Biologic Therapy

Reviewed on July 01, 2024

Introduction

Mild-to-moderate Atopic Dermatitis (AD) may be adequately treated with a combination of trigger avoidance, moisturizers, topical corticosteroids, calcineurin inhibitors and/or crisaborole. However, moderate-to-severe AD is more challenging, with topical treatments often being inadequate, and thus requiring the use of phototherapy and/or systemic therapy to achieve adequate disease control. Corticosteroids, cyclosporine, methotrexate, azathioprine and mycophenolate mofetil are established systemic treatments, but have variable dosing regimens and efficacy and are associated with numerous safety and tolerability concerns that limit their use. As such, there is an unmet need for long-term systemic treatments that are both safe and effective in the treatment of chronic AD.

Recent AD research has begun to elucidate the complex mechanisms and immunologic factors behind the immune-pathogenesis of AD. What follows is a brief description of our current understanding of these…

Introduction

Mild-to-moderate Atopic Dermatitis (AD) may be adequately treated with a combination of trigger avoidance, moisturizers, topical corticosteroids, calcineurin inhibitors and/or crisaborole. However, moderate-to-severe AD is more challenging, with topical treatments often being inadequate, and thus requiring the use of phototherapy and/or systemic therapy to achieve adequate disease control. Corticosteroids, cyclosporine, methotrexate, azathioprine and mycophenolate mofetil are established systemic treatments, but have variable dosing regimens and efficacy and are associated with numerous safety and tolerability concerns that limit their use. As such, there is an unmet need for long-term systemic treatments that are both safe and effective in the treatment of chronic AD.

Recent AD research has begun to elucidate the complex mechanisms and immunologic factors behind the immune-pathogenesis of AD. What follows is a brief description of our current understanding of these processes. In both non-lesional and lesional AD skin, barrier defects permit the entry of allergens that encounter Langerhans cells and dermal dendritic cells (Figure 10-1), leading to activation and recruitment of inflammatory cells. An elevated Th2 response occurs in both the acute and chronic phases of AD and results in increased production of interleukin (IL) IL-4, IL-5, IL-13 and IL-31 that have numerous downstream effects. IL-4 and IL-13 disrupt the skin barrier through decreased expression of barrier proteins and impaired antimicrobial peptide responses. In combination with barrier disruption, this increases the risk of colonization and barrier penetration by allergens and pathogens.

Damage to and inflammation within the epithelium lead to the release of thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, which further drive Th2 differentiation along with IL-10. While the Th2 pathway appears to play a dominant role in the pathogenesis in both the acute and chronic phases of AD, there may a contributory role of the Th22 axis, and to a lesser extent the Th1 and Th17 axes. Th22 and Th17 cells release IL-22 and IL-17, respectively. IL-22 induces epidermal hyperplasia and acts synergistically with IL-17 to alter differentiation protein expression. IL-31 is also involved in acute disease and acts as a mediator of itch by acting on neurons and keratinocytes. Progressive activation of the Th2, Th22 and Th1 axes may occur in chronic lesions. Elevated IFN-γ expression in the Th1 response leads to the production of chemokines, including CXCL9, CXCL10 and CXCL11, which further exacerbate inflammation and immune activation. IL-4 and IL-13 also stimulate immunoglobulin E (IgE) production from B lymphocytes and recruit eosinophils and basophils to inflammatory sites, which together lead to the release of additional pro-inflammatory mediators, potentially further exacerbating AD and allergic disease.

Breakthroughs in our understanding of the immunopathogenic processes behind AD has permitted the development of novel targeted agents, such as monoclonal antibodies, directed against specific immunologic targets involved in AD. Targeted therapies offer several advantages, including high therapeutic target specificity, reduced indirect toxicity, longer half-life permitting less frequent dosing and fewer drug-drug interactions. Two biologic agents are currently approved by the FDA for the treatment of AD, with many more in various stages of clinical development (Table 10-1).

