Recent Developments

Dermatologists Issue Guidelines for Opioid Management Following 87 Common Procedures

New dermatologic procedure recommendations for opioid management seek to help curtail the opioid epidemic and reduce the number of opioid overdose deaths.

The new consensus statement, developed by a group of 40 board-certified dermatologists, including Mohs micrographic surgeons, dermatopathologists, and cosmetic dermatologists, appears online in the Journal of the American Academy of Dermatology.

According to the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH), overdose deaths involving prescription opioids increased nearly 400 percent from 1999 to 2017. In 2017, more than 70,000 Americans died from drug overdoses, and almost 68 percent of these deaths involved a prescription or illicit opioid. While the CDC has released general opioid prescribing recommendations for health care providers, there remains a need for guidelines that are specific to dermatologic procedures to address variation in prescribing patterns and practices.

“The hope is that this will serve as a tool to help safely guide the management of patients’ post-procedural pain,” says dermatologist and Mohs surgeon, Lindsey Collins, MD, FAAD, who played a key role in creating the guidelines. “We think it will help curb potential opioid misuse by addressing pain in a procedure-specific manner.”

After extensive discussion, the panel of dermatologists developed recommendations for 87 of the most common dermatologic procedures, measured by morphine milligram equivalents (MME):

• Routine opioid prescriptions are unnecessary for 66 of the procedures, as these can be adequately managed with acetaminophen and/or ibuprofen.
• A prescription of one to 10 opioid doses (equal to oxycodone 5mg) for the duration of the patient’s recovery may be necessary for 16 of the procedures, including scalp and cheek reconstruction.
• A prescription of one to 15 opioid doses (equal to oxycodone 5mg) for the duration of the patient’s recovery may be necessary for only one of the procedures: upper lip reconstruction, known as the Abbe flap.

No procedure routinely requires more than 15 opioid dosess (equal to oxycodone 5mg).

Lead study author and dermatology resident at the University of Oklahoma Health Sciences Center Justin McLawhorn, MD, says that many of the procedures that require one to 10 opioid doses are performed by dermatologists and Mohs surgeons on a daily basis. In comparison, the sole scenario requiring up to 15 opioid tablets is a complex repair that is not often performed. He also pointed out that the recommendations are presented in a quick-reference manner, enabling dermatologists to easily consult the suggested personalized pain management for their patients.

As Dr. McLawhorn notes the guidelines are not meant to be a one-size-fits-all solution and are only meant to apply to patients who do not experience any complications during or after the procedure. He suggests that dermatologists should have a discussion with their patients about their expectations for managing post-procedural pain, including the risks of opioid use. “These recommendations must be individualized to accommodate each patient on a case-by-case basis while ensuring that all patients receive safe, effective pain treatment,” he said. “The guidelines are another tool in dermatologists’ arsenal that can be used to provide adequate pain counseling for patients undergoing these procedures.”

The authors are also hopeful that the new recommendations will resonate with patients. “We think patients will appreciate that their dermatologists are taking steps to limit the over-prescription of opioid pills,” says Dr. Collins.

The CDC warns that taking prescription opioids for long periods of time can increase the risk of addiction and overdose, yet despite the evidence of potential for abuse and misuse of opioids, more than 191 million opioid prescriptions were given to American patients in 2017.

Statistics such as this one, say the authors, make these guidelines all the more timely and crucial for dermatologists to help lead and serve as patient advocates in confronting the opioid crisis.

Poll: People Who Developed AD Symptoms as Kids Experience More Severe Symptoms

Individuals who begin experiencing atopic dermatitis (AD) symptoms as children have vastly different patient journeys and experiences than those who began experiencing symptoms as adults, a new survey from Health Union suggests.

Of the survey’s 400 respondents, there was a nearly 50-50 split between the respondents who began experiencing symptoms before they turned 18 and those who started experiencing symptoms after turning 18.

Those who experienced AD symptoms prior to age 18 were more likely to have recently dealt with accentuated skin lines, skin cracks, cracks behind the ears, eye symptoms, hives, and bumps or patches that bubble up and weep fluid. They are also impacted by AD symptoms on various parts of their body, including on or around their ears, eyes, mouth, neck, shoulders, hands and skin folds, the survey showed.

Those who experienced symptoms prior to adulthood reported having more than half of their body covered, whereas those who developed symptoms as adults were more likely to report less than five percent of their body covered.

Individuals who were symptomatic before turning 18 were more likely to say they also experience a number of related conditions in conjunction with their AD including allergic contact dermatitis, allergic rhinitis, asthma, food allergies, skin infection, eye problems, and anxiety or depression.

