Dupilumab Treatment Provides Multidimensional Improvement of Signs, Symptoms, and Quality of Life in Children With Severe Atopic Dermatitis: A Pictorial Guide

Children with severe atopic dermatitis (AD) have a multidimensional disease burden characterized by skin lesions over large body surface areas (BSAs), pruritus, sleep deprivation, symptoms of anxiety and depression, and impact on quality of life.^1-4 A recent worldwide survey reported a prevalence of 12.2% of diagnosed AD in children aged 6 to 11 years, with 36.2% and 9.1% of these children having moderate or severe disease, respectively.⁵ Dupilumab, a fully human monoclonal antibody,^6,7 blocks the shared receptor subunit for IL-4 and IL-13, thus inhibiting signaling of these key and central inflammatory cytokines in AD pathophysiology. As of June 2020, dupilumab is approved by the FDA for the treatment of patients aged 6 years and older with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.^8,9 A randomized, double-blind, controlled study of dupilumab (NCT03345914),¹⁰ in which children aged 6 to 11 years were treated for 16 weeks with dupilumab and topical corticosteroids (TCS), demonstrated statistically significant, clinically meaningful, and rapid improvements in AD signs and symptoms, including itch, anxiety, depression, sleep, and quality of life, in children treated with dupilumab plus TCS compared with TCS only.

Here we present selected photographic case studies from that trial, which are characteristic of patients with a response to dupilumab, as a visual demonstration of the treatment effect that cannot be adequately conveyed by text alone.

Methods
LIBERTY AD PEDS was a randomized, double-blind, placebo-controlled, phase 3 trial enrolling 367 children aged 6 to 11 years with severe AD inadequately controlled by topical therapies. Patients were randomized 1:1:1 to placebo, dupilumab 300 mg every 4 weeks (q4w), or dupilumab every 2 weeks (q2w; 100 mg if baseline body weight was <30 kg or 200 mg if baseline weight was ≥30 kg) for 16 weeks. All patients received concomitant TCS. Here we report 12 patients treated with dupilumab in this study, with images before and after 16 weeks of dupilumab treatment, as well as results on several key outcome measures characterizing AD severity, including Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), SCORing Atopic Dermatitis (SCORAD), percent BSA affected by AD, Peak Pruritus Numerical Rating Scale (NRS), SCORAD visual analog scale (VAS) itch, SCORAD VAS sleep loss, Patient-Oriented Eczema Measure (POEM), and Children’s Dermatology Life Quality Index (CDLQI).

Pruritus, an important symptom of AD, was evaluated by two different assessments: Peak Pruritus NRS and SCORAD VAS itch. Both are 10-point scales of pruritus severity; however, for the Peak Pruritus NRS, patients are asked: “On a scale of 0–10, what was the worst level of itch during the last 24 hours?”¹¹ The SCORAD VAS itch asked patients: “What was the average itch in the last 3 days?”

Results
Individual cases include images that correspond to the case at baseline (top left image) and after 16 weeks of treatment (top right image). The rainbow graphics in the figures display change in absolute values from baseline (red circles) to week 16 (blue circles) for each outcome. Similarly, the rainbow colors represent established severity strata validated for EASI,¹² SCORAD,¹² Peak Pruritus NRS,^11,13 POEM,¹⁴ and CDLQI.¹⁵ The rainbow graphics for BSA, pruritus VAS, and sleep loss VAS in all figures do not show distinct color bands, as specific severity strata have not been validated for these outcomes. The spider graphics show percent reduction in each outcome; lines closer to the outer edge of the spider plot represent greater improvement from baseline. 

Case 1. Patient 1 was a 7-year-old boy weighing 20.3 kg with AD diagnosed at age 1 year. He had a personal history of keratoconjunctivitis, allergic rhinitis, asthma, and allergies to sulfa antibiotics, dust mites, and pollen. His AD was uncontrolled despite previous treatment with TCS, systemic corticosteroids, and cyclosporine. After 16 weeks of treatment with dupilumab 300 mg q4w, significant improvements were seen in AD signs (IGA, EASI, BSA, SCORAD) and patient-assessed symptoms (itch, POEM; Figure 1).

Case 2. Patient 2 was a 6-year-old boy weighing 19.9 kg who developed AD at age 1 year. The patient also had a personal history of asthma and allergic rhinitis. Previous treatments for AD included hydroxyzine, topical triamcinolone, hydrocortisone, and tacrolimus, as well as the systemic immunosuppressant cyclosporin. However, the patient reported more than 20 flares of AD in the previous year (flares defined as worsening of AD necessitating treatment escalation). Following treatment with dupilumab 300 mg q4w, signs and symptoms were assessed as mild, with almost complete improvement in sleep loss and quality of life. Before and after photos show improvement in perioral edema/papulation (Figure 2).

