AAD Updates Guidelines for AD Treatment Using Phototherapy, Systemic Therapies

A multidisciplinary workgroup recently updated guidelines from the American Academy of Dermatology (AAD) published in 2014 for treating adults with atopic dermatitis (AD) using phototherapy and systemic therapies.

Although most patients can use emollients and prescription topical therapies to control their AD, the workgroup suggested those with more severe or widespread AD, or whose AD is refractory to topical treatment, to consider using phototherapy or systemic therapies, like injectable monoclonal antibodies (biologics), oral Janus kinase (JAK) inhibitors, or oral antibiotics, to improve disease control and their quality of life (QOL). Consequently, the researchers noted that the guideline’s objective is to provide evidence-based recommendations for AD management in adults and to update those previously published.

To conduct this review, the workgroup used a systematic evidence review process, which involved them identifying and prioritizing clinical questions and outcomes, systemically retrieving and assessing evidence, and assessing evidence certainty and recommendation formulation using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Through a systematic search, they retrieved evidence from systematic reviews and meta-analyses of randomized controlled trials (RCTs) to create their clinical practice guideline.

Adult patient with atopic dermatitis (AD)

Image credit: Monstar Studio - stock.adobe.com

Phototherapy

Although phototherapy is proven to be an effective treatment for multiple skin conditions, the researchers explained that few modern, high-quality RCTs have evaluated its efficacy and safety for AD treatment. Consequently, they used a Cochrane review commissioned to support the guideline, which included 32 clinical trials with 1219 randomized participants. Of the therapies used, narrow-band UV B (313 nm wavelength; 13 trials) was most studied, followed by UVA1 (340-400 nm; 6 trials) and broadband UVB (290-320 nm; 5 trials).

Because of low certainty evidence due to imprecision from small sample sizes and the risk of bias, the researchers explained that they made a conditional recommendation for using phototherapy to treat AD, the most widely used form being narrowband UVB; the researchers explained that this recommendation does not include psoralen plus UVA (PUVA) as they had insufficient evidence to make one for it.

Potential adverse effects from phototherapy include intolerance due to heat from the light source, the risk of skin cancer due to UV radiation exposure, and sunburn-like reactions. Also, the workgroup explained that the biggest shortcoming of UV phototherapy is accessibility as most regimens require treatments 2 to 3 times per week for 10 to 14 weeks; this requires a substantial time commitment from patients, which may not be feasible.

Monoclonal Antibodies (Biologics)

Of available biologics, the workgroup specifically analyzed dupilumab, which targets the IL-4 receptor, and tralokinumab, which targets IL-13; they were the first and second FDA-approved biologics for AD treatment in adults, respectively. They noted that the analyzed RCTs established dupilumab’s efficacy in improving the signs and symptoms of AD and QOL in adults.

“It has an excellent safety track record in clinical trials and few major emergent safety concerns after more than 5 years in clinical practice,” the authors wrote. “We surveyed guideline workshop members as to their favored first-line systemic agent, and all participants favored dupilumab.”

Also, multiple clinical trials found that tralokinumab at standard dosing (600 mg at initiation followed by 300 mg every 2 weeks) significantly improved the signs and symptoms of AD and patients’ QOL. Like dupilumab, there were no major safety concerns identified, but conjunctivitis is a common adverse event for both. Consequently, the workgroup recommended both biologics for AD treatment.

JAK Inhibitors

The workgroup explained that JAK inhibitors, which block the JAK-STAT intracellular signal transduction pathway, are approved or under investigation for the treatment of multiple conditions, including AD. They analyzed upadacitinib and abrocitinib, 2 selective JAK inhibitors that target JAK-1, which are approved for use in moderate to severe AD patients who failed other systemic therapies. The researchers noted that both demonstrated “very high efficacy at reducing the signs and symptoms of AD and improving QOL, with rapid onset of action in their Phase III clinical trial programs among adolescents and adults with AD, leading to moderate certainty evidence.”