Respondents who began experiencing symptoms as adults go through a range of concerns as they seek care and treatment. These respondents were more likely to not agree with their health care professionals on the severity of their condition and more likely to say they don’t feel their AD is under control with their current treatment plan.

Additionally, female respondents who started experiencing symptoms after they turned 18 were more likely than those who started experiencing them before age 18 to say their AD symptoms worsened after a number of life events, including pregnancy, during and after menopause, and after undergoing a hysterectomy.

Atopic Dermatitis In America 2019 surveyed 400 people impacted by atopic dermatitis from March 13 to July 23, 2019.

Psoriasis Onset AGe Determines if Psoriatic Arthritis Patients Develop Arthritis or Psoriasis First

Age of psoriasis onset determines whether arthritis or psoriasis starts first in people with psoriatic arthritis, finds a new study presented at the 2019 ACR/ARP Annual Meeting in Atlanta.

Pustular psoriasis is associated with arthritis onset two years earlier than the intercept interval, and there is an increased delay for nail involvement, plaque psoriasis, or family history of psoriasis from psoriasis to arthritis by approximately two years for each characteristic, the study showed.

This study explored the relationships between the characteristics of skin psoriasis, arthritis, and the timing of arthritis onset using PsART-International, which is a web-based registry of PsA patients under routine care in Turkey, Italy, and Canada. PsART-International includes detailed disease history about the type and onset of skin and joint disease.

“The PsART-International cohort focuses on PsA patients in whom musculoskeletal symptoms start before skin lesions, which is approximately five to 10 percent of all PsA patients. We need more patients to determine related factors,” says Umut Kalyoncu, MD, professor, Internal Medicine and Rheumatology, at Hacettepe University in Turkey, and the study’s lead author. “PsA is a heterogeneous disease for clinical presentation and treatment response. If patients with arthritis first are really a different subgroup, it means that treatment response and prognosis could be different from others. Indeed, in our cohort, achieving minimal disease activity is statistically less frequent in patients with arthritis first.”

The researchers extracted data on demographic characteristics, family history of psoriatic disease regardless of skin or arthritis, types of skin psoriasis, site of skin psoriasis onset and components of PsA ever observed. They tabulated patient characteristics in three groups: arthritis-first, psoriasis-first and synchronous, or onset of skin and joint disease within 12 months. The study’s primary outcome was the absolute time elapsed in months after skin disease to arthritis, with negative values indicating arthritis onset before psoriasis.

The study included 1,631 patients, representing 71 who had arthritis first, 309 with synchronous onset, and 1,251 who had psoriasis first. According to their findings, the age of psoriasis onset, not arthritis, determined if arthritis or psoriasis would appear first. Their analysis also shows a 65-month delay of arthritis onset after psoriasis when other independent variables are set to their baseline values.

“In the cluster analysis, we know that psoriasis has at least six different subtypes: starting age of disease, extensity of skin involvement, psoriasis skin type (pustular or plaque), nail and musculoskeletal involvement. Starting age of psoriasis is particularly important, because it depends on the genetic background,” says Dr. Kalyoncu. “Early-onset psoriasis is strongly associated with HLA-Cw6. However, late-onset psoriasis is not associated with it. In our study, arthritis first is highly related with late-onset psoriasis. This means arthritis-first patients may be a different subgroup of PsA, and treatment response could be worse in these patients as well. If these results are confirmed in other, well-defined PsA cohorts, we may have determined a subgroup of this highly heterogeneous disease.”

Keloid Breakthrough: Mount Sinai Researchers Show Keloid Shrinkage with Dupilumab

Keloid lesions exhibit increased IL-4/IL-13 signaling and respond to Th2-targeting dupilumab therapy, Mount Sinai researchers report.

Researchers, led by Emma Guttman-Yassky, MD, PhD, Vice Chair, Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York, presented a case study of a patient with moderate to severe atopic dermatitis (AD) who also had two keloids: one large and one small.

The patient was treated for AD with dupilimab and approximately seven months later, one of the smaller keloids completely disappeared, with approximately 50 percent reduction in the size of larger keloid. Further investigations of lesional keloid and non-lesional skin from additional keloid patients identified high expression of IL-4R, Il-13 and an important mediator of type 2 pathway, CCL18. (See images below.)

The immune markers in the skin of keloid patients were increased not only in lesional skin but also in their non-lesional skin, which suggests that the entire skin layer of patients with severe keloids is abnormal and prone to additional keloid formation, supporting the use of systemic treatments.

