A 52 weeks dupilumab treatment for moderate to severe atopic dermatitis in Korea: long-term efficacy and safety in real world

Previously, we have reported short term effectiveness and safety of dupilumab in Korea. In this study, we are trying to report the long-term effectiveness and safety of dupilumab in Korea. Ninety-nine patients with moderate to severe AD were analyzed. They were evaluated using Eczema Area and Severity Index (EASI), Numerical Rating Scale (NRS), Patient Oriented Eczema Measure (POEM), and Dermatology Quality of Life Index (DLQI) at baseline, week 16, 32 and 52. Efficacy outcomes showed higher improvement at 52 weeks compared with 16 weeks; high percentual reductions in EASI (88.1%), peak pruritus NRS (65.6%), POEM (67.2%), and DLQI (69.0%) compared to baseline. Proportion of patients achieving EASI 75 and 90 were 90.2% and 53.7%. POEM and DLQI had high correlation with clinical measured outcomes. In the analysis for the factors affecting achievement of EASI 90, female gender (OR 2.5), eosinophilia (OR 0.2) and elevated LDH (OR 0.07) were significantly associated. Most frequent adverse events included facial erythema (19.2%) and conjunctivitis (17.2%), which were mild/moderate and resolved during treatment. In conclusion, dupilumab treatment for 52 weeks in Korean patients with moderate-to-severe AD confirmed long term effectiveness and safety.


Informed consent. Need of informed consent is waived by the Institutional Review Board of National
Medical Center.

Results
Demographics. Of 99 patients, 58 men and 41 women had an average age of 30.92 years; 48 (48.48%) were in their 20 s to 30 s, while 38 (38.38%) were in their 30 s and 40 s. One third of patients (36%) had a family history of allergic diseases and more than half (57.58%) had personal history of other allergic diseases. Among them, allergic rhinitis, allergic conjunctivitis and asthma were the most frequent (85.96%, 29.82%, and 21.05%, respectively). About half (55.56%) of patients had known allergies mostly caused by house dust mite (96.36%). Topical steroid was the most frequent previous treatment used (92.93%) followed by TCI (68.69%). Treatment with systemic steroid and non-steroid immunosuppressive drugs accounted for 86.89% and 61.61% of the subjects, respectively. Cyclosporine was the most common non-steroid immunosuppressant (86.89%). The proportion of oriental medicine and folk remedies were 52.53% and 27.27%, respectively, with oriental medicine in more than half of the cases (Table 1).
Most patients (82.83%) were treated with dupilumab with TCI only over the 52 weeks. For patients initiating dupilumab in combination with other systemic drug for tapering, the initial combination treatment was cyclosporine in 7%, methotrexate in 6%, and oral steroid in 4%.

Efficacy of treatment. Baseline value of efficacy outcomes.
Outcome measures used in this study have been validated for atopic dermatitis and are recommended by HOME 21 . The mean baseline values for EASI, pruritus NRS, POEM, and DLQI are presented in Table 2, and correspond to severe disease.

Changes in laboratory tests
In addition, we separately performed multivariative analysis to identify the effects of several variables at once under adjustment to the baseline EASI. It was also confirmed that female sex (OR 3.321, p = 0.033) and high LDH level (OR 0.252, p = 0.036) were factors associated with achieving EASI 90. (Table 6). None of the patients discontinued from treatment due to conjunctivitis because they thought that the improvement of AD was important and conjunctivitis gradually improved.

