The burden of disease extends to sleep disturbances, decreased work/school productivity (absenteeism and presenteeism), secondary skin infections and a range of mental health disorders. Together the itchy, visible lesions and psychosocial impact of the disease contribute substantially toward cumulative life course impairment affecting relationships and career trajectory inter alia.⁴  

AD usually presents in infancy and often co-occurs with other immunoglobulin E (IgE)-mediated disorders such as allergic rhinitis, asthma, and food allergies. AD affects between 10%-30% of children and between 2%-10% of adults.¹  

Pathophysiologically, AD is driven by immune dysregulation that leads to a deficient skin barrier, which allows irritants and allergens to penetrate, leading to inflammation, pruritus, and typical clinical features. Dysfunctional ceramides, crucial for the skin's barrier function, contribute to this defect.¹  

Immune responses, particularly type 2 (Th2) and type 1 inflammatory cytokines responses, further exacerbate inflammation. Th2 inflammation is largely orchestrated by the cytokines interleukin (IL)-4 and IL-13. In concert, these cytokines impair keratinocyte differentiation leading to perturbed protein and lipid production and ultimately skin barrier defects.¹  

 A further consequence is reduced production of antimicrobial peptides, and thus, AD patients often show Staphylococcus aureus colonisation, complicating the condition.^5,6   

Diagnosis is primarily clinical, with biopsies showing eczematous patterns. In difficult cases, tests like skin prick testing and IgE antibody detection against specific allergens can be useful.¹ 

 Novel approach to the treatment of AD 

 The standard care for AD involves therapeutic patient education  entailing frequent and liberal use of emollients, trigger avoidance, adherence to bath-rules, and appropriate use of topical corticosteroids (TCS) or calcineurin inhibitors. In severe cases, systemic CS and classic immunosuppressants have traditionally been used. The use of these agents is limited due to their side effect profiles and the need for regular monitoring.²  

The use of oral CS to treat flares, while well-intentioned, often leads to rebound disease, resulting in a cyclical process ultimately to the patient’s detriment.⁵  

Suboptimal adherence is common due to patient hesitancy, healthcare practitioners' caution, and treatment inconvenience. Therefore, the development of safer and more effective systemic treatments was identified as a gap in the effective treatment of patients living with AD.² 

The good news is that several novel therapies have been developed or are in the pipeline. One such novel therapy is dupilumab, which was launched in South Africa in 2021 as Dupixent®.7  

Dupilumab is a fully human monoclonal antibody that selectively targets the common alpha chain subunit of IL-4 and IL-13 receptors. This action effectively blocks the signalling of IL-4 and IL-13, crucial Th2 cytokines, which have been implicated in atopic or allergic conditions like AD and asthma.^2,8 

Efficacy and safety profile of dupilumab 

In South Africa, dupilumab is approved for the treatment of adult patients living with moderate-to-severe AD whose disease is not adequately controlled with prescription topical therapies (creams or ointments) or when those therapies are not advisable. Dupilumab can be used with or without topical therapies. The recommended  dose is an initial dose of 600 mg (two 300 mg subcutaneous injections), followed by 300 mg given every other week.⁸ 

Four pivotal randomised, placebo-controlled phase-3 clinical studies evaluated the safety and efficacy of dupilumab, which resulted in the regulatory approval for the treatment of patients living with moderate-to-severe AD.^6,9,10

1.Study of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe AD (SOLO 1): In SOLO 1 and 2, patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous (SC) dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. A total of 38% of patients who received dupilumab every other week and 37% who received dupilumab weekly, achieved the primary endpoint (the proportion of patients who had both a score of 0/1 [clear or almost clear] on the Investigator’s Global Assessment (IGA) score and a reduction of ≥2 points in IGA score from baseline at week 16) compared to 10% in the placebo group.⁶

2.Study of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe AD (SOLO 2): The results were similar in SOLO 2, with the primary endpoint occurring in 36% who received dupilumab every other week and 36% who received dupilumab weekly, compared to 8% who received placebo. In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index (EASI) was reported in significantly more patients who received dupilumab than in patients who received placebo. Dupilumab was also associated with improvement in pruritus and symptoms of anxiety or depression and improvement in QoL.⁶

3.Study to Assess the Efficacy and Long-term Safety of Dupilumab in Adult Participants With Moderate-to-Severe AD (CHRONOS): Patients were randomised (3:1:3) to SC dupilumab 300 mg once weekly, dupilumab 300 mg every other week or placebo. At week 16, 39% of patients who received dupilumab plus TCS every week and 39% who received it every other week versus 12% in the placebo plus TCS group achieved IGA 0/1 and ≥2 points improvement from baseline, and 64% and 69% versus 23% achieved EASI-75 in the weekly, every other week dupilumab group versus and placebo at week 16. Week 52 results were similar demonstrating a sustained reponse.⁹

4.Dupilumab with concomitant topical corticosteroid treatment in adults with AD with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomized phase III clinical trial (CAFÉ): Patients were randomised 1:1:1 to SC dupilumab 300 mg weekly, every other week or placebo. All received concomitant medium-potency TCS from weeks two to 16. Significantly more patients in the dupilumab weekly and  every other week plus TCS achieved ≥75% improvement from baseline in the EASI score at week 16 versus the placebo and TCS group  (59.1% and 62.6% vs 29.6% respectively). Patients also showed significant improvement in pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and QoL.¹⁰

The most common adverse event reported in all studies was conjunctivitis but rarely led to treatment discontinuation.^6,9,10

