Atopic Dermatitis and Psoriasis: Treatments, Considerations, and What’s Coming

Atopic dermatitis (AD) and plaque psoriasis (PsO) are two of the most common cutaneous conditions we treat in dermatology. While these chronic inflammatory disorders have similarities, regarding chronic skin disease burden and impact on quality of life, they may diverge when considering clinical presentation and pathophysiologic inflammatory targets.

In this review, we will discuss the current and emerging therapeutic landscape for AD and PsO in the context of recent and ongoing clinical trial research.

Atopic dermatitis

Atopic dermatitis is the most common chronic inflammatory cutaneous disorder. It is characterized by pruritus and a chronic or chronically relapsing course that can begin during infancy.1 It’s a complex genetic disease often associated with other atopic disorders. Prior to 2017, there were only a limited number of approved therapies for AD, until the FDA approval of a first-in-class biologic treatment. Subsequently, there has been a tremendous wave of topical, oral, and systemic therapies for the management of AD.

Treatment of AD depends on extent of involvement as assessed clinically by body surface area (BSA) and individual factors. In some settings, clinicians are utilizing the Investigator Global Assessment (IGA) and Numeric Rating Score for Itch (NRS-I) for both overall disease evaluation and documentation. The IGA and Eczema Area Scoring Index (EASI) are validated scoring measures to assess the severity of AD. Both are commonly used in clinical studies for AD. EASI scores are more frequently used in clinical trials yet serve as an important reference point in our decision-making tree for treating AD patients. Topical agents are the mainstay of treatment, with topical corticosteroids being the first-line pharmacologic therapy. Typically, treatment involves a combination of moisturizers and topical agents for mild-to-moderate disease and the addition of systemic medications for moderate-to-severe cases.

Specific FDA-approved treatment options for AD include an extensive list of largely generic topical corticosteroid (TCS) creams, lotions, ointments, solutions and gels (classes I–VII depending on presentation and location of disease), including two topical calcineurin inhibitors (TCI), pimecrolimus cream 1% (mild-to-moderate disease) and tacrolimus ointment (0.03%, pediatric, 0.1% adults; moderate-to-severe disease), a topical phosphodiesterase 4 (PDE-4) inhibitor, crisaborole 2% ointment (mild-to moderate disease) and a topical Janus kinase (JAK) inhibitor, ruxolitinib 1.5% cream. Some branded TCS, such as clobetasol, betamethasone and others, are also available with unique vehicle formulations. Phototherapy, such as narrow-band UVB can be used with or without topical therapies and is most commonly utilized to reduce the burden of itch.

Systemic treatment options, typically reserved for moderate-to-severe AD, include short courses of corticosteroids and steroid-sparing agents such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil. These systemic interventions have been used less frequently since the advent of newer biologic and oral small-molecule drugs. Two monoclonal antibodies (dupilumab and tralokinumab), and two oral small-molecule JAK inhibitors (abrocitinib and upadacitinib) have been approved by the FDA to treat moderate-to-severe AD. Other systemic therapies that have either recently become available, will soon be completing trials, or are in early phases of clinical trials, include biologic therapies such as lebrikizumab, nemolizumab, and oral small molecules such as jaktinib, rilzabrutinib, and difelikefalin. Baricitinib, currently approved in the US for severe alopecia areata, is approved only for moderate-to-severe AD in other countries.2

As mentioned previously, several topical agents are approved to treat AD, and many are being evaluated in clinical trials. Crisaborole is a phosphodiesterase-4 inhibitor approved for mild-to-moderate AD in children greater aged 3 months and older. Ruxolitinib cream is a JAK1 and JAK2 inhibitor approved for patients 12 years of age and older. Tofacitinib cream and delgocitinib ointment are other JAK inhibitors being studied for AD. Tapinarof is a novel aryl hydrocarbon receptor agonist that has shown efficacy in clinical trials. Trifarotene is a topical retinoid being studied for its efficacy in AD. Cannabinoids are also being explored in topical and oral formulations for their anti-inflammatory and anti-itch properties in AD.

Two systemic biologic agents are FDA-approved for the management of moderate-to-severe AD. First approved in 2017, dupilumab is a monoclonal antibody that inhibits the action of IL-4 and IL-13 by specifically binding to the IL-4Rα subunit shared by IL-4 and IL-13 receptor complexes. It has long been approved for adults and adolescents; it is now indicated for patients older than 6 months.3 Tralokinumab is another monoclonal antibody targeting IL-13. It is an IL-13 antagonist indicated for moderate-to-severe AD for patients of 12 years of age and older.