Enlarge  Figure 10-1: Immunologic Pathways Involved in the Pathogenesis of Acute AD and Progression to Chronic AD. Source: Adapted from Vakharia PP, Silverberg JI. <em>BioDrugs.</em> 2017;31(5):409-422. Illustrated by Miki Fujiwara.
Figure 10-1: Immunologic Pathways Involved in the Pathogenesis of Acute AD and Progression to Chronic AD. Source: Adapted from Vakharia PP, Silverberg JI. BioDrugs. 2017;31(5):409-422. Illustrated by Miki Fujiwara.

Approved Therapies

IL-4/IL-13 Therapies

Dupixent (Dupilumab)

In March 2017, the FDA approved dupilumab as the first biologic for the treatment of AD. Dupilumab is a human monoclonal antibody directed specifically against interleukin-4 receptor alpha (IL-4Rα), a component of the receptor complex for both IL-4 and IL-13. Thus, dupilumab inhibits both IL-4 and IL-13 signaling.

Dupilumab is indicated for the treatment of children, adolescent and adult patients (age 6 years and up) with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupilumab can be used with or without topical corticosteroids.

Efficacy

The efficacy of dupilumab was assessed in three randomized, double-blind placebo-controlled trials (SOLO 1, SOLO 2 and CHRONOS), which enrolled a total of 2119 patients 18 years of age and older with moderate-to-severe AD not adequately controlled by one or more topical medications. In all three trials, patients in the dupilumab treatment group received 600 mg dupilumab at week 0, followed by 300 mg every other week. In SOLO 1 and SOLO 2, patients received either dupilumab or placebo for 16 weeks. In CHRONOS, patients received dupilumab or placebo with concomitant topical corticosteroids and TCIs for select areas as needed for 52 weeks. The primary efficacy endpoint in all three trials was the change from baseline to week 16 in the proportion of patients with an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-point improvement. Other endpoints included the proportion of patients with Eczema Area and Severity Index (EASI)-75 (an improvement of at least 75% in the EASI score from baseline), EASI-50, EASI-90 and reduction in itch as defined by at least a 4-point improvement in the peak pruritus Numeric Rating Scale (NRS) from baseline to week 16.

Efficacy results at week 16 are shown in Table 10-2. In all three trials, a significantly greater proportion of patients in the active treatment group met the primary endpoint at week 16 compared to the control group (SOLO 1, 38% vs 10%; SOLO 2, 36% vs 9%; CHRONOS, 39% vs 12%). Comparable results were found for all other efficacy endpoints. In CHRONOS, 36% of patients in the dupilumab plus topical corticosteroid group were responders at week 52, (IGA 0 or 1 with a reduction of ≥2 points), compared to 13% in the placebo plus topical corticosteroid group.

Treatment effects across subgroups of patients (weight, age, gender, race and prior treatment) in all three trials were generally consistent with results in the overall study population. Randomization of patients to a dupilumab 300 mg QW dosing schedule had no additional treatment benefit over the Q2W schedule. Differences in treatment responses were not reported between patients with childhood- vs adult-onset AD.

A phase 3 study, CAFÉ, investigated the safety and efficacy of dupilumab with and without concurrent topical corticosteroids in the management of patients with moderate-to-severe AD who were inadequately controlled with, or were intolerant to, the immunosuppressant cyclosporine A. Eligible patients were randomized to receive dupilumab 300 mg QW or Q2W with topical corticosteroids, or placebo and topical corticosteroids. The primary endpoint was the proportion of patients that achieved EASI-75 at week 16. Other secondary endpoints included improvement in itch, quality of life measures and symptoms of anxiety and depression. At week 16, 59% of patients who received dupilumab QW with topical corticosteroids, and 63% of patients who received dupilumab Q2W with topical corticosteroids achieved EASI-75, compared to 30% of patients in the placebo plus topical corticosteroid group (P <0.0001). Measures of skin clearing, itching and patient reported quality of life measures were also significantly improved in the dupilumab-treatment groups relative to placebo.

