Updated AAD Guidelines for the Management of AD with Phototherapy and Systemic Therapies

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New guidelines for the management of adults with atopic dermatitis (AD) using phototherapy and systemic therapies were recently published in the Journal of the American Academy of Dermatology (JAAD). The new guidelines update the previous 2014 recommendations for AD management in patients who do not respond to topical therapies. After their comprehensive review, Davis et al strongly recommend the use of dupilumab, tralokinumab, baricitinib, abrocitinib, and upadacitinib; conditionally recommend phototherapy, cyclosporine, methotrexate, azathioprine, and mycophenolate; and do not recommend systemic corticosteroids.

A multidisciplinary workgroup completed a systematic evidence review process by identifying and prioritizing clinical questions and outcomes, completing systematic retrieval and assessment of evidence, and assessing the certainty of the evidence and formulation of recommendations using Grading of Recommendations, Assessment, Development, and Evaluation. Evidence of the effectiveness and safety of phototherapy and systemic therapies was determined from systematic reviews and meta-analyses of randomized controlled trials (RCTs). A patient representative was also included in the workgroup to provide patient preferences and opinions.

Phototherapy

According to Davis et al, phototherapy using UV radiation is effective for skin conditions such as psoriasis, AD, and cutaneous lymphomas, and although it has been used for decades, “there are few modern, high-quality RCTs evaluating the efficacy and safety of phototherapy for AD.” A Cochrane review was commissioned to support the AAD’s updated guidelines and included 32 clinical trials with 1219 randomized patients. Narrowband UVB (313 nm wavelength) was the most studied treatment (13 clinical trials), followed by 6 clinical trials of UVA1 (340-400 nm) and 5 clinical trials of broadband UVB (290-320 nm).

“Based on low certainty evidence (downgraded due to imprecision from small sample sizes and risk of bias), we make a conditional recommendation for the use of phototherapy to treat AD. Narrowband UVB is the most widely used form of phototherapy; this may be because of its established efficacy for psoriasis and safer track record than UVA1 and broadband UVB. Notably, our conditional recommendation does not include the use of PUVA, for which we have insufficient evidence to make any recommendation,” wrote Davis et al.

The authors noted that potential adverse effects of phototherapy include sunburn-like reactions, intolerance due to heat from the light source, and the risk of skin cancer due to UV radiation exposure. Additionally, one pitfall of phototherapy is accessibility, according to Davis et al.

Monoclonal Antibodies

Dupilumab and tralokinumab are both FDA-approved biologics for the treatment of AD in adults, with overall strong efficacy and safety data. According to Davis et al, dupilumab at standard dosing (600 mg subcutaneously at initiation, then 300 mg every 2 weeks) is slightly less efficacious than higher doses of JAK inhibitors, but has better efficacy than abrocitinib 100 mg daily and comparable efficacy to upadacitinib 15 mg daily. The workgroup surveyed its members on their favorite first-line systemic agent, and all members favored dupilumab. An international expert panel also favored dupilumab as a first-line treatment, however, that survey was conducted before the approval of tralokinumab and other JAKs.

Tralokinumab at standard dosing (600 mg at initiation followed by 300 mg every 2 weeks) significantly improved the signs and symptoms of AD and quality of life in multiple clinical trials, and had no major safety signals, similar to dupilumab. Currently, there are no head-to-head studies comparing tralokinumab to any other systemic therapies. “We recommend both dupilumab and tralokinumab; while there is high-certainty evidence for their efficacy and they appear safe, the overall certainty of evidence was downgraded to moderate certainty due to statistical inconsistency in adverse events analyses,” wrote Davis et al. Conjunctivitis is commonly observed with both dupilumab and tralokinumab.

JAK Inhibitors

Numerous JAK inhibitors are approved or are being studied for the treatment of AD, rheumatoid arthritis, psoriatic arthritis, alopecia areata, and inflammatory bowel disease. Upadacitinib and abrocitinib are 2 selective JAK inhibitors approved for the treatment of patients with moderate to severe AD who have failed other systemic therapies such as immunosuppressants, corticosteroids, antimetabolites, and injectable biologics. According to Davis et al, in most cases, upadacitinib and abrocitinib are not commonly considered first-line systemic therapies. However, both JAKs demonstrate high efficacy at reducing the signs and symptoms of AD, with rapid onset of action in phase 3 clinical trials. Higher doses of upadacitinib (30 mg daily)and abrocitinib (200 mg daily) show the highest efficacy at reducing EASI scores up to 16 weeks compared to all currently available treatments in a network meta-analysis and were superior to dupilumab in head-to-head clinical trials.

