AUSTIN, TEX. – The way Kelly M. Cordoro sees it, the most for which patient.
Dr. Kelly M. Cordoro
“You can look up the dosing and frequency of these drugs; all of that’s available,” she said at the annual meeting of the Society for Pediatric Dermatology. “But how do we think about which drug for which patient? What are the considerations?”
Dr. Cordoro, professor of dermatology and pediatrics at the University of California, San Francisco, described psoriasis as an autoamplifying inflammatory cascade involving innate and adaptive immunity and noted that various components of that cascade represent treatment targets. “We don’t have a true comprehension of the pathophysiology of psoriasis, but as we learn the pathways, we’re targeting them,” she said. “You can target keratinocyte proliferation with drugs like retinoids and phototherapy. You can broadly target T cells, neutrophils, and dendritic cells with methotrexate, cyclosporine, and phototherapy. The newer drugs target the cytokine milieu, including TNF [tumor necrosis factor]–alpha, IL [interleukin]–17A, IL-12, and IL-23.”
There is no one right answer for which drug to prescribe, she continued, except in the cases of certain comorbidities, contraindications, and genetic variants. “For example, if a patient has psoriatic arthritis, then you have methotrexate and all of the biologics that might be disease modifying,” she said. “If a patient has inflammatory bowel disease, it’s critical to know that IL-17 inhibitors will flare that disease, but anti-TNF and IL-12 and IL-23 inhibitors are okay. If a patient has liver and kidney disease, you want to avoid methotrexate and cyclosporine. If there’s a female of childbearing potential you want to be very cautious with using retinoids. I think the harder question for us is, How about the rest of the patients?”
In addition to a drug’s mechanism of action, patient- and family-related factors play a role in deciding which agent to use. For example, does the patient prefer an oral or an injectable agent? Is the patient able to travel to a phototherapy center? Is it feasible for the family to manage visits for lab work and direct clinical monitoring? Does the family have a high level of health literacy and are you communicating with them in ways that facilitate shared decision making?
“The best way to choose a systemic therapy is to develop an individualized assessment of overall disease burden,” said Dr. Cordoro, who is also division chief of pediatric dermatology at UCSF. “Include psychological burden and subjective data in addition to objective measures like body surface area. Look for triggers. Infants are more commonly affected by viral infections and, in a subset, monogenic forms of psoriasis such as deficiency of interleukin 1 receptor antagonist [DIRA]. In general, we try to take a conservative approach in the developing child. As children hit early adolescence and become post pubertal, you have to start thinking about the psychosocial impact [of psoriasis], and we have to start treating patients with the consideration that chronic uncontrolled inflammation can potentially lead to comorbidities down the road. We see this in adults with severe psoriasis and early onset cardiovascular disease, the so-called psoriatic march from chronic inflammation to cardiovascular disease.”
Dr. Cordoro advises clinicians to rethink the conventional “therapeutic ladder” concept and embrace the idea of “finding the right tool for the job right now.” If a patient presents with a flare from a known trigger such as a strep infection, “maybe you want to treat with something more conservative,” she said. “Once you treat, and if the trigger has been managed, they might be better. But some patients will need the most aggressive treatment right out of the gate.”
Tried and true systemic therapies for psoriasis include methotrexate, cyclosporine, acitretin, and phototherapy, but none is approved by the Food and Drug Administration for use in children. “These drugs have decades of experience behind them,” Dr. Cordoro said. “Methotrexate is slow to start but has a sustained profile, so if you can get the patient to respond, that response tends to persist. Methotrexate also prevents the formation of antidrug antibodies, which is important if you are considering use of a biologic agent later on.”
Cyclosporine is best if you need a rapid rescue drug to get the disease under control before moving on to other options. “One in four patients relapse once cyclosporine is discontinued, so the benefit may not be as sustained as with methotrexate,” she said. “Acitretin is a really nice choice when you can’t or don’t want to immunosuppress the patient, and phototherapy is good if you can get it. The advantages of systemic therapies are that they’re easy on, easy off, and you can combine medications in severe situations. Almost all of these drugs can be combined with another, with few exceptions. I would caution that over immunosuppression is the biggest risk ... so this must be done carefully and only when necessary.”
Biologic agents such as TNF inhibitors and IL-12/23 inhibitors are playing an increasing role in pediatric psoriasis. They can be expensive and difficult for some insurance plans to cover, but offer the convenience of better efficacy and less frequent lab monitoring than conventional systemics. In the United States, etanercept and ustekinumab are approved for moderate to severe pediatric plaque psoriasis in patients as young as age 4 and 12 years, respectively. TNF inhibitors have accumulated the most data in children, while data are accumulating in trials of IL-17 inhibitors, IL-23 inhibitors, and PDE4 inhibitors.
“These drugs have reassuring safety profiles; low rates of infection and adverse reactions,” Dr. Cordoro said of biologic agents. “They’ve changed the landscape completely because now the expectation is complete or near-complete clearance. In contrast to the systemic agents, which may be started and stopped repeatedly, you need to think about continuous therapy, because these drugs are immunogenic,” she noted. “Whether antibodies against them become neutralizing or not is a different case. If a patient does have antibodies, it does not mean you have to stop the drug. Dose escalation can help. Increasing frequency of use of the drug can help, but patients will develop antibodies and it may result in loss of efficacy or reactions to the drug,” she added.
“When you’re thinking about using a biologic agent, think about patients who are chronic, moderate to severe, and who will need more long-term therapy. Most importantly, treatment should be individualized, as there is no ‘one size fits all’ approach.”
Dr. Cordoro disclosed that she is a member of the Celgene Corporation Scientific Steering Committee.