Dupilumab provides sustained effectiveness on patient-reported outcomes and favorable safety in patients with moderate-to-severe atopic dermatitis: up to 5-year results from the daily practice BioDay Registry.

BACKGROUND: Long-term daily practice data on patient-reported benefits of dupilumab for atopic dermatitis (AD) remains limited. OBJECTIVE: To evaluate patient-reported outcome measures (PROMs) and the safety of dupilumab in patients with moderate-to-severe AD over a follow-up period of up to 5 years. METHODS: Data were extracted from the prospective, multicenter BioDay registry (October 2017 - 2022) of patients with moderate-to-severe AD treated with dupilumab in daily practice. RESULTS: In total 1223 patients, 1108 adults and 115 pediatric patients, were included. After ≥1 year of treatment, mean Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numeric rating scale (NRS)-pruritus ranged between 7.8-8.7, 3.5-4.2, and 2.9-3.1 in adults, respectively, whilst these PROMs ranged between 8.9-10.9, 4.4-6.4, and 3.0-3.7 in pediatric patients, respectively. At follow-up, overall work impairment decreased from 40.1% to 13.3-16.3% in adults. Furthermore, class I obesity and itch-dominant patients generally had less favorable treatment response. Of all patients, 66.8% reported ≥1 adverse event, with conjunctivitis being the most common(33.7%). LIMITATIONS: The overall percentage of missing values for selected PROMs was 26% in adults and 46% in pediatric patients. CONCLUSION: In addition to favorable safety, dupilumab has demonstrated sustained effectiveness across various PROMs, underscoring the treatment benefits from patients' perspectives.

Real-world Experience of Abrocitinib Treatment in Patients with Atopic Dermatitis and Hand Eczema: Up to 28-week Results from the BioDay Registry.

Limited daily practice data on the effect of abrocitinib in patients with atopic dermatitis are available. The aim of this multicentre prospective study is to evaluate the effectiveness and safety of abrocitinib in patients with atopic dermatitis treated in daily practice. In a subgroup, the effectiveness of abrocitinib on hand eczema was evaluated. A total of 103 patients from the BioDay registry were included in the study: week 4 (n = 95), week 16 (n = 61) and week 28 (n = 39). At week 28, the Eczema Area and Severity Index (EASI)-50/75/90 was achieved by 81.8%, 57.6%, and 18.2%, respectively, and the weekly average pruritus numerical rating scale ≤ 4 by 62.9%. The effectiveness of abrocitinib was not significantly different between dupilumab non-responders and dupilumab-naïve patients/responders, and between upadacitinib non-responders and upadacitinib-naïve patients/responders. Mean ± standard deviation Hand Eczema Severity Index decreased from 27.4 ± 27.7 at baseline to 7.7 ± 12.1 at week 28 (n = 31). Thirty-two patients (31.1%) discontinued treatment due to ineffectiveness (n = 17), adverse events (n = 9) or both (n = 3). The most frequently reported adverse event was nausea (n = 28). In conclusion, abrocitinib is an effective treatment for atopic dermatitis and can be effective for patients with previous inadequate response to dupilumab or upadacitinib. Furthermore, hand eczema can improve in patients treated with abrocitinib for atopic dermatitis.

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.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Influence of pathogenic filaggrin variants on dupilumab treatment in atopic dermatitis.

BACKGROUND: Pathogenic variants in filaggrin (FLG) are associated with an increased risk of atopic dermatitis (AD). OBJECTIVE: We evaluated the influence of FLG variants on the effectiveness of dupilumab treatment in AD. METHODS: This prospective observational study included adult AD patients treated with dupilumab from the BioDay registry. FLG was analyzed with single-molecule molecular inversion probe-targeted sequencing. Novel mutations were confirmed by Sanger sequencing. Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), numeric rating scale (NRS) pruritus, Dermatology Quality of Life Index (DLQI), and Patient-Oriented Eczema Measure (POEM) were assessed at baseline and at weeks 16 and 52. The study was registered at ClinicalTrials.gov as NCT03549416. RESULTS: Genetic analysis of the 285 included patients showed biallelic pathogenic variants (FLG-/-) in 41 (14%), monoallelic pathogenic variants (FLG-/+) in 64 (23%), and wild-type alleles (FLG+/+) in 180 patients (63%). Three novel pathogenic variants were found. We observed no clinically relevant differences in EASI, IGA, NRS pruritus, DLQI, or total POEM scores for patients with and without pathogenic FLG variants at all time points. The FLG-/- group showed significantly higher POEM flaking and dryness scores at week 16 (P < .001 and P = .002, respectively) and week 52 (P < .001 and P = .016, respectively) compared to FLG+/+ as well as significant differences compared to FLG-/+, while differences in delta scores were nonsignificant. CONCLUSION: The effectiveness of dupilumab treatment in AD patients was not influenced by pathogenic FLG variants. However, patients with biallelic pathogenic FLG variants tended to have drier skin before and during dupilumab treatment compared to patients with monoallelic pathogenic variants or wild-type alleles.