A study of 251 adolescents 12 to <18 years old with moderate-to-severe AD assessed the efficacy of two dupilumab regimens: a fixed 300 mg dose given Q4W, and a baseline-body weight dependent dose of 200 mg for <60kg or 300 mg for ≥60 kg given Q2W. Both the Q4W and the Q2W regimens resulted in significantly increased proportions of patients reaching EASI-75 and IGA scores of 0/1 at week 16 compared to the placebo, while the Q2W regimen showed numerically superior efficacy over the Q4W regimen.

A study of 367 children 6 to 11 years old tested the efficacy of dupilumab in combination with topical corticosteroids for the treatment of severe AD. Dupilumab was administered at either a fixed dose of 300 mg given Q4W or at a baseline weight-based dose (100 mg for <30 kg and 200 mg for ≥30 kg) given Q2W. Both regimens resulted in clinically meaningful improvements in AD signs and symptoms as assessed by statistically higher proportions of IGA 0/1 and EASI-75 rates at week 16, and an improved quality of life compared to the placebo. A prespecified analysis stratified by baseline weight showed that 300 mg Q4W and 200 mg Q2W were the optimal dupilumab dosing regimens for <30kg and ≥30 kg children, respectively.

The effectiveness of dupilumab as a treatment for AD has also been reported in real-life clinical settings. In a Dutch cohort of 95 AD patients treated with dupilumab, 38% reached an IGA score of 0/1 by week 16, and mean EASI scores and patient-reported outcome measures both decreased compared to baseline. A Danish observational study of 43 dupilumab-treated AD patients found statistically significant reductions in EASI scores and patient-reported outcome measures at 1 and 3 months compared to baseline. Statistically significant reductions in scoring of atopic dermatitis (SCORAD) and EASI scores at 3 months following dupilumab treatment initiation were also reported for a cohort of 241 AD patients in France, with 16.6% and 48.8% of patients achieving SCORAD-75 and EASI-75, respectively.

A meta-analysis of data from 4 randomized clinical trials (SOLO1, SOLO2, CHRONOS and AD ADOL) demonstrated that dupilumab resulted in significantly greater change from baseline in the weekly average of peak pruritus NRS compared to the placebo (P <0.0001); a significant difference was apparent by day 2 in adult patients and day 5 in adolescent patients. In another meta-analysis of 7 trials (SOLO1, SOLO2, CHRONOS, CAFÉ and three phase 2 dupilumab studies), dupilumab was shown to reduce the risk of serious or severe infections (risk ratio [RR] 0.43; P <0.05), bacterial and other non-herpetic skin infections (RR 0.44; P <0.001), and clinically important herpes infections, including eczema herpeticum and herpes zoster (RR 0.31; P <0.01). An analysis of the data from SOLO1/2, CHRONOS, CAFÉ and another three phase 2 studies also showed that dupilumab treatment significantly reduced the incidence of all-cause hospitalization (at either a QW or Q2W dosing schedule; P <0.5) and AD-related hospitalization (at the QW dosing schedule; P <0.5), and numerically shortened the duration of AD-related hospitalization.

Safety

The safety of dupilumab in patients with AD was assessed in four clinical trials: three randomized, double-blind, placebo-controlled multicenter trials (SOLO 1, SOLO 2 and CHRONOS), and one dose-ranging trial. The adverse events (AEs) that occurred at a rate of at least 1% in the dupilumab or dupilumab plus topical corticosteroid groups and at a higher rate than in their respective control groups are shown in Table 10-3. The most common AEs were injection site reaction and conjunctivitis. In CAFÉ, the proportion of patients reporting AEs was similar among treatment arms, and no new AEs were reported.

In the dupilumab monotherapy trials (SOLO 1, SOLO 2 and the dose-ranging trial), the proportion of patients who discontinued treatment due to an AE was 1.9% in both the dupilumab and placebo groups through week 16. Through week 52, in CHRONOS, the proportion of subjects who discontinued treatment because of an AE was 1.8% in the dupilumab plus topical corticosteroid group and 7.6% in the placebo plus topical corticosteroid group. The safety profile of dupilumab plus topical corticosteroid was generally consistent throughout the 52-week study.

