;160(3):642-644.
  14. O’Neill JL, Chan YH, Rapp SR, Yosipovitch G. Differences in itch characteristics between psoriasis and atopic dermatitis patients: results of a web-based questionnaire. Acta dermato-venereologica. 2011;91(5):537-540.