Introduction

This chapter is intended to discuss novel and emerging pharmaceutic treatments for patients affected by atopic dermatitis (AD). It will give a brief overview of the proposed mechanism of each treatment, the major side effects, and the most recent clinical data from trials and studies. We hope to provide a comprehensive overview of the new treatments available for AD and to make clinicians better informed about the particular strengths and weaknesses of each drug. It should also be noted that many of these treatments are still in development and may not be available for clinical use, and we encourage readers to follow up on the updated results of the trials and studies listed throughout each section. A summary of the medications can be found in Table 23.1 .

Pathogenesis

Sustained barrier defects generated by filaggrin mutations, decreased ceramide synthesis, scratching, increased serine protease activity, and prolonged exposure to reduced environmental humidity result in epidermal dysfunction and allow for penetration of allergens found in pollen, microbes, and food ( ). In response to allergens, trauma, and inflammation, keratinocytes release inflammatory mediators such as interleukin-25 (IL25), IL33, thymic stromal lymphopoietin (TSLP), and pollen-associated lipid mediators (PALMs), which, along with presentation of allergens by dendritic cells, stimulate a T helper type 2 (Th2)-driven immune response ( ). TSLP receptor activates STAT1, STAT3, STAT5/JAK1, and JAK2, which are important for Th2 cell differentiation ( ).

These Th2 cells subsequently produce cytokines and chemokines, including IL4, IL5, IL13, and tumor necrosis factor-α (TNF-α), which stimulate B-cell class switching, immunoglobulin E (IgE) production, and eosinophil survival; induce proliferation of leukocyte adhesion molecules; and direct circulating lymphocytes, macrophages, and eosinophils to cutaneous sites of inflammation ( ). IL4 has been strongly associated with AD and requires numerous agents in the JAK-STAT pathway, including JAK1, JAK3, STAT3, STAT5, and STAT6 to enact its effects ( ). IgE contributes to AD pathogenesis through mast cell activation and subsequent release of preformed mediators such as histamine, IL4, and IL13, as well as through increased expression of FCεRI on Langerhans and dendritic cells, which results in further Th2 activation ( ). Mast cells also stimulate further IgE synthesis by B cells, upregulate integrins on Langerhans cells, and suppress IL12 production by dendritic cells, leading to polarization to the Th2 subtype ( ). Th2 cells also release IL31, which has been associated with higher disease severity, pruritus, chemotaxis of inflammatory cells, and induction of proinflammatory molecules by eosinophils through the JAK-STAT pathway ( ). Eosinophils release various cytokines and chemokines such as IL16, IL12, transforming growth factor-β (TGF-β), and IL13 ( ). The JAK-STAT pathway, through STAT6-mediated gene regulation, also stimulates B-cell differentiation, IgE class switching, and major histocompatibility complex (MHC) class II production ( ).

Similar to the JAK-STAT pathway, JAK-spleen tyrosine kinase (SYK) pathways have also been associated with AD pathogenesis by mediating IL17R-proximal signaling complex formation, which is responsible for upregulation of CCL20 in keratinocytes ( ). CCL20 has been found to attract immature dendritic cells and effector T cells into the dermis of inflamed skin ( ). SYK activation has also been implicated in B-cell survival, degranulation of mast cells, antigen presentation in dendritic cells, and proinflammatory cytokine production by macrophages ( ).

Th17 cells have also been implicated in the pathogenesis of AD as an enhancer, and an increased percentage of Th17 in blood correlates with the severity of AD ( ). Th17 cells release IL17, which enters the inflamed dermis and stimulates keratinocytes to produce proinflammatory cytokines and chemokines, including GM-CSF, TNF-α, IL8, and CXCL10 ( ). Patients with chronic AD have also been found to have increased blood levels of IL22-producing T cells ( ). IL22 induces keratinocyte proliferation and epidermal proliferation, and increased levels of IL22 are correlated with AD disease severity ( ).

Phosphodiesterase (PDE) functions to hydrolyze cyclic adenosine monophosphate (cAMP), and higher levels of PDE activity have been associated with increased IgE synthesis and IL4 production ( ). Increased PDE activity is seen in leukocytes of patients with AD and is thought to contribute to increased serum levels of IL10 and prostaglandin E2 ( ). IL12, which is stimulated by Th2-type cells, is thought to polarize naïve T cells to Th1-type cells and terminate Th2-type cytokine patterns ( ). A switch from Th2 cells to a predominantly Th1 cell response has been associated in the chronic and late phases of AD ( ). Increased levels of IL12, mRNA, and interferon-gamma (IFN-γ) (which are produced by Th1 cells) in AD lesions have also been linked to chronic AD ( ).

