Reviews weigh benefits, harms of topical, systemic treatments for atopic dermatitis

Key takeaways:

• Pimecrolimus improved six of seven assessed outcomes.
• Upadacitinib was among the most effective but also most harmful.
• Biologics had intermediate effectiveness but were among the safest.

With dozens of topical therapies and systemic treatments available for atopic dermatitis, clinicians have many options. But a pair of reviews in The Journal of Allergy and Clinical Immunology may help them narrow down their choices.

“It’s such a challenging field because, in some respects, there’s too much information,” Derek K. Chu, MD, PhD, assistant professor in the department of medicine at McMaster University, told Healio.

“There’s so much information out there, no patient and no clinician can understand all the data and put it all together and make sense of it all,” he continued. “That’s why we need these kinds of analyses.”

Derek K. Chu

In the first review, Chu and his colleagues analyzed 219 randomized controlled trials (RCTs) of 68 topical treatments for AD involving 43,123 participants. In the second review, they analyzed 149 RCTs of 75 systemic treatments involving 28,686 participants.

“We searched all sorts of registers out there to identify and really squeeze out all of the possible randomized trials that addressed either topical treatments in those with primarily mild to moderate disease or, in those with more moderate to severe disease, any systemic treatment including phototherapy, also called ultraviolet light therapy,” Chu said.

Using network meta-analysis, the researchers weighed the benefits and harms of each treatment and then summarized them in tables designed for easy comprehension that can be used with patients in shared decision-making.

“No study has rigorously compared all available topical treatments, or all available systemic and advanced treatments, in this level of detail,” Chu said.

Topical treatments

The analysis assessed how well topical treatments addressed clinician-reported and patient-reported AD severity, itch severity, sleep disturbance, eczema-related quality of life, long-term control, number of patients experiencing AD flares, adverse events including those leading to discontinuation, and skin infections.

With high certainty, analysis found that pimecrolimus improved six out of seven outcomes and was among the best treatments for two of them. High-dose tacrolimus (0.1%) improved five outcomes and was among the best for two, whereas low-dose tacrolimus (0.03%) improved five and was among the best for one.

Analysis with moderate to high certainty found that group 5 topical corticosteroids (TCS) improved six outcomes and were among the best for three of them. Group 4 TCS and delgocitinib (LEO Pharma, Japan Tobacco) both improved four and were among the best treatments for two of them.

None of these interventions or the interventions in the high-certainty group increased any harms, the researchers wrote, and although crisaborole (Eucrisa, Pfizer) and difamilast (Otsuka Pharmaceutical Co.) had intermediate effectiveness, they also had less certain harms. Topical antibiotics alone or in combinations may have been among the least effective treatments, the researchers wrote.

Overall, the researchers wrote, group 5 TCS were among the most effective treatments in maintaining AD control, followed by tacrolimus and pimecrolimus.

“There are nuances, and I encourage readers to look at the full manuscript and, especially, the summary tables,” Chu said.

“For most patients with mild to moderate disease, the treatments that tend to have the best evidence to show the greatest outcomes in a safe and effective manner are those that would be called moderate potency topical corticosteroids, as well as topical calcineurin inhibitors,” he continued.

Pimecrolimus and topical steroids may be among the most effective options for patients aged 2 years and younger, Chu said, but access may make tacrolimus a better choice for older patients. Also, clinicians may increase steroid potency, but that may come with increased harms and decreased certainty in the outcomes.

Emerging treatments may be interesting and effective as well, Chu continued, but they improve fewer outcomes and may have less certain safety including local side effects such as stinging and burning.

Physicians must consider factors beyond the physical effects of these treatments too, Chu said.

“What is best for my patient in this moment?” he asked. “What is it that they value? Can they access it? Is it cost effective for them? All of those things play into knowing what might be the most effective, most safe, and into making sure it’s the right fit for my patient.”

Systemic treatments

The variety of choices among systemic treatments presents clinicians with pros and cons as well, Chu said, as the researchers assessed their impact on AD and itch severity, sleep disturbance, AD-related quality of life, patient anxiety and depression, number of patients experiencing AD flares and adverse events.