Real-world efficacy and safety data

Several real-world studies also evaluated the effectiveness of dupilumab. Stölzl et al (2022) compared the long-term efficacy and safety of dupilumab to ciclosporin using real-world data. This is extremely useful as no head-to-head studies have been performed. The analysis included 1211 patients living with moderate-to-severe AD. Dupilumab demonstrated comparable effectiveness to ciclosporin. However, ciclosporin had higher discontinuation rates (78% and 100% at months 12 and 24) due to side effects and insufficient efficacy. Dupilumab discontinuation was only 5% and 11.4% at those time points. The study concluded that dupilumab exhibited robust, long-term effectiveness and favourable safety in real-life settings.¹¹

An earlier real-world study by Ariëns et al (2019) indirectly compared the effectiveness of dupilumab with cyclosporine. Regression models (adjusted for sex, baseline severity and biomarker levels) were used to estimate various EASI levels responses at two time points (12-16 weeks and 24-30 weeks) to dupilumab 300mg every two weeks (CHRONOS or cyclosporine (University Medical Center).¹²

Among University Medical Center patients, estimated EASI-50 responders were 91% versus 77% (weeks 12-16), and 96% versus 67% (weeks 24–30) for dupilumab versus cyclosporine. EASI-75 responders were 78% versus 56% (weeks 12-16) and 80% versus 47% (weeks 24-30) for dupilumab versus cyclosporine, respectively.¹²

Among CHRONOS patients, estimated EASI-50 responders were 90% versus 74% (weeks 12-16) and 92% versus 53% (weeks 24-30). EASI-75 responders were 75% versus 52% (weeks 12-16) and 74% vs 40% (weeks 24-30) for dupilumab versus cyclosporine, respectively. These results suggest a higher relative efficacy of dupilumab vs cyclosporine.¹²

Eichenfield et al (2022) evaluated the efficacy of dupilumab in 435 adult patients living with moderate-to-severe AD. After 16 weeks of dupilumab treatment, >70% of patients with a baseline IGA score ≥3 achieved an IGA score of ≤2. Those with baseline itch severity scores ≥3 experienced reduced itch intensity (mean score: 7 to 2.8), and patients with baseline body surface area (BSA) affected ≥10% saw a significant reduction in affected BSA (39.3% to 16.3%). Findings aligned with clinical trial results, showing dupilumab's real-world efficacy in improving AD symptoms.¹³

Conclusion

AD is a common and burdensome dermatological condition with severe impacts on patients' QoL. Dupilumab, a human monoclonal antibody targeting IL-4 and IL-13 receptors, has shown remarkable safety and efficacy in treating moderate-to-severe AD.

Four phase-3 clinical trials (SOLO 1 and 2, CHRONOS, CAFÉ) established its favourable benefit/risk ratio, leading to regulatory approval. Dupilumab-treated patients achieved significant improvements in IGA scores, EASI reductions, pruritus alleviation, and QoL enhancements. Additionally, long-term studies demonstrated sustained benefits.

Real-world evidence further supported dupilumab's effectiveness, with substantial proportions achieving clinically meaningful improvements in EASI scores and other measures. Although ocular side effects like conjunctivitis were reported, they rarely led to discontinuation. Overall, dupilumab's positive safety and efficacy profile offers a promising therapeutic avenue for individuals with uncontrolled moderate-to-severe AD, significantly enhancing their QoL and treatment outcomes.

References

1. Kolb L, Ferrer-Bruker SJ. Atopic Dermatitis. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448071/
2. Tod BM, Visser WI. Emerging targeted therapies for atopic dermatitis in the South African context. Current Allergy & Clinical Immunology, 2022.
3. Hang L, et al. The impact of eczema involving visible areas of the skin on patients' quality of life. JEAVD Clinical Practice, 2022.
4. Augustin M, et al. Unveiling the true costs and societal impacts of moderate-to-severe atopic dermatitis in Europe. J Eur Acad Dermatol Venereol, 2022.
5. Visser et al. Contemporary treatments for atopic dermatitis and the dawn of targeted biological therapies. South African General Practitioner, 2021.
6. Simpson EL, et al, SOLO 1 and SOLO 2 Investigators. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med, 2016.
7. Belseck N. First targeted biologic in SA for use in atopic dermatitis. [Internet]. 2021. Available at: https://www.medicalacademic.co.za/news/first-targeted-biologic-in-sa-for-use-in-atopic-dermatitis/
8. Patient information. Dupixent® 300mg solution for injection. [Internet]. 2021. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2022/01/1.3.2-Approved-PIL-Dupixent-300-mg-2021.12.13.pdf
9. de Bruin-Weller M, et al. Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomized phase III clinical trial (LIBERTY AD CAFÉ). BJD, 2017.
10. Blauvelt A, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet, 2017.
11. Stölzl D, et al. Real‐world data on the effectiveness, safety, and drug survival of dupilumab: an analysis from the TREATgermany registry. BJD, 2022.
12. Ariëns LFM, et al. Dupilumab Versus Cyclosporine for the Treatment of Moderate-to-Severe Atopic Dermatitis in Adults: Indirect Comparison Using the Eczema Area and Severity Index. Acta Derm Venereol, 2019
13. Eichenfield LF, et al. Real-World Effectiveness of Dupilumab in Atopic Dermatitis Patients: Analysis of an Electronic Medical Records Dataset. Dermatol Ther (Heidelb), 2022.