Discussion
While real-world studies on the long-term effectiveness and safety of dupilumab treatment have been conducted and published in various countries [9][10][11][12][13][14] , there were limited data on its long-term results in Korean AD patients despite our previous study of dupilumab treatment for 16 weeks. In this study, we assessed long-term effectiveness and safety of 52 weeks of continuous treatment with dupilumab in Korean patients with moderate-to-severe AD.
In addition, we analyzed the correlation between efficacy outcomes and factors affecting the therapeutic effect 15 . Dupilumab significantly improved clinical factors and symptoms of AD in moderate-to-severe patients over the 52-week treatment period, confirming its long-term therapeutic effect and safety.  www.nature.com/scientificreports/ Among the baseline values, DLQI was found to be exceptionally high in Korea compared to other studies including that of Japan [8][9][10][11][12][13][14] . As mentioned in previous studies, no clear improvements were seen in Korean AD patients although various treatments were used to improve their lesions. This is supported by the relatively high proportion of subjects who used oriental medicine and folk remedy as their past treatments 22 .
Overall, this study showed a higher efficacy than the existing clinical trials and other real-world studies [8][9][10][11][12][13][14] ; 88.58% of patients achieved significant improvements in EASI at week 52 in this study, compared to 78.3% in LIBERTY AD CHRONOS, and 76.38% in United Kingdom (UK) real-world data. Although outcomes regarding NRS, POEM, and DLQI were similar to those of UK, the results of this study were effective considering that the data from the UK were relatively from mild patients 8,9 . Compared with the results of a study conducted in Japan, our study showed greater efficacy. Particularly, there was a remarkable difference in that the study in Japan resulted in the reduction by 76.5% in EASI after 12 months 14 . In addition, the achievement of EASI 75 and 90 was 90.24% and 53.66% in this study, compared to 65% and 51% in LIBERTY AD CHRONOS or 63% and 29% in the UK, respectively. The following reasons were considered for the higher percentual of improvement in our data to that of existing clinical trials and real-world studies in other countries. Because of the easy accessibility to hospitals in Korea, the majority of patients regularly visited the hospital every two weeks, and the dermatologist could check their condition every time. Whenever their condition worsened, further treatment was immediately initiated. For example, in the case of a patient with a worsening of eosinophilia, which was thought as a poor prognosis, short-term systemic steroid treatment was applied to support the therapeutic effect of dupilumab. In addition to dupilumab treatment, all patients basically used TCI. Patients were fully informed about the importance of using TCI before initiating treatment and continued to use TCI despite the improvements shown with dupilumab. This combination of TCI and dupilumab is thought to increase the therapeutic effect by acting as a "proactive treatment" 23-25 even after AD has improved. In January 2020, National Health Insurance Service provided coverage for dupilumab treatment in Korea. For insurance coverage, it should satisfy strict conditions with regular dosing intervals and prove the therapeutic effect of dupilumab. If AD worsened, it could no longer be covered by health insurance. Therefore, patients themselves made efforts to use moisturizers or avoid exposure to known allergens; we considered this behavior as "adherence" to the treatment. Based on these results, we could identify the importance of "adherence" and "proactive treatment".
In the correlation analysis, there was a significantly high correlation between NRS, POEM, and DLQI, which are indicators of subjective symptoms, but there was a low correlation with EASI which is considered as a relatively objective marker. This is consistent with previous studies 15,26 that suggested the importance of subjective www.nature.com/scientificreports/ symptoms, in addition to objective symptoms, and particularly shows the usefulness of POEM in evaluating the patient's quality of life.
As suggested in previous studies, our long-term study confirmed that women had a good treatment response, and eosinophilia and high LDH level were associated with a poor treatment response. The real-world study results in which females showed better therapeutic effects than males were also consistent with this study 27 . Compliance and drug distribution according to body weight were considered as the reasons why women have better prognosis. Previous studies have suggested that women have higher treatment compliance than men in AD, contact dermatitis, and psoriasis [28][29][30] . Therefore, these data may have influenced the 'adherence' that appeared during treatment. Although weight and BMI cannot be measured in all patients, if women were assumed to have a lower body weight than men, then the distribution of drugs per unit body weight was higher in females, since the treatment regimen was performed with the same dosage and interval. A clinical trial of dupilumab in children with severe AD also showed a therapeutic effect according to body weight 31 . This