Lotte Spekhorst

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide. AD is characterized by exacerbations and remissions of eczematous skin lesions, persistent pruritus and pain, resulting in sleep disturbance and a significantly reduced quality of life. AD is a highly heterogeneous disease on a clinical as well as a biological level. Both genetic and environmental factors contribute to the complex pathogenesis of AD, resulting in immune dysregulation and epithelial barrier disruption.

Dupilumab is the first biologic approved for the treatment of patients with moderate-to-severe AD and proved high efficacy and safety in large randomized controlled trials. However, we know that the highly regulated situations in these trials can lead to a difference in treatment effect compared to the reality in daily practice. This emphasizes the importance of observational studies in a daily practice setting in order to evaluate the advantages and disadvantages of a treatment in a large and more diverse population.

Given the heterogeneous nature of AD, it is unlikely that every patient will respond the same to a particular treatment. In contrast to the current “one-size-fits-all” approach, there will be a great need for more patient-centered treatment strategies. Furthermore, the number of targeted therapies for AD is growing which also gives the opportunity to work towards personalized treatment. As dupilumab is the first biologic that came on the market, long-term evidence of daily practice use is only available for this advanced systemic treatment option. The studies described in this thesis aimed to assess the performance of dupilumab in daily practice and to optimize dupilumab treatment for the individual patient. In the future, this information may help us choose which patient might benefit most from dupilumab treatment and may contribute to finding the most optimal treatment/dosing strategy for an individual patient during dupilumab treatment.

As shown in Chapter 2, treatment with dupilumab in daily practice resulted in a rapid improvement in clinical outcomes combined with a favorable safety profile. Conjunctivitis was more frequently reported as a side effect compared to the clinical trials. As shown by a patient-reported outcome, the majority of patients was satisfied with dupilumab treatment (Chapter 3). Looking from a different angle with a more holistic approach, by using drug survival, dupilumab had an overall good drug survival persistent up to three years (Chapter 4 and 5), meaning that only few patients discontinued dupilumab treatment due to ineffectiveness and/or side effects. Using immunosuppressive therapy at baseline, absence of treatment effect at week 4, older age and an Investigator Global Assessment-score of very severe AD were found to predict discontinuation of dupilumab treatment ineffectiveness and/or side effects. Overall, above mentioned studies concluded that dupilumab was a safe and effective treatment option for the majority of patients with moderate-to-severe AD in daily practice.

Personalized treatment with dupilumab in AD could also benefit from predictive models. However, as shown in the performed prediction studies (Chapter 5, 7 and 9) developing a prediction model was challenging. Since response to dupilumab was rather homogenous, the number of non-responders was low and number of patients able to taper was high, it was rather difficult to find distinctive clinical or biological characteristics for our prediction models.

A following question was whether it was possible to reduce the dose of dupilumab while maintaining clinical effectiveness. In Chapter 6, a broad range and relatively high serum dupilumab levels were found after 16 weeks of treatment in AD patients, with no relation to treatment response and side effects during the first year of treatment. Therefore, it might be possible that some patients can maintain clinical effectiveness with lower serum dupilumab levels by prolonging dupilumab interval. This was confirmed by our results described in Chapter 8. The results of Chapter 8 were based on our patient-centered dupilumab dosing regimen; in this dosing regimen the dupilumab interval was stepwise prolonged in case of persistent controlled AD. Despite significantly lower serum dupilumab levels, the EASI scores and disease severity biomarkers remained low and stable while using at least half of the standard dosage (Chapter 8). Our dosing regimen was implemented since 2019 in the BioDay registry and guided us towards more personalized treatment with dupilumab. In Chapter 9, we concluded that our disease activity guided dosing regimen was successful in 83.3% of the patients while maintaining controlled disease, with the majority using dupilumab QPW/Q4W. Although a significant effect after start tapering was observed for EASI and NRS pruritus, these scores remained low and still fulfilled the criteria of mild disease.

In total, 401 patients had a dupilumab dose reduction with a total estimated cost saving of 3,977,033.98 EUR between January 2019 and June 2022.

Due to its mode of action, dupilumab treatment in AD patients might also be beneficial for other comorbid atopic diseases, such as asthma and food allergy. In Chapter 10 and 11 we analyzed the effect of dupilumab on the atopic comorbidities food allergy and asthma in AD patients. One year of dupilumab treatment, primarily indicated for AD, resulted in a significant improvement of comorbid asthma, with the largest effect in the first 16 weeks (Chapter 10). Furthermore, dupilumab treatment induced a strong and sustained decrease in specific IgE levels for a variety of food allergens in AD patients with comorbid food allergies, with an estimated decrease of at least 50% for all foods after one year and more than 80% after three years of treatment (Chapter 11). In the context of personalizing treatment, dupilumab might be the most suitable treatment option for AD patients with atopic comorbidities.

Future perspectives

The daily practice studies described in this thesis focused on the long-term treatment effect of dupilumab, the possibility of tapering dupilumab, and the effect on atopic comorbidities asthma and food allergy. Chapter 12 discussed this thesis’ most important findings in the context of the daily performance of dupilumab while moving towards personalized treatment with dupilumab in AD.

The landscape of AD treatment is changing. At time of writing this thesis, two different biologics (dupilumab and tralokinumab) and three small molecules (Janus kinase (JAK)-inhibitors: baricitinib, upadacitinib, and abrocitinib) are registered for the treatment of AD in the Netherlands. These new drugs offer new treatment opportunities for patients with an inadequate response to dupilumab, patients with severe conjunctivitis, and dupilumab-induced skin eruptions. With the current evidence gathered in this thesis, we hope to provide a solid foundation for the daily practice use of dupilumab in patients with AD while moving towards personalized treatment. For example, our patient-centered dosing regimen could be a blueprint for dose reduction for other biologics in AD, such as tralokinumab. In the future, predictive models, by combining clinical- and biological characteristics, might be developed to sufficiently predict response to dupilumab and optimize treatment strategies. However, we have to consider the option that – despite emerging techniques and analysis methods – it might not be possible to accurately predict treatment response.

Hence, introduction of dupilumab has led to a major positive shift in the treatment paradigm of AD, and has significantly improved the quality of life for many AD patients. It will be exciting to see what the future holds for the treatment of AD with subsequent introduction of new advanced targeted therapies.