“This major discovery is the first report to show a successful keloid response to the drug dupilumab, which blocks type 2- driven inflammation via IL-4/I-13 receptors,” Dr. Guttman-Yassky says. “The study also showed a disappearance of not only a small keloid but shrinkage of a huge keloid by 50 percent and therefore stands the chance to revolutionize the treatment of keloids.”

The new findings appear in the Journal of European Academy of Dermatology and Venereology.

FDA Accepts NDA for Cassiopea’s Clascoterone Cream 1% for Acne

The FDA has accepted Cassiopea’s New Drug Application (NDA) for clascoterone cream 1% for review. Cassiopea, a specialty pharmaceutical company developing and commercializing prescription drugs with novel mechanisms of action (MOA) to address long-standing and essential dermatological conditions, is seeking marketing approval for clascoterone cream 1% for the treatment of acne. The FDA has set August 27, 2020 as the Prescription Drug User Fee Act (PDUFA) action date.

Clascoterone, a new chemical entity, is a proposed first-in-class topical androgen receptor inhibitor under FDA review for the treatment of acne (in a 1% cream) and in late-stage development for the treatment of androgenetic alopecia (in a higher strength solution) in males. Although clascoterone’s exact mechanism of action is unknown, laboratory studies suggest clascoterone competes with androgens, specifically dihydrotestosterone (DHT), for binding to the androgen receptors within the sebaceous gland and hair follicles. Because of clascoterone’s likely local effect at the site of application, the risk of off-target, or systemic side effects, is minimized.

Clascoterone cream 1% targets androgen receptors at the site of application, inhibiting the local (skin) effects of DHT a key driver of acne lesion development. Laboratory studies show that clascoterone inhibits lipid production from cultured oil-producing cells (sebocytes) and reduces proinflammatory cytokines, mediators influenced by androgens. Thus, pathways that foster acne lesion development appear to be disrupted by clascoterone at the site of application. Unlike oral hormonal therapies for acne, it may potentially be used in both male and female patients.

Revance Submits BLA to the FDA for DAXI to Treat Glabellar Lines

Revance Therapeutics, Inc. has submitted a Biologics License Application (BLA) to FDA for DaxibotulinumtoxinA for Injection (DAXI) in the treatment of moderate to severe glabellar lines. The submission includes results from the SAKURA Phase 3 trials, which is the largest aesthetic neuromodulator clinical program ever conducted for the treatment of glabellar lines.

“The submission of our BLA represents a significant milestone in the company’s history and initiates our transition from a development company to a commercial organization. I’m incredibly excited about the opportunity to introduce the first truly novel advancement in neuromodulator products in over 30 years. We believe that a long-acting neuromodulator product will fill a significant, unmet need in both aesthetics and therapeutics and that the market is hungry for innovation,” says Mark Foley, President and Chief Executive Officer of Revance.

“As we manufacture our own product in the United States, the BLA filing represents a monumental achievement for a company of our size, which was only made possible through the incredible dedication and commitment of our employees. I would like to sincerely thank all of those involved for their tireless efforts,” Mr. Foley adds. “Based on the SAKURA trial results, DAXI has the potential to provide patients with lasting, natural-looking frown line correction all year long with just two treatments. Following this submission, Revance enters a catalyst-rich calendar year of significant clinical trial readouts and meaningful Company milestones, which we believe will culminate in the approval and launch of DAXI in the aesthetic marketplace.”

DAXI has been evaluated in three Phase 3 trials (SAKURA 1, 2, 3). Both SAKURA 1 and SAKURA 2 demonstrated that half of the patients treated maintained none or only mild frown lines for at least 24 weeks (approximately six months), after a single treatment. Additionally, frown lines did not return to their pre-treatment severity for at least 26–28 weeks for half of the patients treated.

CLOSE UP with Stephan Weidinger, MD, PhD

Like many other dermatologic diseases and conditions, atopic dermatitis (AD) may be more than skin deep. The EPI-CARE (EPIdemiology of Children with Atopic Dermatitis Reporting on their Experience) study sought to get a better handle on the prevalence of AD as well as the multi-dimensional impact it can have on adolescents and their caregivers. The results, which were presented at the European Academy of Dermatology and Venereology Congress in Madrid, paint quite a picture of the toll that severe AD can take on quality of life. In fact, adolescents with severe AD reported missing 10.9 school days per year on average, compared to 6.8 days for those with moderate AD and 3.4 for those with mild AD. Among caregivers of an adolescent with severe AD, 87 percent reported missing at least one day of work in the past four weeks, the study showed. Here, study author Stephan Weidinger, MD, PhD Professor of Dermatology at the Christian-Albrechts-University Kiel in Kiel, Germany talks to Practical Dermatology® about the study findings and their wide-reaching implications.

