Steven R. Feldman, MD, PhD
Amlitelimab is a monoclonal antibody that targets the OX40 ligand (Weidinger et al). It is predicted to have broad potential therapeutic application for multiple immune diseases, including atopic dermatitis. I'm not looking for that. I've been spoiled by drugs that have narrow therapeutic application (like IL-23 blockade and IL-4/IL-13 blockade) that target a specific disease very effectively with very little in the way of side effects.
The OX40 ligand/receptor interaction may be too important. When I Google "OX40 deficiency," the first thing that pops up is a combined T- and B-cell immunodeficiency associated with possible aggressive, childhood-onset, disseminated, cutaneous, and systemic Kaposi sarcoma. That doesn't mean that such a horrible outcome will come with the level of pharmacologic OX40 blockade that we would try to achieve in our patients. Clinical trials don't show horrible adverse events — so far. I'm in no hurry to find out in my patients whether real-life efficacy in large numbers of people treated for long periods of time matches up with the short-term safety profiles seen in relatively small clinical trial populations.
It might be nice to give patients upadacitinib only as needed, for example for a flare of their atopic dermatitis, then cut down the dose or stop altogether until the next flare. The study by Guttman-Yassky and colleagues found that atopic dermatitis came back quickly when upadacitinib was stopped. However, their study looked at patients with chronically bad atopic dermatitis. If we have a patient who tends to flare only intermittently, it may be that we could use upadacitinib or other systemic treatments on an intermittent basis. I know when it came to my son's mild atopic dermatitis, intermittent use of a little triamcinolone ointment was all that was needed. Yes, I know that's a "reactive," roller-coaster approach. Yes, I know that a "proactive" keep-the-disease-away approach sounds better. But I'm realistic when it comes to patients' adherence behaviors. I think there's a lot to be said for minimizing drug exposure and just using treatments as needed. Guttman-Yassky's work makes me believe that a lot of patients will need continuous treatment to keep their severe disease under control. I'm not convinced that everyone will need continuous treatment to be happy with their treatment.
O'Connor and colleagues found that emollient bathing is associated with later development of atopic dermatitis. They defined emollient bathing as baths with oil or emulsifier-based additives. This study illustrates the importance of randomization in a controlled trial. Because their study was not randomized, we don't know whether the emollient bathing caused atopic dermatitis or whether families that had more dry skin or more family history of atopic dermatitis were more likely to use emollient bathing.
When dupilumab was first approved, I prescribed it to my patients to take every 2 weeks as recommended on the label. I'm not so sure how many patients actually used it that way. I suspect that a lot of them took the medicine less often than recommended, especially when they were doing well. This report by Sánchez-García and colleagues suggests that patients who are doing very well on dupilumab may be able to take the drug less often. That's probably not news to my patients who are already taking the drug less often than I told them to.
I think less frequent dosing may become even more common over time, particularly for drugs that may have more safety risks than dupilumab. Many patients with atopic dermatitis probably don't need to be taking drugs all the time. Patients who tend to have flare-ups but who do very well for a long period of time between flares may only need drugs intermittently. It will be interesting to see if our patients can use oral treatments for atopic dermatitis that way.
Siegfried and colleagues assessed how well dupilumab worked in children with atopic dermatitis in different areas of the body: head and neck, trunk, upper extremities, lower extremities. Dupilumab worked well in all these areas, as expected.
Xu and colleagues did a meta-analysis of studies of dupilumab for atopic dermatitis and concluded, not shockingly, that dupilumab is safe and effective for atopic dermatitis. Okay, I believe that. They further concluded: "More long-term, high-quality, controlled studies in different regions are needed for further verification." I don't think so. I think the evidence is clear already.
Studies that measure the levels of things are generally not particularly helpful. The study by García-Reyes and colleagues studied the levels of serum thymic stromal lymphopoietin (TSLP) in patients with atopic dermatitis. TSLP levels were higher in patients with atopic dermatitis compared with patients without atopic dermatitis. This basically tells us nothing about the role of TSLP in atopic dermatitis. The elevated levels could be causing atopic dermatitis or they could be the body's response to having atopic dermatitis.
To tell whether something is causal we have to look at either genetic studies or studies with specific inhibitors. A specific inhibitor study was done by atopic dermatitis expert Eric Simpson and colleagues.1 This was a randomized, placebo-controlled study in which an anti-TSLP antibody was given to patients with atopic dermatitis. Both the anti-TSLP antibody and placebo groups were permitted to use topical steroids. While the anti-TSLP antibody–treated patients did better than placebo-treated patients, the difference did not achieve statistical significance, probably, I believe, because the placebo-treated patients used more topical steroids. When you want to assess whether a drug for atopic dermatitis is better than placebo, you must be careful about how much topical steroid you let patients in the study use!
Additional Reference
- Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80(4):1013-1021. doi: 10.1016/j.jaad.2018.11.059