Effectiveness of antibacterial therapeutic clothing vs. nonantibacterial therapeutic clothing in patients with moderate-to-severe atopic dermatitis: a randomized controlled observer-blind pragmatic trial (ABC trial).

BACKGROUND: Increased Staphylococcus aureus (SA) colonization is considered an important factor in the pathogenesis of atopic dermatitis (AD). Antibacterial therapeutic clothing aims to reduce SA colonization and AD inflammation; however, its role in the management of AD remains poorly understood. OBJECTIVES: To investigate the effectiveness of antibacterial therapeutic clothing + standard topical treatment in patients with moderate-to-severe AD vs. standard therapeutic clothing + standard topical treatment; and, if effectiveness was demonstrated, to demonstrate its cost-effectiveness. METHODS: A pragmatic double-blinded multicentre randomized controlled trial (NCT04297215) was conducted in patients of all ages with moderate-to-severe AD. Patients were centrally randomized 1 : 1 : 1 to receive standard therapeutic clothing or antibacterial clothing based on chitosan or silver. The primary outcome was the between-group difference in Eczema Area and Severity Index (EASI) measured over 52 weeks. Secondary outcomes included patient-reported outcomes (PROs), topical corticosteroid (TCS) use, SA colonization, safety and cost-effectiveness. Outcomes were assessed by means of (generalized) linear mixed-model analyses. RESULTS: Between 16 March 2020 and 20 December 2021, 171 patients were enrolled. In total, 159 patients were included (54 in the standard therapeutic clothing group, 50 in the chitosan group and 55 in the silver group). Adherence was high [median 7 nights a week wear (interquartile range 3-7)]. Median EASI scores at baseline and at 4, 12, 26 and 52 weeks were 11.8, 4.3, 4.6, 4.2 and 3.6, respectively, in the standard therapeutic clothing group vs. 11.3, 5.0, 3.0, 3.0 and 4.4, respectively, in the chitosan group, and 11.6, 5.0, 5.4, 4.6 and 5.8, respectively, in the silver group. No differences in EASI over 52 weeks between the standard therapeutic clothing group, the chitosan group [-0.1, 95% confidence interval (CI) -0.3 to 0.2; P = 0.53] or the silver group (-0.1, 95% CI -0.3 to 0.2; P = 0.58) were found. However, a small significant group × time interaction effect between the standard and silver groups was found (P = 0.03), in which the silver group performed worse after 26 weeks. No differences between groups were found in PROs, TCS use, SA skin colonization and healthcare utilization. No severe adverse events or silver absorption were observed. CONCLUSIONS: The results of this study suggest no additional benefits of antibacterial agents in therapeutic clothing in patients with moderate-to-severe AD.

Dupilumab-Associated Lymphoid Reactions in Patients With Atopic Dermatitis.

Importance: Since the increased use of dupilumab for atopic dermatitis (AD) in daily practice, several cases have been reported on the development of cutaneous T-cell lymphomas (CTCL) and lymphoid infiltrates. Objective: To provide insight in the clinical and histopathologic features of patients with AD clinically suspected for CTCL during dupilumab treatment. Design, Setting, and Participants: This retrospective observational case series included adult (≥18 years) patients with AD treated with dupilumab between October 2017 and July 2022 at the University Medical Center Utrecht in the Netherlands. Main outcomes and measures: Relevant patient, disease, and treatment characteristics were evaluated. Skin biopsies before, during, and after treatment were collected and reassessed. Results: Fourteen patients (54.5% male) with a median (IQR) age of 56 (36-66) years suspected for CTCL with deterioration of symptoms during dupilumab treatment were included. Of 14 patients, 3 were retrospectively diagnosed with preexistent mycosis fungoides (MF). Eleven patients with AD were eventually diagnosed with a lymphoid reaction (LR). These patients showed MF-like symptoms; however, histopathologic findings were different, and included sprinkled distribution of small hyperchromatic lymphocytes in the upper epidermal section, a dysregulated CD4:CD8 ratio, and CD30 overexpression, without loss of CD2/CD3/CD5. The median time to clinical worsening was 4.0 months (IQR, 1.4-10.0). Posttreatment biopsies showed complete clearance of the LR in all patients. Conclusions and relevance: This study found that dupilumab treatment can cause a reversible and benign LR, which mimics a CTCL, though has distinctive histopathologic features.