Why is this topic important to study?

Dr. Weidinger: Understanding the prevalence and burden of AD in children and adolescents is important to delineate the daily burden, medical need, and social burden, and to help public health practitioners and policy-makers to prioritize actions, plan interventions and allocate appropriate resources. It also helps to better understand the disease’s natural course

Describe the research and your findings.

Dr. Weidinger: The EPI-CARE (EPIdemiology of Children with Atopic dermatitis Reporting on their Experience) study was a cross-sectional web-based study of the prevalence and burden of AD in children and adolescents. It was performed globally across Europe, North America (US, Canada), Latin America (Argentina, Brazil, Colombia, Mexico), Asia (Japan, Taiwan), the Middle East (Israel, Kingdom of Saudi Arabia, Turkey, the United Arab Emirates) and Russia, using very stringent definitions of AD. In adolescents, the prevalence of active AD turned out to be higher than expected, ranging from 9.29 percent in the US and 14.7 percent in Europe. This confirms the emerging paradigm of AD as a lifelong disease rather than a disease that often outgrows in childhood. Of note, almost 50 percent of the adolescents with current AD reported an overall moderate to severe disease activity, and the majority reported moderate to severe itch, insomnia, pain, and symptoms of anxiety/depression. Adolescents also reported a high burden of coexisting atopic diseases that increased with AD severity—68.6 percent of those with moderate AD and 81 percent of those with severe AD reported at least one coexisting atopic disease. The patients’ quality of life was substantially affected with increasing levels of disease severity. AD places a large burden on patients, their families, and society.

What is the next step?

Dr. Weidinger: We are currently analyzing the data on children in more detail. Once all data has been carefully evaluated, follow-up projects on specific aspects of the disease will be planned.

Live Zoster Vaccine Safe and Effective for Patients on TNF Blockers

The live zoster virus vaccine is safe for people who are currently receiving tumor necrosis factor inhibitor (TNFi) biologic therapies for various indications, according to new research findings presented at the 2019 ACR/ARP Annual Meeting in Atlanta.

Researchers conducted the Varicella Zoster Vaccine (VERVE) trial, a randomized, placebo-controlled, blinded trial of live, attenuated zoster vaccine (ZV) in more than 600 individuals in the US receiving TNFi therapies.

“Because patients with rheumatic diseases are at higher risk for reactivation of herpes zoster, also known as shingles, prevention of this painful condition is exceedingly important. Shingles manifests in most patients as a painful blistering rash that lasts a few weeks, but serious complications such as disseminated disease, eye involvement and even strokes can occur,” says Jeffrey R. Curtis, MD, MS, MPH, a professor of medicine at the University of Alabama at Birmingham’s Division of Clinical Immunology and Rheumatology, and the study’s lead author. “While the need for prevention in patients with rheumatic diseases is compelling, use of any weakened (attenuated) live virus vaccine is potentially a safety risk. There is a theoretical risk that a live virus vaccine could give a patient the weakened form of infection. A major goal of the trial was to understand the safety of this live virus vaccine and to see if it caused infection in any of the participants.”

After vaccination, follow-up for safety occurred over six weeks, the specified risk window for vaccine-related infections that might occur, according to the FDA. The researchers clinically assessed any suspected cases of varicella infection or shingles, in addition to collecting polymerase chain reaction (PCR) data with subtyping to differentiate wild-type versus vaccine-related infection, and digital photographs of the patients. The researchers also collected serum and peripheral blood mononuclear cell (PBMC) samples at baseline and week six to assess participants’ zoster-related immunity, and then conducted safety follow-up through six months after vaccination, when the participants were unmasked to the treatment arm.

Through the sixth week, the researchers observed zero cases of confirmed disseminated or local varicella infection of either wild-type or vaccine strain. This result yielded an upper bound of the 95 percent confidence interval for a vaccine-related varicella infection rate of approximately one percent. Eight patients that did develop a rash were tested for varicella by PCR, but none were positive for infection.