Case 3. Patient 3 was a 7-year-old boy weighing 21.3 kg who had AD for most of his life. In addition to a history of use of several TCS (desonide, mometasone, triamcinolone, clobetasol) and systemic prednisolone for treatment of AD, the patient was also receiving medication for moderate persistent asthma and seasonal allergic rhinitis. His caregiver also reported a personal history of keratoconjunctivitis. The patient was randomized to 16 weeks of dupilumab 300 mg q4w that led to 100% improvement in IGA, EASI, and BSA scores, a high improvement in quality of life as assessed by CDLQI, and some minor improvements in itch (Figure 3).

Case 4. Patient 4 was a 6-year-old girl weighing 22.3 kg at study baseline who developed AD at the age of 2 years. Prior treatment for AD included topical hydrocortisone, desonide, mometasone, hydrocortisone butyrate, and triamcinolone. The patient also had asthma, seasonal allergic rhinitis, and keratoconjunctivitis. The study treatment consisted of dupilumab 300 mg q4w and led to a decrease in IGA score from severe (4) to moderate (3), as well as a 60% to 80% improvement in signs as assessed by EASI, SCORAD, and affected BSA. The 16-week study regimen also led to considerable improvement in quality of life (CDLQI) and almost 100% improvement from baseline in pruritus and sleep loss. Before and after photos clearly show improvement in excoriations (Figure 4).

Case 5. Patient 5 was a 10-year-old girl weighing 36.7 kg who had AD for most of her life and had 14 flares in the year prior to the study. Prior and concomitant medications for AD included topical hydrocortisone, triamcinolone acetonide, and crisaborole. The patient also had comorbid asthma and allergic rhinitis. Treatment with dupilumab 300 mg q4w for 16 weeks led to a decrease of IGA score from severe (4) to almost clear (1), as well as nearly 80% improvement in EASI and percent BSA affected. Some improvements were also seen in measures of pruritus. Clear improvement in lichenification was observed (Figure 5).

Case 6. Patient 6 was a 9-year-old boy weighing 28.1 kg who was randomized to dupilumab 100 mg q2w. This patient had AD for all his life and had two AD flares within the previous year. The patient also had a history of asthma, allergic rhinitis, and growth hormone deficiency. Previous treatments included oral cetirizine hydrochloride, loratadine, hydroxyzine, cefalexin, and prednisolone. Treatment with dupilumab led to a decrease in IGA score to 2 (mild), almost 100% decrease in EASI, and nearly 80% improvement in BSA. Some modest improvements were also seen in pruritus scores and quality of life. Before and after photos of the elbow clearly show improvement of infiltration/papulation, crusting, and lichenification (Figure 6). 

Case 7. Patient 7 was a 9-year-old girl weighing 28.6 kg with four AD flares in the previous 12 months. The patient developed AD at age 1 year and had a history of other allergies. Prior treatment for AD included topical fluocinolone acetonide, triamcinolone acetonide, clobetasol propionate, mupirocin, tacrolimus, and crisaborole. Treatment with dupilumab 300 mg q4w for 16 weeks led to large improvements in all assessed AD dimensions, including signs, symptoms, and quality of life. Improvements in erythema, edema, and fissures were observed (Figure 7).

Case 8. Patient 8 was an 11-year-old boy weighing 31 kg who had AD throughout his life and five flares within the previous year. The patient also had comorbid asthma and allergic rhinitis. Medications for AD included topical hydrocortisone, mometasone, crisaborole, triamcinolone acetonide, and mupirocin as well as oral prednisolone. The patient was randomized to dupilumab 300 mg q4w, which led to some improvement in signs and quality of life and almost complete suppression of pruritus. In the before and after photos, improvement of dryness, excoriations, erythema, and lichenification can be seen (Figure 8).

Case 9. Patient 9 was an 11-year-old boy weighing 42.1 kg with AD, food allergy, asthma, keratoconjunctivitis, and allergic rhinitis. The patient developed AD at age 1 year and had eight flares within the previous year. Prior and concomitant treatment included alclometasone dipropionate, fluocinonide, tacrolimus, carbinoxamine maleate, crisaborole, prednisone, betamethasone dipropionate, hydrocortisone, and triamcinolone acetonide. The patient received dupilumab 300 mg q4w during the trial. At week 16, AD signs improved to a mild severity level, and measures of sleep loss and itch showed complete improvement. Quality of life also improved by 100%. Photos show improvements in oozing/crusting, erythema, and edema (Figure 9).