Baricitinib is currently approved for the treatment of AD in Europe, but not yet FDA-approved in the US for AD. “While no head-to-head clinical trials were done, network meta-analysis suggests baricitinib is less efficacious than upadacitinib and abrocitinib,” wrote Davis et al.

As commonly discussed with JAK inhibitors, the AAD’s guidelines mention boxed warnings associated with JAK inhibitors after a rheumatoid arthritis trial of tofacitinib reported major adverse cardiovascular events and malignancies in patients 50 years and older. It is important for clinicians to be aware of the risks associated with JAK inhibitors, but those risks should not scare clinicians away from prescribing JAKs. Davis et al additionally recommend that clinicians should encourage shingles vaccines for older patients before beginning JAK inhibitors. Complete blood count with differential, liver enzymes at baseline (and after initiation or dose-escalation), lipids after initiation, and testing for viral hepatitis, tuberculosis, and pregnancy at baseline should all be performed.

Antimetabolites and Immunosuppressants

Cyclosporine, methotrexate, azathioprine, and mycophenolate were conditionally recommended by the AAD guidelines based on low or very low certainty evidence. Evidence was downgraded for risk of bias and imprecision due to small sample sizes. According to Davis et al, in one head-to-head clinical trial, cyclosporine was more effective than methotrexate for up to 16 weeks, after which they were similarly effective. In another clinical trial, azathioprine and methotrexate had almost identical efficacy through 12 weeks of treatment. In a network meta-analysis, cyclosporine dosed between 3 and 5 mg/kg per day is more effective than methotrexate and azathioprine. There is even less randomized trial evidence supporting the use of mycophenolate.

Cyclosporine, methotrexate, azathioprine, and mycophenolate require baseline and ongoing laboratory monitoring for adverse effects. Cyclosporine is commonly associated with renal impairment and hypertension, methotrexate is associated with liver damage, and azathioprine and mycophenolate are associated with cytopenias.

“Systemic corticosteroids are commonly prescribed for people with moderate-to-severe AD. This may be because they are very effective in the short term and easy to prescribe, with general practitioners and specialists familiar with their use for many other diseases. However, we conditionally recommend against systemic corticosteroids for use in AD,” wrote Davis et al.

Systemic Therapies With Insufficient Data and Gaps in Research

Davis et al noted that there is insufficient data to recommend the use of PUVA phototherapy, systemic antibiotics, oral antihistamines, montelukast, apremilast, ustekinumab, intravenous immunoglobulin, interferon gamma, omalizumab, tumor necrosis-alpha inhibitors, systemic calcineurin inhibitors (other than cyclosporine), or mepolizumab for the treatment of AD.

When considering what’s next in AD management, the authors wrote that more RCT data is needed to better understand the use of phototherapy for the treatment of AD. Comparisons of different phototherapy modalities and comparing phototherapy to other treatments such as systemic therapies would provide additional clarity.

“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. Active comparators enable a better understanding of how new treatments fit into the current treatment paradigm, improving shared decision-making for patients and clinicians. Robust evidence would also be helpful to understand how phototherapy and systemic medication regimens can be best used to achieve longterm control of AD,” wrote the authors.

Davis et al stated that all AD clinical trials should include core outcome measures from the Harmonizing Outcomes Measures for Eczema (HOME) group, including EASI (Eczema Area Severity Index), Patient Oriented Eczema Measure (POEM), 24-hour Peak Pruritus Numeric Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and either the Recap of Atopic Eczema (RECAP) or Atopic Dermatitis Control Tool (ADCT).

Concluding Thoughts

After their comprehensive review, when AD is more severe or refractory to topical treatment, Davis et al strongly recommend the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and updacitinib. The authors make conditional recommendations in favor of phototherapy, cyclosporine, methotrexate, azathioprine, and mycophenolate, and they advise against the use of systemic corticosteroids.

Reference

Davis D, Drucker A, Alikhan A, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2023. doi.org/10.1016/j.jaad.2023.08.102.