Pruritus in AD is caused by numerous mediators, including histamine, neuropeptides, neurotransmitters, cytokines, proteinases, and arachidonic acid derivatives ( ). Histamine induces IL13 and IL31 production and activates sensory neurons, primarily through histamine-1 receptors (H ₁ R) and histamine-4 receptors (H ₄ R) ( ). Through H ₄ R, histamine also activates mast cells, basophils, and eosinophils ( ). One potent releaser of histamine from mast cells is compound 48/80, which, upon injection, has been shown to cause itching in mice ( ). Similarly, increased concentrations of substance P, a neuropeptide that induces itching through neurokinin receptors (NK1R,) and neuropeptide Y are present in patients with AD ( ).

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a type of nuclear receptor that has an increased expression in the monocytes and T lymphocytes of AD patients and is responsible for keratinocyte differentiation and permeability barrier homeostasis ( ).

Dihomo-γ-linolenic acid (DGLA) is a fatty acid that has been found to be significantly lower in the serum of patients with AD than in healthy volunteers ( ). DGLA is also metabolized into antiinflammatory eicosanoids, and oral administration of DGLA in mice prevents the development of AD by suppressing the activation of mast cells and keratinocytes ( ).

Recalcitrant and moderate to severe AD often require systemic treatment. Immunosuppressants such as methotrexate, cyclosporine A, mycophenolate mofetil, and azathioprine have traditionally been used; however, significant side effect profiles can limit their long-term use. Newer immunomodulators (i.e., biologics and small-molecule inhibitors) selectively target specific cytokines and regulators involved in AD pathogenesis and have much more desirable side effect profiles.

Currently, the only Food and Drug Administration (FDA)–approved biologic medications for AD are dupilumab and crisaborole. There are a number of new and promising treatments currently under investigation. This chapter provides a summary and review of systemic therapies that target specific mediators involved in the pathogenesis of AD and its related symptoms. Included are those therapies that have been specifically approved for AD, those undergoing clinical trials, and those that have demonstrated efficacy to a significant degree.

Treatments targeting pathogenic cytokines

Treatments targeting pathogenic antibodies: Anti-IgE

Omalizumab is a humanized anti-IgE IgG monoclonal antibody that prevents the binding of IgE to FCεRI and CD23 on B cells, causing a reduced number of FCεRI on basophils and reduced IgE synthesis by B cells, resulting in decreased expression of proinflammatory cytokines such as IL5, IL8, and IL13 ( ). Omalizumab has demonstrated significant efficacy in both pediatric and adult patients with AD ( ). However, several studies have also demonstrated no improvement of disease with omalizumab therapy, and it is hypothesized that lack of filaggrin mutations and lower elevations of total serum IgE are associated with a favorable response to omalizumab ( ).

Ligelizumab is another anti-IgE monoclonal antibody that binds to the Cε3 domain of IgE and inhibits the binding of free IgE to mast cells and basophils. Two randomized, placebo-controlled, double-blind clinical trials of 183 adults with a history of atopy found that ligelizumab demonstrated greater of suppression of serum IgE and IgE bound to mast cells and basophils compared to omalizumab ( ). Similarly, a double-blind, randomized, placebo-controlled, parallel-group multicenter study in 37 adult subjects with mild allergic asthma comparing the effects of ligelizumab to omalizumab found that there were was a greater inhibition of skin prick test response with ligelizumab compared to omalizumab ( P < .0001) ( ). A phase 2, randomized, double-blinded, placebo-controlled, parallel-group, proof of concept study of 22 adult participants with moderate to severe AD has been completed, but results have not yet been published (A study evaluating the safety and efficacy of QGE031 in atopic dermatitis patients, 2017).

Treatment targeting immune cells: Anti-CD20

Rituximab is a chimeric monoclonal anti-CD20 antibody that causes decreased immunomodulatory functions and loss of antigen presenting capability by B cells ( ). An open-label pilot study of four women and two men with severe AD who were refractory to topical corticosteroid and/or calcineurin inhibitor therapy were given two doses of 1000 mg of rituximab, 2 weeks apart ( ). All patients experienced significant improvement of AD lesions within 4 to 8 weeks of treatment, as measured by their EASI scores (29.4 ± 4.3 at baseline vs. 8.4 ± 3.6 at 8 weeks, P < .001), and EASI scores remained low at weeks 16 and 24. There was also a reduction of spontaneous IL13 production by peripheral blood mononuclear cells ex vivo (25.7 ± 5.7 pg/mL vs. 5.5 ± 4.1 pg/mL, P = .18), indicating a reduction of activated T cells in blood. Skin histology following treatment was notable for decreased hyperkeratosis, acanthosis, spongiosis, and dermal inflammatory cells. In a case study of three adult patients with severe AD unresponsive to standard therapy, patients experienced a reduction in peripheral blood CD19+ B-cell numbers following rituximab treatment, but they did not experience significant clinical benefit as measured by EASI ( ).