Biologicals for pediatric patients with atopic dermatitis: practical challenges and knowledge gaps.

Biologicals are becoming increasingly important in the therapeutic landscape of pediatric patients with moderate-to-severe atopic dermatitis (AD). Currently, dupilumab and tralokinumab are registered for the treatment of moderate-to-severe AD, and novel biologicals are expected to follow. Dupilumab was the first biological registered for AD in pediatric patients and was recently approved for patients aged six months to five years. Current and emerging biologicals may address the unmet need for effective and safe treatment options for pediatric AD patients, however, little is known about the practical implementation of biologicals in infants and preschoolers (aged <6 years), including the timing of treatment initiation, discontinuation, and long-term administration of the subcutaneous injections. Currently, only a small number of biologicals are approved for the treatment of infants and preschoolers for other inflammatory diseases. Consequently, data on the practical implementation of biological treatment remain scarce. In addition, long-term effects, impact on co-morbidities, and impact on live-accentuated vaccination are still unknown. With the introduction of biologicals for AD from the age of six months, potential challenges within the implementation of biologicals may arise. Therefore, we aim to discuss current practical challenges and knowledge gaps of the treatment with biologicals in infants and preschoolers with AD.

Prognostic Factors for Long-term Aesthetic Outcome of Infantile Haemangioma Treated with Beta-blockers.

Parents of infants treated with beta-blockers for infantile haemangioma are often concerned about the long-term aesthetic outcome. This cross-sectional study assessed the influence on the long-term aesthetic outcome of characteristics of the infantile haemangioma, the beta-blocker treatment, and the infant. The study included 103 children aged 6-12 years, treated with beta-blockers (propranolol or atenolol) for infantile haemangioma during infancy (age at treatment initiation ≤1 year) for ≥6 months. Dermatologists and parents scored the Patient Observer Scar Assessment Scale, and the child scored a visual analogue scale. Dermatologists identified whether telangiectasia, fibrofatty tissue, and atrophic scar tissue were present. The long-term aesthetic outcome of infantile haemangioma was judged more negatively by dermatologists and parents in case of a superficial component, ulceration, older age at treatment initiation, higher cumulative dose, and/or shorter follow-up time. According to children, infantile haemangioma located on the head had better aesthetic outcome than infantile haemangioma located elsewhere. Close monitoring, particularly of infantile haemangioma with a superficial component, is essential for early initiation of treatment, and to prevent or treat ulceration. These outcome data can support parental counselling and guide treatment strategy.

Successful tapering of dupilumab in patients with atopic dermatitis with low disease activity: a large pragmatic daily practice study from the BioDay registry.

BACKGROUND: Limited data are available regarding patient-centred dosing of dupilumab for atopic dermatitis (AD) in daily practice. OBJECTIVES: To evaluate our patient-centred dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings. METHODS: This prospective multicentre study included adult patients with AD, participating in the BioDay registry, treated with dupilumab for ≥ 1.3 years. Interval prolongation was considered in the case of dupilumab standard dose for ≥ 1 year and persistent controlled AD [Eczema Area and Severity Index (EASI) ≤ 7; ≥ 6 months]. Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after the start of tapering. Prognostic factors for successful tapering were analysed with logistic regression and a cost-savings analysis was performed. RESULTS: A total of 595 patients were included, of whom 401 patients [mean EASI 2.5 (SD 2.3); NRS-pruritus of 2.4 (SD 1.9) at the start of tapering] prolonged their dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (P < 0.001); however, scores remained low. Predicting successful tapering showed nonsignificant odds ratios for all incorporated variables. The estimated cost savings was €3 977 033.98 for 401 patients between January 2019 and June 2022. CONCLUSIONS: This study showed successful tapering of dupilumab in 83.3% of patients with AD who attempted tapering, while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be beneficial both for the patient and from a socio-economic perspective.

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.

Economic and Humanistic Burden in Paediatric Patients with Atopic Dermatitis.