Several biologic agents have completed phase III clinical trials, and their approval is hoped for later this year. Lebrikizumab is a monoclonal antibody being evaluated in clinical trials for blockade of IL-13 signaling targets. It selectively prevents the formation of the IL-13Rα receptor signaling complex, thus blocking IL-13 signaling.4

Nemolizumab is a monoclonal antibody that targets the interleukin-31 receptor, a cytokine involved in the itch-scratch cycle characteristic of AD. In trials, it has shown promise for reducing itch and improving eczema lesions.5

Abrocitinib is an oral JAK1 inhibitor that has shown efficacy in clinical trials and is being investigated in patients 12 years of age or older with moderate to severe AD.6 The expected EASI-75 at week 12 is 62.9% for abrocitinib 200 mg and 43.0% for abrocitinib 100 mg. Abrocitinib decreases itch very rapidly, with improvements in itch noticeable within 24 hours after administration.7

Upadacitinib is another oral JAK1 selective inhibitor. It is approved for refractory moderate-to-severe AD in patients 12 yearts of age and older. In the Measure Up 1 and Measure Up 2 studies the EASI-75 at week 16 was 70% for upadacitinib 15 mg and 80% for upadacitinib for 30 mg.8

Jaktinib is a JAK1, JAK 2 and JAK 3 inhibitor being investigated for AD. This “pan-JAK” blocks JAK-STAT signaling pathways and reduces inflammation due to a decrease in proinflammatory cytokines IL-2, IL-4, IL-6, IL-7, and IL-10. Rilzabrutinib is a bruton tyrosine kinase inhibitor in trials for AD. Difelikefalin is a novel, selective kappa opioid receptor agonist. Oral difelikefalin is being studied for reduction in pruritus for AD, having previously established a role in treatment of uremic pruritus.⁹ Tezepelumab (TSLP) is an anti-thymic stromal lymphopoietin monoclonal antibody in phase 2a clinal trial in the treatment of moderate-to-severe AD. TSLP acts directly on a subset of transient receptor potential ankyrin (TRPA)-positive sensory neurons to trigger itch via calcium-dependent release. TSLP plus TCS showed an EASI-50 of 64.7% versus placebo plus TCS 48.2%.¹⁰ It is also being studied in asthma with similar outcomes and low adverse events. Anti-OX40 antibody drugs are potential treatments for moderate-to-severe AD. OX40 is a key regulator of T-cell proliferation and memory formation that is only expressed on activated T-cells. This mechanism of action is of great therapeutic interest in clinical studies of AD and asthma. Rocatinlimab, GBR830 and amlitelimab are three drugs in this class being studied for efficacy and safety in the treatment of moderate-to-severe AD.¹¹

There are more than 80 topical, oral, and biologic agents recently or currently in clinical trials for the treatment of AD. These pipeline drugs represent an exciting time for the management of this complex and challenging condition. Research continues to explore a new and evolving therapeutic landscape for patients with AD.

Plaque Psoriasis

Plaque psoriasis is a common chronic inflammatory cutaneous disorder typically characterized by erythematous papules and plaques with silvery-white scales.¹² There are other, less common clinical presentations of psoriasis, including guttate, erythrodermic, inverse, and pustular psoriasis. While most cases of PsO are not severe enough to directly affect overall health and are treated in the outpatient setting, uncommon, life-threatening presentations may occur that require an aggressive approach to treatment, including potential inpatient management.¹³ In this brief review, we will focus primarily on PsO, which accounts for 80% to 90 % of all cases of psoriatic skin disease.

The treatment of PsO largely depends on the extent of involvement in the clinical presentation. In addition to assessment of body surface area (0-3% [mild], 3-10% [moderate], > 10% [severe]) of involvement as a “guide” establishing therapeutic selection, severity of disease and ultimate choice of therapy may also be dictated by involvement of “special sites” or “challenging-to-treat” areas such as the scalp, face, nails, palms/soles, and genitalia.¹⁴ As mentioned during the discussion of AD, IGA measurement tools are also used to quantify extent of disease. While mild-to-moderate disease and challenging to treat areas may be adequately managed with topical and/or localized therapies (70% to 80% of cases), patients with a moderate spectrum and certainly those with moderate-to-severe disease presentations often require more complex systemic management.