Case 10. Patient 10 was a 9-year-old boy weighing 42.7 kg with AD since age 1 year. During the previous year, the patient had seven AD flares; patient also had comorbid asthma and allergic rhinitis. Treatment for AD included hydrocortisone, triamcinolone acetonide, and systemic immunosuppressants cyclosporine and prednisone. Concomitant medications for other allergic conditions included ketotifen and hydroxyzine hydrochloride. In this patient, 16 weeks of treatment with dupilumab 300 mg q4w showed clear improvement in AD signs, with almost complete suppression of itch and sleep loss. Improvements were observed of erythema, edema, and skin dryness in the before and after photos (Figure 10).

Case 11. Patient 11 was a 10-year-old boy weighing 32.9 kg randomized to dupilumab 200 mg q2w. He developed AD 9 years prior and experienced 25 AD flares in the previous year. The patient also had asthma, keratoconjunctivitis, and allergic rhinitis. Medications included triamcinolone acetonide, mometasone furoate, tacrolimus, and clobetasol for AD and alclometasone, hydroxyzine, doxycycline, sulfamethoxazole/trimethoprim, acyclovir, erythromycin, hydrocortisone, dapsone, moxifloxacin, and alclometasone dipropionate for his other comorbidities. Treatment for 16 weeks with dupilumab led to almost complete improvement in signs as assessed by EASI and BSA affected by AD, pruritus, and major improvement in quality of life. This patient had a prurigo-like phenotype, with improvement of nodules and papules, with residual postinflammatory hyperpigmentation (Figure 11). 

Case 12. Patient 12 was a 6-year-old boy weighing 22.2 kg with AD since birth. The patient had 12 AD flares in the year prior to the study and was also receiving treatment for asthma and other allergies. Treatment included topical hydrocortisone, fluticasone propionate, triamcinolone, and clobetasol as well as oral hydroxyzine, prednisone, and cefalexin. Treatment with dupilumab 100 mg q2w led to approximately 60% to 80% improvement in measures of AD signs and pruritus. The photos show clear improvement of the prurigo-like lesions on the trunk and arm (Figure 12).

Discussion and Conclusion
This series presents 12 case studies of children aged 6 to 11 years with severe AD who received dupilumab plus TCS in a pivotal phase 3 trial. Before treatment, these patients presented with a high burden of AD, including skin lesions, pruritus, affected sleep, and a high adverse impact on quality of life. Following 16 weeks of treatment with dupilumab plus TCS, all 12 patients experienced significant clinical benefit in most parameters. Although some patients did not achieve an optimal response in one or two individual measurements, all had marked improvement in most clinically relevant measures, thereby highlighting the importance of using multiple tools to assess the overall impact of treatment for AD.

In conclusion, these selected case studies demonstrate the multidimensional and clinically relevant improvement of signs, symptoms (pruritus), and quality of life in children aged 6 to 11 years with severe AD that can be achieved with dupilumab.

Dr Shumel is senior medical director at Regeneron Pharmaceuticals, Inc, in Tarrytown, NY. Dr Rossi is senior medical director at Sanofi Genzyme in Cambridge, MA.

Disclosure: Dr Shumel is an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Rossi is an employee and may hold stock and/or stock options in Sanofi Genzyme. This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Medical writing/editorial assistance provided by Carolyn Ellenberger, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.

Acknowledgements: We thank the patients and their caregivers, who provided full consent for the publication of their photos, and the investigators who participated in this study. We also thank Amy Praestgaard, El-Bdaoui Haddad, and Adriana Mello of Sanofi Genzyme and Linda Williams of Regeneron Pharmaceuticals, Inc, for their contributions. Marthe Vuillet and Dr Rossi of Sanofi Genzyme developed the spider grams and rainbow graphics shown in Figures 1-12.

Dr Shumel was the medical director responsible for designing and running the study. Dr Rossi conceived the idea of the manuscript, selected the patient photos, created figures, and drafted the manuscript with the medical writer. Drs Rossi and Shumel interpreted the data, provided critical feedback on the manuscript, approved the final manuscript for submission, and are accountable for the accuracy and integrity of the manuscript. 

Editor’s note: This article was submitted independently from advertising. The editorial staff believes this article, given the recent FDA approval of dupilumab for patients as young as 6 years, is of high interest to our readership and has chosen to give it extended coverage in this issue.

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