Data concerning the economic and humanistic burden in patients with paediatric atopic dermatitis (AD) and their families are scarce. This retrospective study investigated these burdens in paediatric patients with AD using maintenance treatment with topical corticosteroids and/or conventional systemic immunosuppressants. Patient-reported outcomes regarding quality of life, AD severity, and parental work-related impairment were completed at inclusion. Data on healthcare resource utilization and medication prescription were collected retrospectively over the previous 12 months. Patients were categorized into mild, moderate or severe AD, based on Eczema Area and Severity Index score and medication use. Costs per patient per year per AD severity category were calculated. A total of 101 patients (median age 11.0 years (interquartile range 7.5-14.0), 47.5% men) were included, of whom 38 had mild AD, 37 moderate AD, and 26 severe AD. Mean ± standard deviation (SD) total costs patient per year for mild, moderate and severe AD were €1,812 ± €1,280, €2,680 ± €3,127, and €5,861 ± €3,993, respectively. Highest total direct and indirect costs were found in patients with severe AD, mainly due to higher healthcare and medication costs. Highest humanistic burden was found in patients with moderate AD. For example, the median (interquartile range) Patient-Oriented Eczema Measure score was significantly higher in these patients compared with mild and severe AD (19.0 (15.0-24.0) vs 12.0 (8.8-15.0) and 17.0 (9.5-22.0), respectively). AD in paediatric patients incurs considerable direct and indirect costs, especially in patients with severe AD. The high humanistic burden in patients with moderate AD underlines the need for effective and safe new treatment options for children with AD.

Effectiveness of Upadacitinib in Patients with Atopic Dermatitis including those with Inadequate Response to Dupilumab and/or Baricitinib: Results from the BioDay Registry.

Clinical trials showed that upadacitinib, a selective Janus kinase-1 inhibitor, is effective for treatment of moderate-to-severe atopic dermatitis. However, daily practice studies are limited. This multicentre prospective study evaluated the effectiveness of 16 weeks of upadacitinib treatment for moderate-to-severe atopic dermatitis in adult patients, including those with previous inadequate response to dupilumab and/or baricitinib, in daily practice. A total of 47 patients from the Dutch BioDay registry treated with upadacitinib were included. Patients were evaluated at baseline, and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed by clinician- and patient-reported outcome measurements. Safety was assessed by adverse events and laboratory assessments. Overall, the probabilities (95% confidence intervals) of achieving Eczema Area and Severity Index ≤ 7 and Numerical Rating Scale - pruritus ≤ 4 were 73.0% (53.7-86.3) and 69.4% (48.7-84.4), respectively. The effectiveness of upadacitinib was comparable in patients with inadequate response to dupilumab and/or baricitinib and in patients who were naïve for these treatments or who had stopped such treatments due to adverse events. Fourteen (29.8%) patients discontinued upadacitinib due to ineffectiveness, adverse events or both (8.5%, 14.9% and 6.4%, respectively). Most frequently reported adverse events were acneiform eruptions (n = 10, 21.3%), herpes simplex (n = 6, 12.8%), nausea and airway infections (both n = 4, 8.5%). In conclusion, upadacitinib is an effective treatment for patients with moderate-to-severe atopic dermatitis, including those with previous inadequate response to dupilumab and/or baricitinib treatment.

Non-Infectious Uveitis Secondary to Dupilumab Treatment in Atopic Dermatitis Patients Shows a Pro-Inflammatory Molecular Profile.

Severe uveitis is a rare complication of interleukin-4 receptor alpha blocking by dupilumab in topic dermatitis (AD) patients. The aim of this study was to describe five moderate-to-severe AD patients who developed uveitis during dupilumab treatment and to compare the proteomic profile of aqueous humor (AqH) of dupilumab-associated uveitis (n=3/5 available samples) with non-infectious uveitis (n=27) and cataract controls (n=11). Included patients were treated at the University Medical Center Utrecht (the Netherlands). Active dupilumab-associated uveitis complicated by serous detachment, cystoid macular edema, or secondary glaucoma developed within a median of 6.0 months (interquartile range 2.3-16.5 months) after starting dupilumab. Uveitis resolved after discontinuation of dupilumab and/or treatment with local or systemic corticosteroids. Proteomic profiling of AqH revealed that the molecular profile of dupilumab-associated uveitis resembled that of non-infectious uveitis. In conclusion, dupilumab-associated uveitis is a severe adverse event of dupilumab therapy, requiring urgent referral to an ophthalmologist.