Treatment options for psoriasis encompass a range of modalities. Currently topical therapy options include corticosteroids, vitamin D analogs, retinoids, calcineurin inhibitors (off-label), and newer non-steroidal therapies such as tapinarof and roflumilast.¹⁵

In recent years, systemic therapies have expanded to treat patients with more than 5% body surface area involvement, those with difficult-to-treat areas, (eg, scalp, nails, palmoplantar), those with more extensive disease, and certainly those more at risk of or with active psoriatic arthritis (PsA). Systemic options include immunosuppressive or immunomodulatory drugs such as methotrexate, cyclosporine, apremilast, deucravacitinib, and biologic agents targeting the immune system. Biologic agents, such as anti-tumor necrosis factor (TNF) agents are less frequently used due to the advent of newer antibodies against interleukin (IL) pathways and janus kinase (JAK) inhibitors, which have shown significant efficacy in moderate to severe psoriasis.^16-18 Particularly, medications such as risankizumab, brodalumab, ixekizumab, guselkumab, and secukinumab, as confirmed by multiple metanalyses, have demonstrated high PASI 75, 90, and 100 response rates in improving psoriasis.^19-21 Bimekizumab is a new IL-17A and IL-17F inhibitor approved for moderate to severe psoriasis. Bimikizumab has shown significant PASI 75 data at week 4 and PASI 90 of 85% and 91% at week 16.²² Oral medications such as cyclosporine and methotrexate are used less frequently since the advent of newer, safer agents such as apremilast and deucravacitinib. We now have head-to-head trials comparing different biologics and one between oral therapies, thus providing more precise efficacy than placebo.^23,24 Upadacitinib and tofacitinib, JAK inhibitors that are FDA-approved for PsA, are also available for patients who prefer oral treatment over subcutaneous injections and who likely have underlying psoriatic joint disease. It is important to note that systemic therapies require varying levels of monitoring. Factors such as drug side effects, medical history, patient preference, availability, and cost play crucial roles in treatment selection.

Research continues to explore promising agents and innovative approaches. Biologic agents continue to be developed to target specific pathways involved in the pathogenesis of psoriasis. These agents include IL-17 inhibitors sonelokimab (a novel IL-17 nanobody), and izokibep, a newer-generation IL-17A inhibitor which has also been evaluated in clinical trials for PsO, PsA, and hidradenitis suppurativa. Other novel agents include IL-36 inhibitors such as A-552 and spesolimab, retinoic-acid-receptor-related orphan receptor gamma t (RORγt) inhibitors like VTP-43742, and Rho-associated protein kinase 2 (ROCK2) inhibitors like KD025, all of which hold the potential to transform psoriasis management. Spesolimab is an interleukin-36 receptor (IL-36R) antagonist, approved by the FDA and currently administered intravenously for the treatment of generalized pustular psoriasis (GPP).

In addition to our current topical therapies, advancements in enhancing the efficacy of topical medication delivery for PsO treatment are being explored. Techniques that involve nanoparticles, microneedles, nanofibers, and hydrogels are actively researched, with nanoparticles being the most extensively studied and microneedles and nanofibers showing promise. Small-molecule oral agents are also under development and include tumor necrosis factor inhibitors, IL-23 inhibitors, IL-17 inhibitors, phosphodiesterase-4 inhibitors, JAK inhibitors, A3 adenosine receptor agonists, and sphingosine-1-phosphate receptor 1 agonists, several of which are entering phase III trials. Oral microbials have also demonstrated success in early early studies.

Finally, biomarker development strategies involving the identification and validation of reliable biomarkers (eg, cytokine targets) that play a critical role in the pathophysiology and diagnosis of disease states such as psoriasis and AD may assist in predicting treatment response and guiding therapeutic decisions. This said, while certain biomarker analytics have shown promise in predicting disease severity and potential outcomes, further validation is necessary to effectively establish their clinical utility.

Biomarker and other diagnostic innovations offer great potential in improving transdermal medication delivery and refining treatment outcomes. Despite the strides made in understanding psoriasis and diversifying our treatment options, challenges persist in achieving optimal patient outcomes. Nevertheless, with the continuous evolution of both systemic and topical treatments, the future of psoriasis management continues to hold promise for increased efficacy and improved disease control.

Disclosures: Dr. Glick has served as an advisor, investigator, and/or speaker for the following companies: AbbVie, Amgen, Arcutis Biotgerapeutics, AstraZeneca, BMS, Brickell Biotech, Cara Therapeutics, ChemoCentryx, CorEvitas Registry PSO, CorEvitas Registry AD, Dermavant Services, Dermira, Galderma, Janssen, Leo Pharma, Lilly, Novartis, Incyte, EPI/Novan, Nimbus Lakshmi, Inc., Ortho Dermatologics, Pfizer, PROSE Regeneron, Sanofi/Genzyme, Sun Pharma, and UCB. Registry for AD. He is also a stockholder in Top MD.

Drs. Sharma and Khalil report no relevant interests.

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