Treatments targeting immune signaling: JAK-STAT/JAK-SYK

Topical JAK inhibitors

Delgocitinib is a topical JAK inhibitor that inhibits JAK1, JAK2, JAK 3, and tyrosine kinase 2 ( ). A phase 2, randomized, double-blind, vehicle-controlled study of 103 pediatric patients randomized in a 1:1:1 ratio to receive 0.25% or 0.5% delgocitinib ointment or a vehicle ointment for 4 weeks demonstrated that at the end of treatment, mEASI scores in both delgocitinib groups were significantly more reduced compared to the vehicle group (0.25% group: −54.2%, P < .001; 0.5% group: −61.8%, P < .001) ( ). In a phase 2, randomized, vehicle-controlled, intergroup comparison study involving 327 adult patients assigned to a vehicle group, delgocitinib 0.25% group, delgocitinib 0.5% group, delgocitinib 1% group, delgocitinib 3% group, and a tacrolimus group twice daily for 4 weeks found that changes in the least-squares mean percentage from baseline in mEASI scores for the delgocitinib 0.25%, 0.5%, 1%, and 3% groups were −41.7%, −57/1, −72.9%, and −12%, respectively, which were signifi-cantly reduced compared to the vehicle group ( P < .001). As of 2020 there have been no head-to-head trials comparing topical JAK inhibitors to other nonsteroidal antiinflammatory pharmaceuticals in patients with AD.

A phase 1, nonrandomized, parallel-assignment, open-label, pilot pharmacokinetic study of ruxolitinib (JAK1/2 inhibitor) phosphate cream, in 60 pediatric patients with AD is currently active ( ).

A phase 2, randomized, dose-ranging, vehicle-controlled and triamcinolone 0.1% cream-controlled study to establish safety and efficacy of ruxolitinib phosphate cream in adults with AD has also been completed, but results are not yet available ( ).

Calcineurin inhibitors

Tacrolimus and pimecrolimus are calcineurin inhibitors that bind to FK506-binding protein (FKBP), thereby inhibiting the activation of calcineurin and its downstream signaling pathway; this results in decreased production of inflammatory cytokines ( ). Tacrolimus and pimecrolimus have the same mechanisms of action, but pimecrolimus has an altered skin penetration profile ( ). A meta-analysis of 12 independent randomized clinical trials comparing topical calcineurin inhibitors to topical corticosteroids in the treatment of AD in pediatric and adult patients found that there were similar improvements (81% vs. 71%, P = .01) and treatment success (72% vs. 68%, P = .04) ( ). The number of adverse events and adverse events related to treatment was higher in patients treated with calcineurin inhibitors compared to those treated with corticosteroids (adverse events: 74% vs. 64%, P = .02; adverse events related to treatment: 11% vs. 8%, P = .002).

Phosphodiesterase inhibitors

Crisaborole is a topical antiinflammatory PDE4 inhibitor that causes inhibition of proinflammatory and T-cell cytokine production ( ). In two identically designed, vehicle-controlled, double-blind studies (AD-301 and AD-302), 1522 patients age 2 years and older with AD were given crisaborole ointment twice daily for 28 days or a vehicle ( ). Patients treated with crisaborole achieved higher Investigator’s Static Global Assessment (ISGA) scores at day 29 compared to those treated with vehicle (AD-301: 32.8% vs. 25.4%, P = .38; AD-302: 31.4% vs. 18.0%, P < .001). A phase 4, multicenter, open-label safety study of crisaborole ointment in 137 children age 3 months to less than 24 months with mild to moderate AD has been completed, but results are not yet available ( ).

