Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

Biomarkers in atopic dermatitis.

Atopic dermatitis (AD) is a complex and highly heterogeneous inflammatory skin disease. Given the highly heterogeneous character of AD, it is unlikely that every patient will respond equally to a particular treatment. The recent introduction of novel targeted therapies for AD has driven the need for patient stratification based on immunologic biomarkers. We have reviewed the use of different types of biomarkers as potential tools in the movement toward personalized medicine in AD, comprising different ways of endotyping patients with AD based on immunologic profiles and predictive biomarkers. The application of biomarkers will result in better characterization and stratification of patients and allow better comparison of current and new treatments. The ultimate goal will be to switch from the current generalized "one-drug-fits-all" management to more personalized "patient endotype-specific" management.

Dupilumab-associated ocular surface disease in atopic dermatitis patients: Clinical characteristics, ophthalmic treatment response and conjunctival goblet cell analysis.

BACKGROUND: Dupilumab-associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the frequency and severity of DAOSD, ophthalmic treatment response and to learn more about the effect of dupilumab on conjunctival goblet cells (GC). METHODS: This prospective study included dupilumab-treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)-CD45-Mucin 5 AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed. RESULTS: Ocular surface disease (OSD) was present in 91.3% (n = 63/69) patients at baseline. DAOSD was observed in 28.9% (n = 20/69) patients, in whom GC numbers remained stable and the percentage of CK19-CD45-MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n = 10/69) patients. Of the 85.5% (n = 59/69) patients without DAOSD or with controlled DAOSD at Week 28, 40.7% (n = 24/59) patients received anti-inflammatory ophthalmic drugs. CONCLUSIONS: Ocular surface disease is common in moderate-to-severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19-CD45-MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment.

Unraveling heterogeneity in pediatric atopic dermatitis: Identification of serum biomarker based patient clusters.

BACKGROUND: Increasing evidence shows that pediatric atopic dermatitis (AD) differs from adult AD on a biologic level. Broad biomarker profiling across a wide range of ages of pediatric patients with AD is lacking. OBJECTIVE: Our aim was to identify serum biomarker profiles in children with AD aged 0 to 17 years and compare these profiles with those previously found in adults with AD. METHODS: Luminex multiplex immunoassays were used to measure 145 biomarkers in serum from 240 children with AD (aged 0-17 years). Principal components analysis followed by unsupervised k-means clustering were performed to identify patient clusters. Patients were stratified into age groups (0-4 years, 5-11 years, and 12-17 years) to assess association between age and cluster membership. RESULTS: Children aged 0 to 4 years had the highest levels of TH1 cell-skewing markers and lowest levels of TH17 cell-related markers. TH2 cell-related markers did not differ significantly between age groups. Similar to the pattern in adults, cluster analysis identified 4 distinct pediatric patient clusters (TH2 cell/retinol-dominant, skin-homing-dominant, TH1 cell/TH2 cell/TH17 cell/IL-1-dominant, and TH1 cell/IL-1/eosinophil-inferior clusters). Only the TH1 cell/TH2 cell/TH17 cell/IL-1-dominant cluster resembled 1 of the previously identified adult clusters. Although no association with age or age of onset seemed to be found, disease severity was significantly associated with the skin-homing-dominant cluster. CONCLUSION: Four distinct patient clusters based on serum biomarker profiles could be identified in a large cohort of pediatric patients with AD, of which 1 was similar to previously identified adult clusters. The identification of endotypes driven by distinct underlying immunopathologic pathways might be useful to define pediatric patients with AD who are at risk of persistent disease and may necessitate different targeted treatment approaches.

Patient-centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis.

BACKGROUND: At present, no real-world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a patient-centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers. METHODS: Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient-centered dosing regimen. Group A (n = 30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B (n = 30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C (n = 30) prolonged dupilumab interval with 66%-75% (300 mg/6-8 weeks). AD severity score, patient-reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time. RESULTS: Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)-pruritus temporarily significantly increased after interval prolongation but remained low (median NRS-pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR = 17.1-45.6); 12.5 mg/L (IQR = 1.7-22.3)) compared with the levels during the standard dosage (88.2 mg/L [IQR = 67.1-123.0, p < .001]). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period. CONCLUSIONS: This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient-centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time.

Identification of Risk Factors for Dupilumab-associated Ocular Surface Disease in Patients with Atopic Dermatitis.

This study identified risk factors for the development of dupilumab-associated ocular surface disease in patients with moderate-to-severe atopic dermatitis in a large prospective daily practice cohort. Data from the Dutch BioDay Registry were used to assess the risk of developing dupilumab-associated ocular surface disease, by performing univariate and multivariate logistic regression analyses. A total of 469 patients were included, of which 152/469 (32.4%) developed dupilumab-associated ocular surface disease. Multivariate analysis showed a statistically significant association of the development of dupilumab-associated ocular surface disease with a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at the start of dupilumab (odds ratio 5.16, 95% confidence interval 2.30-11.56, p < 0.001). In conclusion, a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at baseline was associated with the development of dupilumab-associated ocular surface disease in patients with atopic dermatitis.

Confirmation of multiple endotypes in atopic dermatitis based on serum biomarkers.