“The clinical significance of the trial is to provide high-quality direct evidence of the safety of this live virus vaccine in patients who previously were warned not to use it because of the theoretical risk for it to cause infection,” says Dr. Curtis. “It also opens the door for the idea that for TNFi users, perhaps other live virus vaccines also may be safe and might be considered in certain circumstances. Future directions for this research group are to rigorously study the new adjuvanted shingles vaccine to better understand its safety, tolerability, and effectiveness in patients with RA and inflammatory bowel disease, using similar methods. A trial of this new shingles vaccine is being planned for these patients and likely will begin in 2020.”

Post-Market Price Changes Alone Account for Most Recent Spending Growth for Biologics

Annual spending on biologics by US public programs and beneficiaries nearly doubled from 2012 to 2016, according to research presented at the 2019 ACR/ARP Annual Meeting in Atlanta. Post-market drug price changes alone accounted for the majority of recent spending growth, and manufacturers’ rebates have little impact on rising costs.

The American public spends billions of dollars each year on biologics, but it is still unclear what factors are driving recent increases in spending and per-patient costs for these drugs. This statistical cost analysis characterized changes in total spending and unit prices for biologics in Medicare and Medicaid and quantified the major sources of spending increases on biologics for public programs and their beneficiaries. Rising drug costs were the main reason for the new study.

“The potential drivers of biologic spending increases have different implications for patient and taxpayer expenditures, and ways to control costs,” says Natalie McCormick, PhD, post-doctoral fellow at Massachusetts General Hospital and Harvard Medical School, and the study’s lead author. “If more patients are receiving biologics, total spending may increase, but the average costs for each patient may not. In contrast, price increases can have a considerable impact on patients’ out-of-pocket costs, as biologics are in specialty tiers where patients pay a percentage of the list price, not a copayment. This can have financial and clinical consequences, as high out-of-pocket costs have posed barriers to biologic initiation and adherence.”

The researchers accessed Medicare Parts B and D and Medicaid drug spending data from 2012 to 2016. These data contained aggregated prescription claims for all beneficiaries enrolled in Medicare Part B (fee for service) and Part D (stand-alone or Medicare Advantage Plans), or Medicaid. All biologics approved by the U.S. Food and Drug Administration (FDA) for one or more rheumatic diseases through December 2014 were included in the study. For each biologic and calendar year, the researchers extracted total annual spending, and number of recipients, claims and doses dispensed, and then calculated the drug unit price or average cost per dose.

For the statistical analysis, they calculated five-year changes in total spending and unit prices for each biologic and in-aggregate, after adjusting for general inflation to 2016 dollars. Then, they isolated the contributions of four sources of spending growth: drug prices, number of recipients (or uptake), treatment intensity (the mean number of doses per claim), and the annual number of claims per recipient for each biologic. They conducted their analysis by including statutory Medicaid rebates, as these decrease public spending, and both excluding and including Medicare rebates, as these are paid by drug manufacturers to pharmacy benefit managers (PBMs) and Part D plans, but do not directly impact patient or taxpayer spending. They used time-varying rebates reported by the Congressional Budget Office.

The study’s results showed that from 2012 to 2016, annual spending by US public programs and beneficiaries nearly doubled from $5.3 billion to $10.3 billion for the 11 biologics included in the study. Drug prices increased by a mean of 52 percent in Medicare Part D and 20 percent in Part B. Controlling for general inflation, unit price increases alone accounted for 56 percent or $1.7 billion of the five-year, $3.0 billion spending increase within Part D. Increased uptake accounted for 37 percent or $1.1 billion. After they accounted for time-varying rebates, price hikes for these drugs were still responsible for 53 percent or $1.4 billion of the Part D spending increase.

Adalimumab and etanercept, two of the oldest biologics, were prescribed to the largest numbers of Part D beneficiaries and also had the biggest unit price increases. Medicaid spending and price trends were similar to Part D. The majority of spending growth for the oldest Part B drugs--rituximab, abatacept and infliximab--was due to price increases, while increases in the number of recipients was the main driver of spending growth for the five newer drugs—golimumab, ustekinumab, tocilizumab, certolizumab, and belimumab.

“With prices increasing, our findings underlie the importance of rheumatologists and patients discussing the costs of DMARD treatment and options for mitigating cost concerns and barriers to effective treatment. These will differ depending on each patient’s financial circumstances and extent of their Medicare coverage,” says Dr. McCormick. “We did not have access to individual-level data in this study but would like to investigate how price increases may impact patients’ out-of-pocket costs and adherence to therapy over the long term, and which diagnoses had the biggest increases in biologic uptake. It will also be interesting to assess the impact of biosimilars on public spending.”