Conjunctivitis and keratitis occurred more frequently in subjects who received dupilumab in clinical trials. As such, patients should be advised to report new onset or worsening eye symptoms.

Dosage and Administration

Dupilumab is administered by subcutaneous injection and is currently only available in a single-dose pre-filled syringe with needle shield. The recommended dose for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by one 300 mg injection given every other week. It may be used with or without topical corticosteroids or TCIs. Injections can be self-administered by patients into the thigh or abdomen, except for the two inches around the navel. If administered by a caregiver, the upper arm can also be used. For the initial dose, each of the two 300 mg dupilumab injections should be administered at different sites. The injection site should be rotated with each injection, and injections should ideally not be administered into skin that is tender, damaged, bruised, or scarred. If a dose is missed, the injection should be administered within 7 days of the missed dose, followed by continuation of the original schedule. If not administered within 7 days, then the patient should wait until the next dose.

Adbry (Tralokinumab)

The second biologic approved for treatment of moderate-severe AD, tralokinumab, was granted FDA approval in December 2021.Tralokinumab is a human monoclonal antibody which specifically targets IL-13, blocking its interaction with the IL-4/13 receptor and downstream signaling. Because it binds the IL-13 cytokine directly and not the shared receptor, tralokinumab inhibits IL-13 but not IL-4 signaling.

Tralokinumab is indicated for treatment of moderate-to-severe atopic dermatitis in adult patients (aged 18 years and up) whose AD is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Like dupilumab, tralokinumab can be used with or without topical corticosteroids.

Efficacy

The efficacy of tralokinumab for treatment of AD was assessed in three multinational, double-blind, randomized, placebo-controlled trials (ECZTRA 1, 2 and 3). ECZTRA 1 and ECZTRA 2 were 52-week studies of identical design which randomized 1596 patients with moderate-to-severe AD 3:1 to receive either tralokinumab 300 mg (following a loading dose of 600 mg) or a placebo Q2W for 16 weeks. Patients who achieved a clinical response in the initial 16-week period were then re-randomized 2:2:1 to either tralokinumab 300 mg Q2W, tralokinumab 300 mg Q4W, or placebo for a 32-week maintenance period. ECZTRA 3 was a 32-week trial which randomized (2:1) 380 patients with moderate-to-severe AD to receive tralokinumab 300 mg or a placebo Q2W, with optional topical corticosteroids in both groups. Like in ECZTRA 1 and 2, after the initial 16-week period, patients who responded to tralokinumab were re-randomized (1:1) to either continue receiving tralokinumab 300 mg Q2W or switch to tralokinumab 300 mg Q4W for a 16-week maintenance period. The primary endpoints in all three trials were the proportion of patients with an IGA score of 0/1 and the proportion achieving EASI-75 at week 16. Maintenance endpoints included the proportion of patients achieving an IGA score of 0/1 and the proportion achieving EASI-75 at week 52 (ECZTRA 1 and 2) and week 32 (ECZTRA 3).

Efficacy results at week 16 from ECZTRA 1-3 are shown in Table 10-4. Significantly higher proportions of patients treated with tralokinumab achieved an IGA score of 0/1 at week 16 compared to those in the placebo group in ECZTRA 1 (15.8% vs 7.1%), ECZTRA 2 (22.2% vs 10.9%), and ECZTRA 3 (38.9% vs 26.2%). The proportion of patients achieving EASI-75 at week 16 was likewise significantly higher in the tralokinumab group compared to the placebo in all three trials (ECZTRA 1, 25.0% vs 12.7%; ECZTRA 2, 33.2% vs 11.4%; ECZTRA 3, 56.0% vs 35.7%). All three studies also reported significant improvements in the patient-reported Dermatology Life Quality Index compared to baseline, both at week 16 and at week 32/52.