BACKGROUND: Atopic dermatitis (AD) is a highly heterogeneous disease, both clinically and biologically, whereas patients are still being treated according to a "one-size-fits-all" approach. Stratification of patients into biomarker-based endotypes is important for future development of personalized therapies. OBJECTIVE: Our aim was to confirm previously defined serum biomarker-based patient clusters in a new cohort of patients with AD. METHODS: A panel of 143 biomarkers was measured by using Luminex technology in serum samples from 146 patients with severe AD (median Eczema Area and Severity Index = 28.3; interquartile range = 25.2-35.3). Principal components analysis followed by unsupervised k-means cluster analysis of the biomarker data was used to identify patient clusters. A prediction model was built on the basis of a previous cohort to predict the 1 of the 4 previously identified clusters to which the patients of our new cohort would belong. RESULTS: Cluster analysis identified 4 serum biomarker-based clusters, 3 of which (clusters B, C, and D) were comparable to the previously identified clusters. Cluster A (33.6%) could be distinguished from the other clusters as being a "skin-homing chemokines/IL-1R1-dominant" cluster, whereas cluster B (18.5%) was a "TH1/TH2/TH17-dominant" cluster, cluster C (18.5%) was a "TH2/TH22/PARC-dominant" cluster, and cluster D (29.5%) was a "TH2/eosinophil-inferior" cluster. Additionally, by using a prediction model based on our previous cohort we accurately assigned the new cohort to the 4 previously identified clusters by including only 10 selected serum biomarkers. CONCLUSION: We confirmed that AD is heterogeneous at the immunopathologic level and identified 4 distinct biomarker-based clusters, 3 of which were comparable with previously identified clusters. Cluster membership could be predicted with a model including 10 serum biomarkers.

Dupilumab shows long-term effectiveness in a large cohort of treatment-refractory atopic dermatitis patients in daily practice: 52-Week results from the Dutch BioDay registry.

BACKGROUND: Real-life data on long-term effectiveness and safety of dupilumab in atopic dermatitis patients are limited. OBJECTIVE: To study 52-week effectiveness and safety of dupilumab in a prospective multicenter cohort of adult patients with treatment-refractory atopic dermatitis. METHODS: Patients treated with dupilumab and participating in the Dutch BioDay registry were included. Clinical effectiveness and safety were evaluated. RESULTS: Two hundred ten atopic dermatitis patients were included. Mean percentage change in Eczema Area and Severity Index score after 16 weeks was -70.0% (standard deviation 33.2%) and further decreased to -76.6% (standard deviation 30.6%) by week 52. A greater than or equal to 75% improvement in the score was achieved by 59.9% of individuals by week 16 and by 70.3% by week 52. The most reported adverse effect was conjunctivitis (34%). Limited patients (17; 8.1%) discontinued dupilumab treatment. LIMITATIONS: Because of the lack of a control group and observational design, factors of bias may have been induced. CONCLUSION: Treatment with dupilumab resulted in a rapid improvement in clinical outcome measures, and effectiveness further improved during the 52-week follow-up period.

Rapid and Sustained Effect of Dupilumab on Work Productivity in Patients with Difficult-to-treat Atopic Dermatitis: Results from the Dutch BioDay Registry.

Dupilumab treatment improves signs, symptoms, and quality of life in patients with moderate-to-severe atopic dermatitis. This study evaluated the impact of dupilumab treatment on absenteeism, presenteeism, and related costs in a large multi-centre cohort of adult patients with difficult-to-treat atopic dermatitis in daily practice. Patients treated with dupilumab participating in the Dutch BioDay Registry reporting employment were included. Absenteeism, presenteeism, and related costs at baseline and during follow-up were calculated using the Work Productivity and Activity Impairment questionnaire. A total of 218 adult patients with moderate-to-severe atopic dermatitis were included. Total work impairment reduced significantly from baseline (35.5%) to week 52 (11.5%), p < 0.001. Median weekly productivity losses reduced significantly from baseline (€379.8 (140.7-780.8)) to week 52 (€0.0 (0.0-211.0), p < 0.001). In this study, dupilumab treatment demonstrated a significant improvement in work productivity and reduction in associated costs in a large cohort of patients with difficult-to-treat atopic dermatitis in daily practice.

Dupilumab is very effective in a large cohort of difficult-to-treat adult atopic dermatitis patients: First clinical and biomarker results from the BioDay registry.

INTRODUCTION: Dupilumab has recently been approved for the treatment of moderate to severe atopic dermatitis (AD) in adults. Daily practice data on dupilumab treatment are scarce. OBJECTIVE: To study the effect of 16-week treatment with dupilumab on clinical response and serum biomarkers in adult patients with moderate-severe AD in daily practice. METHODS: Data were extracted from the BioDay registry, a prospective multicenter registry. Sixteen-week clinical effectiveness of dupilumab was expressed as number of patients achieving EASI-50 (Eczema Area and Severity Index) or EASI-75, as well as patient-reported outcomes measures (Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Numeric Rating Scale pruritus). Twenty-one biomarkers were measured in patients treated with dupilumab without concomitant use of oral immunosuppressive drugs at five different time points (baseline, 4, 8, 12, and 16 weeks). RESULTS: In total, 138 patients treated with dupilumab in daily practice were included. This cohort consisted of patients with very difficult-to-treat AD, including 84 (61%) patients who failed treatment on ≥2 immunosuppressive drugs. At week 16, the mean percent change in EASI score was 73%. The EASI-50 and EASI-75 were achieved by 114 (86%) and 82 (62%) patients after 16 weeks of treatment. The most reported side effect was conjunctivitis, occurring in 47 (34%) patients. During dupilumab treatment, disease severity-related serum biomarkers (TARC, PARC, periostin, and IL-22), eotaxin-1, and eotaxin-3 significantly decreased. CONCLUSION: Treatment with dupilumab significantly improved disease severity and decreased severity-related serum biomarkers in patients with very difficult-to-treat AD in a daily practice setting.

Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.

BACKGROUND: Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. OBJECTIVE: We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. METHODS: Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components. RESULTS: Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-ß, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin. CONCLUSION: AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.