Proceedings From the First Bridging the Gaps in Atopic Dermatitis Conference

The inaugural Bridging the Gaps conference, held in 2024, gathered working-group experts from several dermatology disciplines across the United States in a Working Group to deliberate on the prevailing challenges and treatment approaches in the field of atopic dermatitis (AD). The topics (including AD pathogenesis, the atopic march, treatment landscape, and therapeutics in the pipeline) had been selected during pre-conference meetings by a chair and expert panel and were covered within 7 sessions. This publication highlights key insights from the Bridging the Gaps in Atopic Dermatitis expert-panel discussion.

The Pathogenesis of AD
AD is a heterogeneous, immune-mediated disease with numerous cytokines implicated in the inflammatory response.¹,² Immune cells drive the cytokine activation, skin-barrier defects, inflammation, itch, skin microbiome dysfunction, and tissue remodeling associated with AD.³ The physical presentation of AD, or phenotype, varies with different skin types.⁴ Molecular endotype also plays an important role in individual patient symptoms (eg, pruritus), and a better understanding of the pathophysiology of AD and the relative contributions of specific cytokines can enable development of more targeted therapies against the appropriate underlying molecular alterations.⁵

Atopic March and Triad
AD tends to peak in infancy and early childhood.⁶ Evidence suggests this primes the body for T-helper cell 2 (Th2)–mediated diseases over time. These include food allergies, asthma, and, later, allergic rhinitis, which has an increased incidence between the ages of 5 and 10 years.⁶ This progression (often called the atopic march) suggests that Th2-mediated diseases are related, eventually resulting in multiple comorbidities.⁶,⁷ Practitioners should ask patients if they have a personal or family history of AD, allergic rhinitis, or asthma (often called the atopic triad) as these conditions may share a genetic link.⁶ Early intervention may stave off later allergic multimorbidity.⁸,⁹

One of the most troubling symptoms of AD is pruritus.¹⁰ Even mild itchiness has been associated with a significant reduction in quality of life (QOL), underscoring the need for patient outcomes of little or no itch.¹⁰ Clinical assessment of treatment response should account for skin clearance and itch, as skin improvement is insufficient without substantial changes in pruritus.

AD is also associated with other skin findings, such as keratosis pilaris, lichenification, pityriasis alba, hyperlinear palms, atopic pleats (also known as Dennie-Morgan lines), and allergic shiners.⁷,¹¹ Practitioners are encouraged to proactively educate patients with AD about these conditions.

Treatment Options in AD
Topicals
Current Guidelines and Recommendations
Gentle skin care practices, proper skin hygiene, and the use of moisturizers and emollients represent the foundation of AD management.¹² Cases of moderate AD require prescription topicals including steroids, traditional nonsteroids (eg, the calcineurin inhibitors tacrolimus and pimecrolimus), and the phosphodiesterase inhibitor crisaborole.¹³ Patients with more severe AD often require systemic treatment.¹³

Novel Nonsteroidal Topicals for AD
Topical therapies for AD have evolved in recent years. Ruxolitinib cream is a topical Janus kinase (JAK) inhibitor approved in 2021. It was given strong recommendation for use in the updated 2023 American Academy of Dermatology (AAD) guidelines for the management of AD with topical therapies, and it has produced rapid improvements in disease severity in clinical trials and real-world settings.¹²,¹⁴⁻¹⁶ Additional nonsteroidal topical therapies include roflumilast cream, a phosphodiesterase-4 inhibitor, and tapinarof cream, an aryl hydrocarbon receptor agonist.¹⁷⁻¹⁹ Both therapies were associated with notable skin clearance and reductions in itch in clinical trial results.¹⁷˒²⁰˒²¹ When selecting the most appropriate topical therapy for AD, panelists indicated that it is important to consider the extent and location of skin involvement, patient preferences (eg, treatment vehicle), whether it is an adjunct to systemics, prior treatments and response, coexisting skin conditions, age, lifestyle, potential compliance issues, complexity of instructions, and pregnancy status. Many panelists avoid topical JAK inhibitors in pregnancy as they await supportive data.

Topical Treatment Use and Access
The panelists agreed that with newer nonsteroidal treatments, topical corticosteroids will hopefully play a reduced role in AD management and be reserved for patients who either fail to respond to other therapies or experience a marked flare (and need only initial short-duration use). Topical corticosteroids can induce skin atrophy, especially with long-term use, and may decrease epidermal lipid production and subsequently increase transepidermal water loss (TEWL).²² Conversely, ruxolitinib has not been associated with skin atrophy and may decrease TEWL.¹⁶ Nonsteroid topicals can also be used as a proactive maintenance treatment. Lastly, these agents may provide and sustain disease remission, which distinguishes them from some other traditional topical therapies. Despite the benefits of newer therapies, the panelists acknowledged that access, insurance coverage, and lack of familiarity may limit patient use of these agents.