At 52 weeks in ECZTRA 1 and 2, IGA 0/1 and EASI-75 responses were maintained by 51-60% of patients who continued to receive tralokinumab 300 mg Q2W, but also by 39-51% of patients who switched to a Q4W regimen for maintenance, suggesting that a less frequent dosing regimen represents a maintenance option for patients with a response to initial tralokinumab therapy. Interestingly, 21-47% of patients randomized to the placebo in the maintenance phase maintained their initial response, suggesting that tralokinumab may induce longer remission in a subset of patients.

At week 32 in ECZTRA 3, 89% of week 16 IGA 0/1 responders in the Q2W maintenance group maintained their response, as did 77.6% of IGA 0/1 responders in the Q4W maintenance group. Similarly high rates of response maintenance were observed with EASI-75, with 92.5% of responders in the Q2W group and 90.8% in the Q4W group maintaining their response.

Safety

The safety of tralokinumab was assessed in three multinational, double-blind, randomized, placebo-controlled trials (ECZTRA 1, 2 and 3). In all three studies, the incidence of AEs was similar between the tralokinumab-treated and placebo groups, and their severity was in most cases mild-to-moderate. The most common AEs included viral upper respiratory tract infection, upper respiratory tract infection, conjunctivitis, skin infection, pruritus, headache and (in ECZTRA 3) injection-site reaction (Table 10-5). Of these, upper respiratory tract infection and conjunctivitis occurred more often in the tralokinumab groups compared to the placebo in all three trials. In ECZTRA 3, viral upper respiratory tract infection, headache and injection-site reaction were also more common among tralokinumab-treated patients.

Among eye disorders, considered AEs of special interest, conjunctivitis was the most common, occurring in 10% or fewer patients in the tralokinumab groups, and was generally mild-to-moderate in severity. Like with dupilumab, patients taking tralokinumab should be advised to report new onset or worsening eye symptoms.

Dosage and Administration

Tralokinumab is available in the form of pre-filled 150 mg syringes and is administered by subcutaneous injection. The recommended dosage of tralokinumab consists of an initial dose of 600 mg (four 150 mg injections), followed by a dose of 300 mg (two 150 mg injections) every two weeks thereafter. A dosage of 300 mg every four weeks may be considered in patients weighing less than 100 kg who achieve clear or almost clear skin. Tralokinumab may be used with or without topical corticosteroids. TCIs can be used concurrently with tralokinumab, but should be restricted to the affected areas.

After training in subcutaneous injection technique, patients can self-administer tralokinumab into the thigh or abdomen, except for the two inches around the navel. The upper arm may also be used if the injections are administered by a caregiver. For both the initial (four 150 mg injections) and the subsequent (two 150 mg injections) doses, each injection should be administered to a different site within the same body area. The injection site should be rotated with each injection, and injections should never be administered into skin that is tender, damaged, bruised, or scarred. If a dose is missed, the injection should be administered as soon as possible, after which the original dosing schedule should continue.

Therapies Not Currently Recommended for the Treatment of AD

Interleukin 12/Interleukin 23 Therapies

IL-12 leads to differentiation and clonal expansion of Th1 cells, whereas IL-23 leads to Th17 and Th22 cell production. IL-23 has also been demonstrated to be elevated in serum and skin lesions of patients with AD compared to those without. As such, agents that target the IL-12/IL-23 pathways were studied in the management of AD.

Ustekinumab

Ustekinumab, a fully human monoclonal antibody directed against the p40 subunit of IL-12 and IL-23, is in phase 2 clinical development for the treatment of AD. Under the brand name Stelara, ustekinumab is currently approved for the treatment of moderate-to-severe plaque psoriasis, active psoriatic arthritis and moderately-to-severely active Crohn’s disease.