Apremilast is an oral PDE4 inhibitor approved for the treatment of adults with moderate to severe psoriasis and psoriatic arthritis ( ). A phase 2, double-blind, placebo-controlled trial of 185 patients with moderate to severe AD who received apremilast 30 mg twice daily, 40 mg twice daily, or placebo for 12 weeks found that at week 12, patients who received apremilast 40 mg twice daily showed significantly greater improvement from baseline in EASI score compared to patients who received placebo (−31.6% vs. −11%, P < .04) ( ). Tissue biomarker data in patients taking apremilast 40 mg twice daily also showed substantial reductions in epidermal hyperplasia and inflammatory markers. Of note, those taking apremilast 30 mg twice daily did not experience statistically significant changes in EASI score versus placebo and did not have notable changes in inflammatory biomarkers. In a case series of four adults with AD since childhood who were treated with apremilast for 10 weeks to 9 months, there was clearance or reduction of eczematous papules, erythema, plaques, and pruritus ( ).

Opioid agonists

Initially developed for treatment of irritable bowel syndrome, asimadoline is a peripherally acting κ-opioid agonist that has also been found to inhibit the itch caused by compound 48/80 ( ). A phase 2, randomized, double-blind, single-group assignment study evaluating the efficacy of asimadoline in adults with AD with pruritus is completed, but results are not yet available ( ).

Aryl hydrocarbon receptor (AhR) agonists

Tapinarof (5-[(E)-2-phenylethenyl]-2-[propan-2-yl] benzene-1, 3-diol) is a nonsteroidal, fully synthetic, hydroxylated stilbene compound classified as an AhR modulating agent that binds and activates the AhR, causing downregulation of proinflammatory cytokine expression and impacting barrier gene expression in human keratinocytes ( ). In a phase 1, open-label, two-cohort sequential study that assessed the pharmacokinetics, safety, and efficacy of tapinarof in 11 adults with moderate to severe AD, administration of tapinarof (1% or 2%) resulted in at least 50% total EASI by day 21 and a decrease in pruritus ( ). In a phase 2, randomized, double-blind, vehicle-controlled, six-arm, multicenter trial of 247 adult patients with AD who were given tapinarof 1% twice daily, tapinarof 1% once daily, tapinarof 0.5% twice daily, tapinarof 0.5% once daily, vehicle twice daily, or vehicle once daily, the rate of treatment success, as measured by IGA score, with tapinarof 1% twice daily was statistically significantly higher than the rate with vehicle twice daily (53% vs. 24%, α = 0.05 level) ( ).

Anti-H4 receptor (H4R)

JNJ 39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is an H4R antagonist that has demonstrated effectiveness in reducing pruritus in healthy subjects ( ). In a phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of 88 Japanese adults with moderate AD who were administered one JNJ-3975879 (100 mg and 300 mg) or placebo, decreases in median EASI were observed (−3.7 and −3.0, respectively), but these changes were not significant compared to placebo (−1.30, P = 1.672 and 0.1992, respectively) ( ). The trial was also prematurely discontinued due to side effects of neutropenia.

In a phase 2, randomized, double-blind, placebo-controlled, parallel group study, 98 adult participants with moderate to severe AD were administered adriforant (30 mg orally daily) for 8 weeks ( ). This study has been completed, but results are not yet available.

Dihomo-γ-linolenic acid (DGLA)

DS107 is an agent containing DGLA ( ). In a phase 2a, randomized, placebo-controlled, parallel assignment trial of 102 adult participants with moderate to severe AD who received oral DS107 or placebo, patients administered DS107 experienced a statistically significant decrease in IGA compared to placebo ( P = .57) as well as a statistically significant reduction of itch assessed by VAS compared to placebo ( P = .015) ( ). In a phase 2b, randomized, double-blind, multicenter, vehicle-controlled study in which 326 patients with mild to moderate AD were given DS107 cream (1% and 5%) or placebo, patients receiving DS107 experienced a dose-dependent response in IGA and EASI-75, and those administered 5% DS107 cream achieved statistically significant changes in both IGA and EASI-75 ( P = .029 and .019, respectively) ( ). A phase 2, randomized, double-blind, placebo-controlled, parallel assignment study to assess efficacy and safety of oral DS107 in adult patients with moderate to severe AD is currently recruiting ( ).