is considered meaningful, although it should be verified through validated and controlled trials. www.nature.com/scientificreports/ It has been previously suggested that high eosinophilia may be associated with poor therapeutic efficacy of dupilumab 32 . It has also been observed that in these patients, short-term systemic steroids can lower eosinophils and raise the effect of dupilumab. One study suggested that high LDH level is associated with decreased effect of dupilumab under adjustment to the baseline EASI 33 . An ongoing study attempted to investigate the degree of influence of markers known to be related to disease activity in AD on the therapeutic effects of dupilumab treatment. In addition to IgE, TEC and LDH, a total of 18 markers including soluble IL 2 receptor, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin were included 34 . Recently, various therapeutic agents that block each stage of the pathophysiology of AD have been developed [4][5][6] and are considered as a good treatment option. Therefore, predictive biomarkers are important as they are used to identify patients who are more responsive to certain therapeutic agents that show good therapeutic effects. In this study, biomarkers that affect the prognosis of dupilumab treatment were identified, which is expected to maximize the effect of dupilumab treatment.
Studies about skin biopsy performed before and after dupilumab treatment showed the significant decrease in cytokines associated with type 2 inflammation, such as IL-13 and IL-31, and T cells and dendritic cells, and in epidermal thickness 35,36 . In this study, skin biopsy was performed twice at the same site, before initiating of dupilumab treatment and at 16 weeks (Fig. 3). The epidermal thickness and irregular acanthosis markedly decreased after treatment, and the expression of T cells in the dermis and ki 67, a proliferation marker at the base of the epidermis, was also significantly reduced. Since biopsy was not performed on all patients, increased number of samples in future studies could provide meaningful results for comparison.
Facial erythema is a side effect that has not been specifically reported in existing clinical trials, even though it may have a possible connection with dupilumab treatment in the clinical setting. The cause is not simple; there are various possibilities from exacerbation of existing atopic lesions, rebound by tapering or discontinuation of existing therapeutic agents, allergic contact dermatitis, seborrheic dermatitis positive reaction to Malassezia yeast, to unknown side effects of dupilumab. In rare cases reported, acute cutaneous lupus erythematosus is likely to be stimulated by dupilumab in our SLE patient [37][38][39][40][41][42][43] . Therefore, it is necessary to investigate the epidemiologic and clinical characteristics of facial erythema that occurred after dupilumab treatment.
In the previous 16-weeks study 15 , there was a significantly lower rate of conjunctivitis in contrast to the results of existing clinical trials and other real-world studies conducted during the same period. However, the frequency of conjunctivitis increased to a similar degree as in other studies over 16-52 weeks of the treatment period. One study suggested that AD patients treated with dupilumab had an increased risk of developing conjunctivitis 44 . In particular, there was high risk of conjunctivitis in patients with severe AD prior to initiation of treatment, and high frequency in cases of prior conjunctivitis or increased thymus and activation-regulated chemokines, IgE, or eosinophils before initiation of treatment [45][46][47] . Although the etiology of conjunctivitis in dupilumab-treated patients remains unknown, the following causes are considered. The reduced ocular cytokine due to dupilumab forms an environment which favors the growth of Demodex mites 48 . Eosinophilia after dupilumab treatment 46 , increase in downstream activity of OX40 ligand 49 , inhibition of IL-13 and indirect decreased production of mucin in the goblet cells of the conjunctiva are also potential factors that affect conjunctivitis 50 . In addition, it has been suggested that there is no need to discontinue dupilumab or adjust the interval to control conjunctivitis. Accordingly, patients with prior conjunctivitis are not contraindicated for dupilumab, but ophthalmology treatment is recommended prior to initiation of dupilumab 44 . Conjunctivitis is an important side effect related to dupilumab treatment. Therefore, identification of symptoms by the dermatologist is crucial, and the treatment of conjunctivitis should be properly performed through cooperation with the ophthalmologist.

Conclusion
Retrospective real-world studies are very important to define the effectiveness of new drugs. In this long term 1 year study including 99 Korean patients, we confirmed the continuous therapeutic benefit of dupilumab, with most patients responding to treatment. We identified potential factors associated with response such as female sex, baseline eosinophilia, and high LDH levels were Additionally, this study confirmed that "adherence" and "proactive treatment" can increase the therapeutic effect of dupilumab in real life. This study is useful in the understanding of long-term dupilumab treatment in Asian patients with moderate to severe AD.