Weighing the options
As biologic therapies expand indications to children and adolescents, what do dermatologists need to know about balancing the risks and benefits?
By Allison Evans, Assistant Managing Editor, February 1, 2023
Over the past five years, younger patients have steadily gained access to a range of FDA-approved targeted biologic treatments with lower risk profiles than traditional treatments that target the entire immune system. Up until relatively recently, pediatric dermatologists had few FDA-approved options to treat their young patients with atopic dermatitis (AD) and psoriasis who fail to respond to first-line therapies.
This month in DermWorld, pediatric dermatologists discuss the advantages of biologic therapy for some patients as well as how to explain the risks and benefits with patients, families, and caregivers.
Biologic agents do have a faster onset of action and greater efficacy in general, though there are no head-to-head studies of each biologic against various conventional therapies, said pediatric dermatologist Kelly M. Cordoro, MD, FAAD, professor of dermatology and pediatrics and division chief of pediatric dermatology and McCalmont Family Endowed Professor in pediatric dermatology at the University of California, San Francisco, who co-authored the psoriasis guidelines of care for pediatric patients published in JAAD.
“Targeted therapies have little-to-no risk of end organ damage, such as concerns about rare but possible liver or kidney damage from drugs such as methotrexate and cyclosporine, respectively,” she explained. “That said, conventional systemic treatments remain viable treatment options for many patients. While biologics have transformed the way we treat patients, the oldies remain goodies and should be considered in some cases. Choice of therapy requires a deep knowledge of the benefits and risks of each drug in individual patients. There is no one-size-fits-all approach.”
“The first thing I try to tell patients and their families about biologics is that this is a commitment — this isn’t a temporary thing,” said pediatric and cosmetic dermatologist Karan Lal, DO, MS, FAAD, member of the Society for Pediatric Dermatology. “People can develop antibodies to biologics, and so the patient could get stuck in a position of not having a treatment that’s going to work if they start and stop treatment.”
When to use a biologic
For both atopic dermatitis and psoriasis, it really is an assessment of the extent and severity of the disease — the course of the disease, the impact of the disease on the patient and the family, and in some cases, the comorbidities of the disease, said Lawrence Eichenfield, MD, FAAD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital-San Diego and professor of dermatology and pediatrics and vice chair of the department of dermatology at UC San Diego School of Medicine.
Dr. Eichenfield describes his conversation with patients and their families as “unpacking the backpack of issues.” He asks: ‘When was the last time your skin was totally clear?’ “Often, I’m met with the response, ‘Totally clear?’ This helps document the chronicity of the disease.”
“I also ask patients about the workarounds they do because of their disease,” he said. “Do they change their clothes or only wear certain types of clothes so that their skin isn’t exposed? Do they minimize certain activities because it triggers flares of disease?”
With pediatric patients in particular, it’s important to discuss the impact of the disease on the family as well. There is a lot of burden that goes with continuous management with topical therapy, Dr. Eichenfield noted.
Many factors play into treatment selection for a particular patient, including quality of life, sleep deprivation, psychosocial stress, and lack of responsiveness to other treatments. “If a child has not responded to any other alternative therapies that I deem to be safer, whether for eczema that may be phototherapy, topical steroids, or if the child has been on medications like cyclosporine for longer than six months, then it’s time for a biologic,” Dr. Lal said.
“Part of our assessment is seeing how patients have done with prior therapy, since we really are looking to find patients whose disease is unable to be sufficiently managed or controlled with topical agents,” Dr. Eichenfield said. “There are some patients who are so severe when they’re presenting to us that we may move to biologic therapies very quickly.”
A risk-benefit discussion
Deciding to prescribe a biologic for a pediatric or adolescent patient is always a risk-benefit discussion and a shared decision with caregivers, noted Dr. Cordoro. “We provide as much accurate and balanced information as possible in order to arrive at the best decision for each patient. The goal is to avoid under-treatment of inflammatory skin diseases while limiting the risk of potential adverse effects.”
Dr. Eichenfield finds it helpful to quantify the severity and extent of disease for the patient by letting them know what their global score is and what their body surface area involvement is. “I think this helps patients and the family understand that there is a quantification of how significant their disease is. It can help them see how the disease has impacted them, and that we have the option of biologic therapies with the potential to markedly change the aspects of the disease and the life of the individual — versus not.”
The risk-benefit analysis is similar but dissimilar to adults because it involves family decision-making rather than patient decision-making, Dr. Eichenfield said. “There’s a little bit more premium placed on safety data because children have a long life ahead of them. While caretakers and parents are looking out for the best interests of their children, they’re also trying to decide if the disease is significant enough to warrant systemic therapy.”