Biologics
Current Guidelines and Recommendations
According to the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters and AAD guidelines, systemic therapy with biologics is strongly recommended for patients with moderate to severe AD that is not adequately controlled with topical therapy.²³˒²⁴ Systemic steroids are not recommended, but AAD guidelines note a few exceptions for use—during acute, severe exacerbations or as bridge therapy for other systemic biologics.²⁴

Approved Biologics
Dupilumab, which blocks interleukin (IL)-4 and IL-13 signaling, is approved for patients at least 6 months old with moderate to severe AD.²⁵,²⁶ Tralokinumab, which inhibits IL-13 signaling, is indicated for patients at least 12 years old with moderate to severe AD.²⁶,²⁷ Lebrikizumab, which recently received FDA approval for patients 12 years and older, binds to IL-Rα1 but does not prevent binding to IL-Rα2.²⁶ Although the three monoclonal antibodies affect the same pathway, they have different binding sites, half-lives, and affinities that could affect clinical outcomes.²⁶ In separate phase 3 trials, significantly more participants with moderate to severe AD achieved clear or almost clear skin with dupilumab and tralokinumab than did those who received placebo (P < .001 and P = .002, respectively).²⁸⁻³³ Similarly, in another phase 3 trial regarding moderate to severe AD, lebrikizumab plus topical steroids demonstrated significant improvements in all key efficacy end points compared with placebo with topical steroids (P < .05).³⁴ For all three biologics, conjunctivitis was a notable adverse event (AE) in their respective clinical trials.²⁸⁻³⁴

Panelists stressed that it is important not to make direct comparisons among these agents, as the clinical trials used different methodologies and end points. Unlike JAK inhibitors (discussed below), approved biologics do not require clinical laboratory monitoring.

The panel noted nearly a decade of clinical experience with dupilumab and discussed cases of conjunctivitis and facial/neck erythema. A baseline ocular assessment is useful, regardless of therapy, as ocular inflammation and associated comorbidities are common in patients with AD and could affect vision. Additionally, proactive treatment with preservative-free eye lubricants may be helpful.³⁵ For patients who experience facial dermatitis, the panel suggests tralokinumab or a JAK inhibitor as alternatives to dupilumab or adding topical ruxolitinib to the treatment regimen.

Dose Modifications and Disease Remission
With controlled AD, it is possible to reduce the dosage of dupilumab, tralokinumab, and lebrikizumab to once every 4 weeks for certain patients and maintain disease stability.³²,³⁶⁻³⁸ Panelists indicated they wait until patients have stable disease for at least a year prior to offering dosing modifications, and the timing interval can be adjusted if patients have a flare.

JAK Inhibitors
Numerous cytokines and their isoforms activate the JAK/STAT pathway, which may be associated with the itch, inflammation, barrier dysfunction, and immunoglobulin E production in AD.³⁹ Upadacitinib and abrocitinib are oral JAK inhibitors, both approved for patients 12 years and older with refractory, moderate to severe AD whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable.⁴⁰,⁴¹ Ruxolitinib cream, discussed earlier, is a topical JAK inhibitor approved for use in patients at least 12 years old with mild to moderate AD.¹⁴ Panelists noted that JAK inhibitors are associated with a rapid and meaningful change in skin clearance and itch burden.

Understanding the Boxed Warning for JAK Inhibitors
JAK inhibitors have been available for over 10 years in rheumatoid arthritis (RA). The boxed warning for all JAK inhibitors (for serious infections, mortality, malignancy, major adverse cardiovascular events [MACE], and thrombosis) is based on results from the ORAL Surveillance study that was conducted after FDA approval; investigators compared tofacitinib, a JAK inhibitor, to a tumor necrosis factor (TNF) inhibitor in patients at least 50 years old with RA and at least one cardiovascular risk factor.¹⁴,⁴⁰⁻⁴² However, the boxed warning fails to state that almost all patients were receiving oral immunosuppressants, and approximately half of the patients had a smoking history.⁴² Further, in a post hoc ORAL analysis that excluded older smokers, there was no signal for cancer.⁴³ It took 567 person-years of exposure to tofacitinib, 5 mg, to elicit one more MACE compared with a TNF inhibitor.⁴² Based on Numbers Needed to Harm statistics, there was a very small increased risk for blood clots in patients given tofacitinib versus a TNF inhibitor, and those most at risk had a prior venous thromboembolic event.⁴⁴