Several case reports were published regarding the efficacy of ustekinumab in patients with AD, with mixed results. Several have demonstrated effectiveness, whereas others have not. In addition, two phase 2, randomized clinical trials were performed, but failed to demonstrate improvements with ustekinumab. The first assessed ustekinumab with concomitant topical corticosteroids in 33 patients with moderate-to-severe AD. At weeks 12, 16 and 20, ustekinumab had no significant effect on improvement in SCORAD-50 response rates. The second assessed the effect of ustekinumab in 79 Japanese adult patients with severe-to-very-severe AD, with no improvements in EASI scores, IGA response rates, or DLQI at week 12. In both trials, ustekinumab was well-tolerated.

The nonsignificant results from the phase 2 clinical trials have abated the expectations regarding the effectiveness of ustekinumab in the treatment of AD. Given the lack of evidence, treatment with ustekinumab is currently not recommended.

Human Immunoglobulin E (IgE)

The exact role of IgE in the pathogenesis of AD remains controversial. However, a large proportion of patients with AD do have elevated IgE levels and are prone to atopic disorders. Given that IgE blockade is efficacious in other atopic diseases, such as allergic asthma, several clinical studies have investigated the efficacy of anti-IgE therapy in AD.

Omalizumab

Omalizumab is a humanized monoclonal antibody directed against free human IgE and membrane-bound IgE on the surface of B cells. Preventing IgE from binding to its high-affinity receptor on basophils and mast cells prevents degranulation and the release of pro-inflammatory mediators. Omalizumab can also potentially inhibit downstream antigen presentation to T cells by preventing the binding of IgE to its low-affinity receptor on dendritic cells. Omalizumab is approved for moderate-to-severe persistent asthma and chronic idiopathic urticaria, and is currently in a phase 4 clinical trial for pediatric patients with severe AD (NCT02300701).

One systematic review of omalizumab in the treatment of AD analyzed results from 26 studies, of which two were randomized controlled trial (RCTs). Of the 174 included patients,129 (74.1%) experienced some beneficial effect from treatment. Omalizumab therapy was also found to be well-tolerated. However, considering the lack of controls in 24 of the 26 studies, the conclusions of this review should be interpreted with caution. Another systematic review and meta-analysis, consisting of two RCTs and 11 case series of at least three patients, found that only 43% of the 103 included patients achieved excellent clinical response after omalizumab treatment, with 30.1% showing insignificant clinical change or even deterioration. This systematic review was also limited by lack of controls for the 11 included case series.

Ligelizumab

Ligelizumab is another humanized monoclonal antibody directed against IgE; however, unlike omalizumab, it has yet to be approved by the FDA for any other indications. A phase 2 trial comparing the efficacy of ligelizumab versus cyclosporine or placebo in the treatment of moderate-to-severe AD found that ligelizumab had no beneficial effect on improvement of EASI scores at week 12 compared with placebo.

Summary

Currently, there is inconsistent evidence to support the use of anti-IgE agents in patients with AD. However, considering that the studies which failed to show clinical improvement did demonstrate decreased serum IgE levels following treatment, this indicates that the drugs had their intended effect. Thus, IgE may play a limited role in the pathogenesis of AD. Future studies are warranted to elucidate subsets of patients that would benefit from anti-IgE therapy.

Tumor Necrosis Factor Alpha (TNF-α)

TNF-α is a proinflammatory cytokine involved in the pathogenesis of multiple chronic inflammatory diseases with skewed Th1 responses, including psoriasis and rheumatoid arthritis. TNF-α enhances the Th1 and Th17/IL-23 pathways, and was shown to be produced by dendritic cells in the acute phase of AD.

In a case series of nine patients with moderate-to-severe AD, the TNF-α inhibitor infliximab demonstrated an initial clinical improvement in EASI and pruritus scores. However, only two patients maintained the improvements at the end of the study. In a case report, an adult with severe AD obtained significant improvement with maintenance following treatment with infliximab. Mixed findings were found in case series and reports with etanercept. Of concern, there were reports of AD worsening in patients secondary to TNF-α inhibitor treatment. Considering the limited demonstration of efficacy, risk of worsening symptoms and associated AEs (eg, infusion reactions, infection, malignancy), TNF-α inhibitors are not currently recommended for the treatment of AD.