It can be useful to discuss the alternatives to not treating with biologic therapies, including comorbidities, as a way to fuel the positives of intervening, Dr. Eichenfield added. “What could be the impact on the child or teen over their lifetime? What are the known sequelae of not treating adequately, whether that’s atopic dermatitis, anxiety, depression, ADHD, and even emerging data on cognitive dysfunction over time.”
Sometimes, it may simply come down to the willingness of the patient, Dr. Lal said. “I may have a patient who is 14 years old and has mild but persistent eczema and is really bothered by it. It’s not severe, but it’s never clear. I’ll offer that patient dupilumab because it’s a very safe biologic. It’s not a true immunosuppressant, and it’s something that is going to do more good than harm.”
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Dupilumab for atopic dermatitis
Dupilumab was first approved for adolescent patients as young as age 12 in 2019. The indication was extended to age six in 2020 and extended once again to six months in June 2022. Approval was based on data from a 16-week pivotal phase 3 trial that evaluated the efficacy and safety of dupilumab added to standard-of-care topical corticosteroids in children aged six months to five years with uncontrolled moderate-to-severe atopic dermatitis. Patients who received the combined treatment experienced a 70% average improvement in disease severity from baseline, compared with a 20% improvement among those in the TCS-only group. They also experienced a 49% improvement in itch, compared with a 2% improvement among their counterparts in the TCS-only group.
“In the extended data sets, the general safety of dupilumab has been consistent with very little label changes and without great concerns about immunosuppression or long term-effects,” Dr. Eichenfield noted.
While dupilumab has been a solid choice for pediatric dermatologists treating pediatric AD patients, more biologics are currently in clinical trials for pediatric indications for AD. Lebrikizumab recently completed its core phase 3 trial with adolescent data, which means an indication including adolescents may be coming in the near future, Dr. Eichenfield said. Additionally, tralokinumab has completed adolescent AD studies, with younger patient studies in process, and nemolizumab, an IL-31 blocker, is in phase 3 trials for pediatric AD.
“There is increasing evidence supporting the safety and efficacy of targeted therapies for treatment of moderate-to-severe pediatric psoriasis,” Dr. Cordoro said. “Anti TNF-α, anti-IL-12 and 23, and anti- IL-17 therapies have been approved in the United States and Europe for psoriasis in children older than four years (etanercept) and six years (ustekinumab, secukinumab, and ixekizumab).”
“Fairly recently, we’ve had this expansion of different types of biologic agents, carrying some incredibly high efficacy, but also with various mechanisms of action and the ability to treat without as many injections per year as prior therapies,” Dr. Eichenfield said.
There are currently four biologic drugs approved for the treatment of pediatric psoriasis in the United States: etanercept, ustekinumab, secukinumab, and ixekizumab. (The European Medicines Agency approved adalimumab for the treatment of psoriasis in children aged four and older who have had insufficient response to topical therapy and phototherapy). Additionally, six drugs are currently in phase 3 clinical trials for pediatric psoriasis: brodalumab, guselkumab, risankizumab, tildrakizumab, certolizumab pegol, and deucravacitinib.
“For pediatric psoriasis patients, the discussion about biologic therapy may be more complex,” said Dr. Lal. “Psoriasis biologics are a little bit more immunomodulatory and have a higher side-effect profile than dupilumab.”
Although etanercept was the first FDA-approved biologic for pediatric psoriasis in 2016 and has also been the most studied in pediatric populations, it’s no longer the treatment of choice for many dermatologists because of the more frequent dosing schedule, explained Dr. Lal. “Who’s going to inject their kid twice a week?”
“While psoriasis patients may do fairly well on a traditional (and inexpensive) medication like methotrexate, it may not give patients the best outcomes,” Dr. Lal added. “If a child is doing fine on methotrexate without any side effects, I’m fine with it. Often, however, methotrexate may not give patients the outcome they want. They’re not going to be as clear as they want to be, and that’s when I go down the biologic pathway.”
Access to treatment
“It is very difficult to get biologics in some cases because they are very expensive, and insurers often require ‘step therapy’ whereby a child’s condition must fail to respond to phototherapy and/or conventional systemics before a biologic will be approved,” Dr. Cordoro said.
“I’m not just going to prescribe it and it’s going to happen,” Dr. Lal added. “I always have to do something else, like a prior authorization, an appeal, and occasionally I have to do a peer-to-peer. Prescribing a biologic is more work than not prescribing a biologic.”
Often, pediatric dermatologists prescribe medications off-label, although now that children are included in clinical trials, there are many more “on-label” options available. “Importantly, just because a medication is FDA approved does not mean it is the best medicine for a given patient at a given time,” said Dr. Cordoro. “Payers use this to their advantage and deny treatments if they are not approved, but this is not medically rational in many cases — and the child suffers because medications necessary to treat them might remain out of reach.”
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“In both psoriasis and atopic dermatitis, the biologic agents have been miraculous to a degree — changing our ability to impact the life of the affected individuals and regularly bringing children and teens to a state where their disease may be minimally manifest and have minimal impact on their life,” Dr. Eichenfield said.