Studies of certain JAK inhibitors have shown rapid, sustained relief with limited safety signals.³⁹,⁴⁵,⁴⁶ The panel noted that while JAK inhibitors are immunosuppressive, serious AEs have been rare in their collective experience. It is important to contextualize the boxed warning with patients; the warnings may be applicable only in certain instances. Most of the panelists conduct recommended bloodwork at 3 and 6 months, and many continue testing to 12 months and beyond; this helps patients feel reassured that they are being followed for potential AEs. Commercial insurance generally covers clinical laboratory monitoring.⁴⁷ Panelists advise patients not to get pregnant while taking JAK inhibitors.

Pediatric Use and Guidance
The number of AD drugs available for pediatric use has grown in recent years. Agents include topical corticosteroids, calcineurin inhibitors, crisaborole, ruxolitinib, and tapinarof; the biologics dupilumab, lebrikizumab, and tralokinumab; and the oral JAK inhibitors upadacitinib and abrocitinib. Ruxolitinib cream is expected to receive an expanded age indication by the FDA for children at least 2 years old.

Special Considerations
Childhood is a critical period in the development of AD. A meta-analysis of adults and adolescents who had AD demonstrated that dupilumab reduced the risk of new or worsened allergies by 34 % and of new allergies by 37 % versus placebo.⁴⁸ Early immunomodulatory events in babies (eg, type of birth, whether they were breast-fed, receipt of antibiotics) can also alter the trajectory of disease. In addition, allergen exposure through damaged skin, as often found in AD, may promote sensitization.⁴⁹ Of note, the administration of live vaccines should be avoided while children are receiving dupilumab therapy. Cases must be considered on an individual basis, and additional research is needed.⁵⁰,⁵¹

Other Treatment Regimes
Some panelists are comfortable with using ruxolitinib cream and dupilumab in combination. However, they do mention hesitation regarding off-label use and insurance issues.

The Aron regimen is a compounded product of betamethasone valerate, 0.1 %; mupirocin cream; and vanicream or plastibase.⁵² It can be applied 4 to 6 times daily for flares, and dosing can be tapered with improvement.⁵² Panelists use it as a second-line therapy for AD, including disease that affects the face, and find it particularly effective in children.

Emerging AD Studies and Therapies
Novel Therapies and Molecular Targets
Zelnecirnon (RPT-193) showed promise as an inhibitor of CCR4; however, a phase 2b trial (NCT05399368) was halted for liver failure in one patient possibly related to zelnecirnon.⁵³ A high-affinity anti-IL-13 monoclonal antibody, APC777, is currently being investigated in a phase 2 study (NCT06395948). Other pipeline agents, such as rocatinlimab and amlitelimab, target OX40, which is a costimulatory immune checkpoint molecule primarily expressed by T cells that maintains the immune response and plays a key role in AD pathogenesis.⁵⁴⁻⁵⁶ Both rocatinlimab and amlitelimab are under investigation in phase 3 trials and have demonstrated skin improvements and overall tolerability in phase 2 studies.⁵⁵,⁵⁶

Although early results with OX40/OX40L antibodies are encouraging, panelists noted the novelty of the target pathway may drive a need for more data and challenges with trial recruitment.

Real-World Studies
Real-world (RW) studies may provide clinically relevant patient-centric data outside of clinical trials⁵⁷; however, since RW studies are not heavily regulated like clinical trials, their designs could generate inaccurate or skewed results. In March 2024, the FDA released draft guidance for industry and investigators on observational studies to address this challenge.⁵⁷,⁵⁸ Numerous RW studies have been conducted with AD therapies. Examples include a 1-year safety analysis of ruxolitinib cream; efficacy of dupilumab using data from electronic medical records; upadacitinib long-term efficacy and safety; upadacitinib efficacy and safety in patients switched from dupilumab; tralokinumab long-term efficacy and safety; tralokinumab’s effect on patient QOL; and tralokinumab safety and efficacy in patients switched from dupilumab to tralokinumab due to ocular disease.⁴⁶,⁵⁹⁻⁶⁴

Conclusions
The panelists emphasized that patient and provider education is key to improving outcomes in AD; with the emerging array of therapeutic options, finding effective treatment should no longer be a rate-limiting step. Further, nurse navigators and in-office support are great resources to build confidence in the management of AD, such as in properly performing injections. Short- and long-term disease-management strategies are required, and many tools are now available to support a holistic, proactive care approach.

This article was reviewed and approved by Dr Stein Gold.

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