 

References

  • Silverberg JI. Clinical Management of Atopic Dermatitis. 2nd ed. Professional Communications Inc. 2022
  • Adbry [package insert]. Madison, NJ: Leo Pharma, Inc; December 2021.
  • Agusti-Mejias A, Messeguer F, Garcia R, Febrer I. Severe refractory atopic dermatitis in an adolescent patient successfully treated with ustekinumab. Ann Dermatol. 2013;25(3):368-370.
  • Auriemma M, Vianale G, Amerio P, Reale M. Cytokines and T cells in atopic dermatitis. Eur Cytokine Netw. 2013;24(1):37-44.
  • Bangert C. Efficacy, safety and pharmacodynamics of a high-affinity anti-IgE antibody in patients with moderate to severe atopic dermatitis: a randomized, double-blind, placebo-controlled, proof of concept study. Presented at: 25th EADV Congress; September 28-October 2, 2016; Vienna, Austria.
  • Batista DI, Perez L, Orfali RL, et al. Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis. J Eur Acad Dermatol Venereol. 2015;29(6):1091-1095.
  • Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-1494.
  • Brandt EB, Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2011;2(3).
  • Buka RL, Resh B, Roberts B, Cunningham BB, Friedlander S. Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol. 2005;53(2):358-359.
  • Cassano N, Loconsole F, Coviello C, Vena GA. Infliximab in recalcitrant severe atopic eczema associated with contact allergy. Int J Immunopathol Pharmacol. 2006;19(1):237-240.
  • de Wijs L, Bosma A, Erler N, et al. Effectiveness of dupilumab treatment in 95 patients with atopic dermatitis: daily practice data. Br J Dermatol. 2020;182: 418-426.
  • Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc; March 2017.
  • Eichenfield LF, Bieber T, Beck LA, et al. Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis. Am J Clin Dermatol. 2019;20(3):443-456.
  • Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132.
  • Gittler JK, Shemer A, Suarez-Farinas M, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130(6):1344-1354.
  • Grimstad O, Sawanobori Y, Vestergaard C, et al. Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis. Exp Dermatol. 2009;18(1):35-43.
  • Harskamp CT, Armstrong AW. Immunology of atopic dermatitis: novel insights into mechanisms and immunomodulatory therapies. Semin Cutan Med Surg. 2013;32(3):132-139.
  • Harskamp CT, Armstrong AW. Immunology of atopic dermatitis: novel insights into mechanisms and immunomodulatory therapies. Semin Cutan Med Surg. 2013;32(3):132-139.
  • Holm JG, Agner T, Sand C, Thomsen SF. Omalizumab for atopic dermatitis: case series and a systematic review of the literature. Int J Dermatol. 2017;56(1):18-26.
  • Ito T, Wang YH, Duramad O, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202(9):1213-1223.
  • Jacobi A, Antoni C, Manger B, Schuler G, Hertl M. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. 2005;52(3 Pt 1):522-526.
  • Kawasaki H, Nagao K, Kubo A, et al. Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol. 2012;129(6):1538-1546.e6.
  • Khattri S, Brunner PM, Garcet S, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol. 2017;26(1):28-35.
  • Liu FT, Goodarzi H, Chen HY. IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol. 2011;41(3):298-310.
  • Liu YJ. Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med. 2006;203(2):269-273.
  • Mangge H, Gindl S, Kenzian H, Schauenstein K. Atopic dermatitis as a side effect of anti-tumor necrosis factor-alpha therapy. J Rheumatol. 2003;30(11):2506-2507.
  • McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol. 2013;131(2):280-291.
  • Miajlovic H, Fallon PG, Irvine AD, Foster TJ. Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus. J Allergy Clin Immunol. 2010;126(6):1184-1190.e3.