Neurokinin-1 receptor (NK1-R) antagonist

NK1-R antagonists prevent the interaction between NKR-1 and substance P, which is involved in the pathogenesis of nonhistaminergic pruritus ( ). Aprepitant is an oral NK1-R antagonist approved for treatment of nausea during chemotherapy ( ). In a prospective study of 20 patients with chronic pruritus refractory to therapy who were treated with aprepitant 80 mg for 3 to 13 days, patients experienced a significant decrease in pruritus intensity on the VAS (8.4 at baseline vs. 4.9 after treatment, P < .001) ( ). In an open, randomized trial of 39 patients with moderate to severe AD who were given aprepitant 80 mg daily for 7 days (n = 19) or topical treatment alone (n = 20), there were significant reductions in SCORAD (40.5–32.0, P < .01), mean VAS (5.5–3.8, P < .05), and scratching movements (77.3–48.3, P < .05) in the aprepitant group ( ). However, these reductions were not significant when compared to the control group.

Serlopitant is a NK1-R antagonist developed for chronic use in treatment of overactive bladder ( ). In a phase 2, randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose finding and efficacy study of 222 adult participants with pruritus lasting longer than 6 weeks refractory to antihistamines and steroids who were given serlopitant (0.25 mg, 1 mg, or 5 mg) or placebo once daily for 6 weeks, participants taking 1 mg and 5 mg of serlopitant experienced a dose-dependent decrease in VAS pruritus score compared to placebo ( P = .022 and P = .13, respectively) ( ). Mean overall Dermatology Life Quality Index (DQLI) was also lower in treatment groups, although statistically significant improvements were only seen in the 1 mg group. In a phase 2, randomized, double-blind, placebo-controlled, parallel assignment study of 484 adults and adolescents with pruritus who were given daily oral doses of serlopitant (1 mg or 5 mg) or placebo for 6 weeks, there was no significant decrease in Worst Itch Numeric Rating Scale (WI-NRS) score in either treatment group ( P = .11 and P = .17, respectively) by the end of the treatment period ( ).

In a phase 2, randomized, double-blind, placebo-controlled multicenter study of 168 adult subjects with chronic, AD-associated pruritus refractory to antihistamine and corticosteroids, participants were either given placebo or oral tradipitant (VLY-686), another NK1-R, for 8 weeks ( ). Subjects receiving trapiditant experienced significantly greater improvement on the worst itch VAS scale (−44.2 vs. −30.6, P = .019), the total SCORAD index (−21.3 vs. −13.6, P = .008), objective SCORAD (−13.3 vs. −7.2, P = .005), Clinician Global Impression of Change (CGI-C) (2.6 vs. 3.3, P = .007), Patient Global Impression of Change (PGI-C) itch (2.6 vs. 3.2, P = .025), and PGI-C AD (2.7 vs. 3.5, P = .007) compared to placebo ( ). An earlier phase 2, randomized, double-blind, placebo-controlled, proof of concept study in 69 adult participants with AD and chronic pruritus who were given oral tradipitant or placebo for 4 weeks also demonstrated significant improvement in VAS for itch from baseline for patients who received tradipitant ( P < .0001) ( ; ). However, the change was not significant compared to placebo. A phase 3, randomized, double-blind, placebo-controlled, parallel-assignment, efficacy study of tradipitant in adult patients with chronic pruritus and AD is currently recruiting ( ).

PPAR-γ

Rosiglitazone is a PPAR-γ agonist approved for treatment of type 2 diabetes mellitus that has been shown to inhibit TLSP-induced dendritic cell maturation and reduce severity of skin lesions and scratching behavior in mice ( ). In a case series of six patients with severe AD, the addition of rosiglitazone (2–4 mg PO twice daily) to treatment with corticosteroids, antihistamines, and/or calcineurin inhibitors caused a BSA reduction of more than 65% in five patients and a decreased number of flares compared with baseline ( ).

Summary

Traditional therapies for AD are limited to immunosuppressants whose use can be limited by harmful and unwanted side effects. The development of targeted treatments offers safer and more specific options. Although many of the therapies mentioned in this chapter have shown much promise, only two, crisaborole and dupilumab, have been approved by the FDA for use in AD patients. Furthermore, these new treatment options are often expensive and costly. As of January 2020, the list price for Dupixent is $3019.50 for a 4-week supply ( ). To usher in this new era of AD therapy, further large-scale, randomized, placebo-controlled, double-blind, multicenter trials are needed to determine efficacy and safety. More research into the specific mediators and their receptors involved in the pathogenesis of AD may also be beneficial so that further potential therapies can be developed and tested in head-to-head trials and subanalyses, and evaluated among different patient demographics. It is also necessary to conduct large-scale trials in pediatric populations due to the significantly higher prevalence of AD in this population ( ). Finally, trials involving a combination of target-specific treatments would be very valuable to determine drug interactions. Table 23.1 summarizes the list of currently available and emerging targeted treatment medications for AD.