Certainly, side effects exist, but studies show that the risk profiles for biologics are quite favorable. Biologics used for psoriasis can cause a slightly increased risk of infection in the skin, either from bacteria, fungus, or virus, while common side effects for AD patients on dupilumab include nasopharyngitis, infections, conjunctivitis, and injection-site reactions.
“FDA approval provides some reassurance about safety and efficacy, but efficacy and side effects of long-term use remain unknown for a large subset of biologics given the relative novelty of targeted therapies. My personal experience has been very positive, with very few adverse effects overall in large numbers of patients. But there are no guarantees and/or such a thing as a ‘no-risk therapy.’ These are serious medications and must be used with caution by knowledgeable physicians,” Dr. Cordoro said.
“Believe it or not, I have not had any side effects in my pediatric patients with any of the psoriatic biologics,” Dr. Lal said. “With dupilumab, I’ve had two patients develop conjunctivitis, but it was easily managed.”
According to a safety review of pediatric biologic treatments for psoriasis, only 38.7% of patients aged 18 and younger reported one or more adverse effects. Injection site reactions were the most commonly reported adverse effect in 19% of pediatric patients, followed by infections in 11.3%.
In a recent review of the safety and efficacy profile of biologics in children with psoriasis, serious adverse events incidences were low with the IL-17 inhibitor ixekizumab (1%), the IL-12/23 inhibitor ustekinumab (3%), and the TNF inhibitor etanercept (0%). Monoclonal antibodies inhibiting IL-17 signaling and newer IL-12/23 antagonists may offer even greater disease control in pediatric psoriasis with similar or fewer serious adverse events than TNF-inhibitors.
In general, Dr. Lal has minimal concerns about prescribing his young patients biologics. “When parents and patients have concerns about safety, I emphasize that I can only treat them in the vacuum of my knowledge, but I really have to focus on how much the child is suffering and how bothersome the condition is to the patient and parents. I can’t tell patients whether or not they will develop cancer in 20 years because there are so many other factors like whether they will become a smoker, where they live, and genetics.”
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“I base monitoring on the patient at hand and the specific drug I am prescribing. Monitoring should be individualized to the clinical context. Some patients may need little or no monitoring other than an annual test for tuberculosis while others may need more screening labs depending on their medical scenario and comorbidities,” Dr. Cordoro said.
“I teach my residents to be mindful of bloodwork,” Dr. Lal said. “If you’re starting an otherwise healthy child on a biologic, you don’t need to put them through all this bloodwork. We’re learning that it really doesn’t change the outcomes. Why are we ordering the CBC or CMP when these medications aren’t even metabolized through the kidney or bone marrow?”
“With some of the psoriatic agents, there’s a recommendation to do tuberculosis screening prior to the initiation of the agents and on an annual basis,” Dr. Eichenfield added.
Another area of concern for parents and dermatologists may be adjusting vaccination schedules for children on immunosuppressive therapies. Generally, biologic agents do well with non-live vaccines, Dr. Eichenfield said. “Some have been specifically studied to show that they do not negatively impact the efficacy of the non-live vaccines.”
“Live vaccines, however, remain generally unstudied, though there is a groundswell of effort of people to either get official studies or start to report patients who receive live vaccines,” Dr. Eichenfield noted. “In the meantime, we don’t have specific recommendations about how to do live vaccines in the face of our commonly used biologic agents other than the general rule of trying to have patients get up to date on their vaccinations before initiating biologic therapy.”
For Dr. Lal, it depends on the half-life of the medicine, although it is not a science yet. “For example, if a patient is taking ixekizumab once a month, I’ll recommend they be off the therapy for one month. For dupilumab, I usually say to stop the treatment for two weeks before vaccination just to be precautious.”
“We don’t have great data, but many experts will recommend withholding the vaccine until several weeks off of biologic treatment, then giving the vaccination while withholding the biologics for three to four weeks more. Then restart the biologic agent as a way to not overly delay vaccination schedules,” Dr. Eichenfield said.
Weighing the options
“Though there are new drugs available and in the pipeline, we must not forget that there are many options to choose from,” Dr. Cordoro said. “There is rarely one right answer and therefore the risk of medications balanced with the risk of untreated or undertreated disease is important to impart to caregivers of children with inflammatory skin disease.”
Care of children with severe skin disease is nuanced and requires consideration of multiple factors. “Sometimes, such as in the case of infection-induced flare of pre-existing mild psoriasis, a brief course of acitretin or methotrexate may the best move to control the flare and return the disease to baseline rather than committing a patient to a long-term biologic. Other times, in rapidly progressive or more severe disease, immediate initiation of a biologic is the best decision. The more tools and knowledge we have available, the better we are able to manage our patients now and over time,” Dr. Cordoro said.