The workgroup explained that, in a network meta-analysis and clinical trials comparing them to dupilumab, higher doses of upadacitinib (30 mg daily) and abrocitinib (200 mg daily) demonstrated the highest efficacy at reducing Eczema Area and Severity Index (EASI) scores up to 16 weeks of treatment among all currently available treatments. Conversely, they found lower doses (upadacitinib, 15 mg daily; abrocitinib, 100 mg daily) to be somewhat less efficacious but still show “excellent improvement” in AD signs and symptoms.

Despite its effectiveness, the workgroup noted that patients should take caution if prescribed JAK inhibitors as the FDA applied warnings of increased risk of cancer, blood clots, serious heart-related events, and death. Patients prescribed JAK inhibitors are also at an increased risk of herpes zoster, or shingles; the workgroup recommended patients be vaccinated for shingles before initiating a JAK inhibitor, especially older patients.

Antimetabolites and Immunosuppressants

The workgroup gave cyclosporine, methotrexate, azathioprine, and mycophenolate, the most recommended older systemic therapies for AD, conditional recommendations based on low or very low certainty evidence from related trials. Through a head-to-head clinical trial, they found cyclosporine to be more effective than methotrexate for up to 16 weeks, after which they were similarly effective. In another clinical trial, the researchers found azathioprine and methotrexate to have essentially identical efficacy through 12 weeks of treatment. Also, a network meta-analysis found cyclosporine dosed between 3 and 5 mg/kg per day to be more effective than methotrexate and azathioprine. Conversely, there is less evidence supporting mycophenolate use.

The workgroup explained that the medications also have some negative aspects as each can increase the risk of serious infections. Additionally, they noted that each has its own specific potential end-organ toxicities.

"Because of lower certainty evidence relative to newer medications, the potential for serious adverse events including infections and organ dysfunction, the need for stringent laboratory monitoring, and the absence of FDA approval for use in AD, we do not consider these medications to be first-line treatments," the authors wrote.

Also, despite being commonly prescribed for those with moderate to severe AD, the researchers conditionally recommended against systemic corticosteroids. This is due to low certainty clinical trial evidence, consisting only of a single trial of prednisolone vs cyclosporine that was discontinued prematurely because of rebound flares in the prednisolone arm.

“Because of the substantial risk of serious adverse events with systemic corticosteroids even with short-term use, they are not recommended for AD,” the authors wrote. “Clinicians might consider short courses of systemic corticosteroids in limited circumstances, such as when no other options are available, or as a bridge to other long-term therapies.”

Gaps in Research and Conclusions

The workgroup noted that, currently, there are insufficient data to make a recommendation for the use of various treatments in patients with AD, including PUVA phototherapy, oral antihistamines, and systemic antibiotics.

“As new systemic therapies continue to be developed and tested, we encourage the inclusion of active comparator arms in RCTs, rather than relying solely on placebo-controlled trials,” the authors wrote. “Active comparators enable a better understanding of how new treatments fit into the current treatment paradigm, improving shared decision-making for patients and clinicians.”

More data are also needed for therapies the workgroup conditionally recommended. The workgroup explained that more RCT evidence is needed to better understand the role of phototherapy in AD treatment. Additionally, they suggested conducting larger clinical trials to improve the certainty of evidence for medications cyclosporine, methotrexate, azathioprine, and mycophenolate. Lastly, the researchers noted the need for formal cost-effectiveness analyses, comparing older to newer treatments.

Based on current data, the workgroup recommends patients to consider phototherapy or systemic medications if their AD is more severe or refractory to topical treatment.

“In this clinical practice guideline, we make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baracitinib, and upadacitinib,” the authors concluded. “We make conditional recommendations in favor of phototherapy, cyclosporine, methotrexate, azathioprine, and mycophenolate, and against systemic corticosteroids.”

Reference

Sidbury R, Alikhan A, Bercovitch L, et al. Guidelines of care for the management of atopic dermatitis in adults with topical therapies. J Am Acad Dermatol. 2023;89(1):e1-e20. doi:10.1016/j.jaad.2022.12.029