In the clinical opinion of Kaiane A. Habeshian, MD, dermatologists shouldn’t think twice about using systemic agents in pediatric patients with severe dermatologic diseases.
Dr. Kaiane Habeshian
“By the time patients come to us pediatric dermatologists, they have been treated by multiple other doctors, and are frustrated,” Dr. Habeshian said during a virtual meeting held by the George Washington University department of dermatology. “Childhood eczema affects not only patients, but the whole family. For instance, if the child is not sleeping due to itch, their parents are probably not sleeping, either. Parental well-being and workplace productivity are affected, and finances are affected.”
Only a limited number of medications are Food and Drug Administration approved in pediatric patients for common dermatologic indications. These include dupilumab for atopic dermatitis (AD), etanercept and ustekinumab for psoriasis, adalimumab for hidradenitis suppurativa, and omalizumab for chronic idiopathic urticaria. “The approvals are mainly for the adolescent age group, except for etanercept, which is approved at the age of 4 years and above,” said Dr. Habeshian of the department of dermatology at Children’s National Hospital, Washington.
. “These agents are approved for other indications in infants and have many years of data to describe their use in these other conditions, although comprehensive randomized, controlled studies in pediatric patients for dermatologic conditions are lacking,” she said. “What’s in clinical trials for pediatric skin disease? There are multiple ongoing clinical studies of biologic agents in pediatric dermatology, mainly for psoriasis and also for dupilumab in younger patients, as well as a JAK [Janus kinase] inhibitor for alopecia areata.”
Dr. Habeshian noted that while some clinicians may have a knee-jerk reaction to go straight to dupilumab, which was approved in March of 2019 for adolescents with moderate to severe AD, that agent is not currently approved for the most sizable pediatric population with this condition – those under 12 years of age. “FDA approval is important in part because it helps establish safety and optimal dosing, which is often different and weight based in children,” she said. “In addition, FDA approval significantly impacts access to these newer, more expensive medications.”
Speaking from her experience treating patients in the DC/Maryland/Virginia area, Medicaid has consistently denied dupilumab coverage in children under age 12, “even in severe eczema that is suboptimally controlled with both methotrexate and cyclosporine, despite multiple levels of appeal, including letters of medical necessity and peer-to-peer evaluation,” she said. “This can vary across the country among states. However, dupilumab has been completely unattainable in those under 12 in our practice.”
When dupilumab is approved, most insurers first require step therapy with off-label agents for at least 3 months, as well as documented failure of topical corticosteroids, calcineurin inhibitors, crisaborole ointment, and phototherapy (if done). “It’s important to document an objective measure of severity at the very first visit with the SCORAD [scoring atopic dermatitis] or IGA [investigator global assessment],” she said. “Often, that is required if there is any hope for coverage. A familiarity with these requirements is often acquired through trial and error, and may change over time. This can lead to many delays in getting patients these treatments.” Additional information to consider documenting include the disease impact on quality of life, sleep, and school attendance, any hospitalizations for AD flares or secondary infections, and comorbid disease such as asthma.
Meanwhile, dupilumab is under priority review for children aged 6-11 years with moderate to severe AD, with a target action date of May 26, 2020. “It’s unclear how recent events [with the COVID-19 pandemic] will impact that, but there is something to look forward to, and give us hope for our patients,” she said.
Typically, Dr. Habeshian starts her pediatric patients with moderate to severe AD on methotrexate, which she characterized as “a time-tested, affordable, and very accessible option. It requires a little bit less monitoring upon initiation than cyclosporine, and it can be used for longer periods of time before weaning is required.”
In cases when disease is severe or intolerable, she often starts methotrexate and cyclosporine together. “I will usually start right at the 0.5 mg/kg per week rather than titrating up, because this maximizes the response and reduces the amount of blood work needed, unless they have an underlying risk factor for GI distress, or obese patients who are at increased risk for LFT [liver function test] elevation,” she noted. “Patients will note some improvement as early as 2 weeks on methotrexate, but I counsel them to expect 4-6 weeks for maximum improvement. We do not do a test dose of methotrexate at our institution. If there is a slight LFT elevation upon checking labs, ensure that the labs were done at least 4-6 days after the dose, because transient LFT dose elevations are common in 3-4 days.”
GI distress is by far the most common clinical side effect of methotrexate. “We do not do much intramuscular injection of methotrexate, so we rely a lot on folic acid, which reduces the risk of GI distress and elevated LFTs without reducing efficacy,” she said. “We recommend daily folic acid for simplicity, or folic acid 6 days per week.”