For example, physicians have treated patients with more severe AD who did not respond to topical treatments with immunosuppressants such as azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate and phototherapy in addition to many novel agents, although their effectiveness and safety are uncertain.

“We did find that there actually is some evidence it may be effective, but the trials overall were not as robust as some of us would have thought before the studies went through critical appraisal. There are not many patients studied, so the certainty that they actually improve outcomes as big as we estimated is lower,” Chu said.

The data were much better for monoclonal antibodies, or biologics, Chu continued.

With high certainty, dupilumab (Dupixent; Regeneron Pharmaceuticals, Sanofi), lebrikizumab (Eli Lilly) and tralokinumab (Adbry, LEO Pharma) had intermediate effectiveness and were among the safest treatments with no major side effects and modest increases in conjunctivitis.

Oral Janus kinase (JAK) inhibitors also can be very effective, Chu said.

Specifically, high doses of upadacitinib (Rinvoq, AbbVie) were among the most effective treatments for five of the six outcomes. High doses of abrocitinib (Cibinqo, Pfizer) and low doses of upadacitinib were among the most effective treatments for two outcomes. Low-dose baricitinib (Olumiant, Eli Lilly) was among the least effective treatments.

However, JAK inhibitors were among the most harmful in increasing adverse events.

“The FDA has put a black box warning on all oral JAK inhibitors because of an association with the possibility of cancer, heart attack, stroke, other blood clots, serious infections, and overall mortality,” Chu said.

Deciding on treatment

Chu advised physicians to begin all treatment with a review of the patient’s history, especially if the patient has extensive disease.

“Do they actually respond to topical treatments? And if they do, how well do they respond?” Chu suggested.

The review of available topical treatments and their outcomes gives physicians and patients a starting point for discussing care, Chu said.

Also, Chu said, the review found that applying treatment once a day likely will produce the same results as twice daily treatment.

“It might simplify the regimen for patients,” he said.

Treatment goals should include gaining and maintaining control of active disease via proactive therapy, Chu said.

“It’s actually quite good evidence about what treatment to use,” Chu said. “Use those summary tables as a discussion point, and it will very helpfully bring people through.”

Patients also should practice nonpharmacological options such as trigger avoidance and good skin care, Chu said. But if these practices and topical treatments do not yield results, he said, it may be time to consider systemic therapies.

Again, Chu said, the summary tables in the review of systemic therapies would be a good resource in discussing systemic options with patients and that they can be part of handouts or posters to facilitate shared decision making. Chu and his colleagues are now developing guidelines for clinicians as they walk patients through these decisions.

“The new guidelines are going to be this huge document that runs through all these different scenarios for clinicians about how exactly they can best decide with their patients,” Chu said.

These guidelines also will illustrate the importance of new research and meta-analysis for filling in gaps in research, he said.

“Even though there are some treatments that have been around for a long time, there are big gaps in terms of maybe not addressing what might be most important to patients,” Chu said.

“Maybe they addressed those certain interventions, just clinical signs of eczema, just how the patient looks, but they never asked the patient how they feel,” he continued. “We now need new trials to fill those gaps.”

Also, immunosuppressants may benefit underserved patients, but the data on their use remain uncertain.

“We need them also to be high certainty for what they can do and how well they compare against those new drugs like dupilumab or the oral JAK inhibitors,” Chu said. “It could be cents on the dollar vs. $20,000 a year. It’s a big difference and an important one to society. We need to sort that out.”

Despite these additional gaps, Chu said that both reviews represent the state of the art in comprehensive analyses that were not possible before. He also said that the input of the American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters guideline development group, along with their patient family partners, was invaluable.

“We’re very thankful for their participation, and I think this will inform the guidelines, which I think also will be very helpful for everyone to achieve the best outcomes for patients with AD,” Chu said.

References:

• Chu AWL, et al. J Allergy Clin Immunol. 2023;doi:10.1016/j.jaci.2023.08.029.
• Chu DK, et al. J Allergy Clin Immunol. 2023;doi:10.1016/j.jaci.2023.08.030.

For more information:

Derek K. Chu, MD, PhD, can be reached at chudk@mcmaster.ca.