  • Montes-Torres A, Llamas-Velasco M, Perez-Plaza A, Solano-Lopez G, Sanchez-Perez J. Biological treatments in atopic dermatitis. J Clin Med. 2015;4(4):593-613.
  • Nic Dhonncha E, Clowry J, Dunphy M, Buckley C, Field S, Paul L. Treatment of severe atopic dermatitis with ustekinumab: a case series of 10 patients. Br J Dermatol. 2017;177(6):1752-1753.
  • Nograles KE, Zaba LC, Shemer A, et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009;123(6):1244-1252.e2.
  • Olesen CM, Holm JG, Nørreslet LB, Serup JV, Thomsen SF, Agner T. Treatment of atopic dermatitis with dupilumab: experience from a tertiary referral centre. J Eur Acad Dermatol Venereol. 2019;33(8):1562-1568.
  • Paller AS, Siegfried EC, Thaçi D, et al. Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: A randomized, double-blinded, placebo-controlled phase 3 trial. J Am Acad Dermatol. 2020;83(5):1282-1293.
  • Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol. 2003;112(6):1147-1154.
  • Regeneron Press Release. ‘Regeneron and Sanofi announce that dupilumab used with topical corticosteroids (TCS) was superior to treatment with TCS alone in long-term phase 3 trial in inadequately controlled moderate-to-severe atopic dermatitis patients. Released June 2016. Accessed October, 2017.
  • Ruiz-Villaverde R, Galan-Gutierrez M. Exacerbation of atopic dermatitis in a patient treated with infliximab. Actas Dermosifiliogr. 2012;103(8):743-746.
  • Saeki H, Kabashima K, Tokura Y, et al. Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study. Br J Dermatol. 2017;177(2):419-427.
  • Samorano LP, Hanifin JM, Simpson EL, Leshem YA. Inadequate response to ustekinumab in atopic dermatitis–a report of two patients. J Eur Acad Dermatol Venereol. 2016;30(3):522-523.
  • Shroff A, Guttman-Yassky E. Successful use of ustekinumab therapy in refractory severe atopic dermatitis. JAAD Case Reports. 2015;1(1):25-26.
  • Silverberg JI, Rubini NPM, Pires MC, et al. Dupilumab treatment reduces hospitalizations in adults with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol Pract. 2022;12:S2213-2198(22)00004-6.
  • Silverberg JI, Toth D, Bieber T, et al; ECZTRA 3 study investigators. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184(3):450-463.
  • Silverberg JI, Yosipovitch G, Simpson EL, et al. Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS. J Am Acad Dermatol. 2020;82(6):1328-1336.
  • Simpson EL, Paller AS, Siegfried EC, et al. Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial. JAMA Dermatol. 2020;156(1):44-56.
  • Sonkoly E, Muller A, Lauerma AI, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117(2):411-417.
  • Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immuno. 2002;3(7):673-680.
  • Stelara [package insert]. Horsham, PA: Janssen Biotech, Inc; September 2016.
  • Suarez-Farinas M, Dhingra N, Gittler J, et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013;132(2):361-370.
  • Thepen T, Langeveld-Wildschut EG, Bihari IC, et al. Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol. 1996; 97:828-837.
  • Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244-279.
  • Vakharia PP, Silverberg JI. Monoclonal antibodies for atopic dermatitis: progress and potential. BioDrugs. 2017;31(5):409-422.
  • Wang HH, Li YC, Huang YC. Efficacy of omalizumab in patients with atopic dermatitis: a systematic review and meta-analysis. J Allergy Clin Immunol. 2016;138(6):1719-1722.e1.
  • Wollenberg A, Blauvelt A, Guttman-Yassky E, et al; ECZTRA 1 and ECZTRA 2 study investigators. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184(3):437-449.
  • Wright RC. Atopic dermatitis-like eruption precipitated by infliximab. J Am Acad Dermatol. 2003;49(1):160-161.
  • Zaba LC, Suarez-Farinas M, Fuentes-Duculan J, et al. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol. 2009;124(5):1022-10.e1-395.