Dr. Habeshian said that many pediatric patients can swallow the 2.5 mg tablets of methotrexate “because they’re quite small, and most patients don’t have a problem taking the methotrexate when it’s crushed and mixed with food such as apple sauce or pudding. However, it is critical to discuss proper handling to avoid lung toxicity.” This includes placing the pills in a plastic bag prior to crushing, avoiding inhalation, and avoiding handling near pregnant women and pets, she noted. In addition, she said, “in adolescents, we need to consider the teratogenicity of methotrexate, as well as the possibility of alcohol consumption worsening liver complications. If I prescribe methotrexate in patients of childbearing age, I will counsel them extensively regarding the risk of fetal death and birth defects. If needed, I will start combined oral contraceptives. Ultimately, I’m willing to use these medicines safely, with significant counseling.”
When addressing the risk of methotrexate overdose, she reminds parents to store the medication in a safe place, out of the reach of children. “Patients are at the highest risk of overdose complications if they are given the medication multiple days in a row rather than a one-time, single high dose,” she said. “The literature suggests that one-time overdoses of methotrexate – deliberate or accidental – are unlikely to cause acute bone marrow suppression or hepatitis. This is probably because GI absorption of methotrexate reaches a saturation point, and the kidneys passively and actively excrete the medication at quite a rapid pace so that the methotrexate is often undetectable in the blood at 24 hours post ingestion. I do prescribe a limited supply to help prevent accidental overdoses. In part, this is because if the patient is receiving the medication daily, they’ll run out very quickly, and it will come the family’s attention and to your attention that it’s not being administered correctly.”
Another treatment option to consider for cases of moderate to severe AD is cyclosporine, “which works extremely quickly,” Dr. Habeshian said. “It is very good to rapidly control severe disease while methotrexate or other modes of treatment kick in. It’s best used as a bridge, given the risks of renal damage with long-term use. I like to limit its use to 6 months.”
Cyclosporine comes in two formulations: a modified oral formulation and a nonmodified oral formulation. The modified formulation is absorbed much better than the unmodified formulation. “We start at 5 mg/kg divided b.i.d., which is higher than the recommended dosing for dermatologic conditions in adults,” she said. “This is because children may not absorb the medication as well and may have improved renal clearance. Higher doses may be needed to achieve the desirable effect. In contrast to methotrexate, cyclosporine is available in a capsule, so it cannot be crushed.”
The choice of medication for psoriasis is generally guided by insurance step therapy requirements and is limited in the pediatric population (new guidelines on the care of pediatric psoriasis patients can be found at J Am Acad Dermatol 2020; 82[1]:161-201). In Dr. Habeshian’s experience, methotrexate is the go-to for most patients. “It treats concomitant psoriatic arthritis and can be used as monotherapy or combined with biologics,” she said. “Cyclosporine is useful for erythrodermic, pustular, and severe plaque psoriasis as a bridge. Other options include etanercept weekly in patients age 4-17 years and ustekinumab weekly dosing in patients age 12-17 years.”
Acitretin can be a useful adjunct for younger patients who are unable to obtain biologic agents. “It is most useful in widespread guttate and pustular psoriasis, but can be used be used in plaque psoriasis as well,” Dr. Habeshian said. “It is usually dosed as 0.1-1 mg/kg per day. Improvement in plaque disease is generally seen in 2-3 months of therapy, so it has a slow onset, whereas improvement in pustular psoriasis is seen within 3 weeks.” The most common side effects are dry skin and mucous membranes, while an important consideration is the potential for inducing premature bone toxicity. “It is thought that the risk is relatively low if the daily and total doses are kept low,” she said. “There is no consensus for monitoring bone health. Some clinicians will consider radiography periodically.”
Dr. Habeshian concluded her talk by noting that clinicians should give vaccinations/boosters before starting systemic therapy in young children. “The safety and efficacy of live immunization administered to children on biologics is not known,” she said. “Therefore, if live vaccination is needed, it’s generally recommended to postpone initiating biologic treatment.” The MMR and varicella vaccines are given at 12-15 months of life, with a booster at 4-6 years. The varicella vaccine should be given at least 6 weeks before starting immunosuppressive therapy, and the MMR vaccine at least 4 weeks before starting therapy.
The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled because of the COVID-19 pandemic. Dr. Habeshian reported having no disclosures.