Real-world reported adverse events related to systemic immunomodulating therapy in patients with atopic dermatitis: Results from the TREAT NL (TREatment of ATopic eczema, the Netherlands) registry.

BACKGROUND: Evidence on the (long-term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real-world data is sparse. OBJECTIVES: To describe real-world reported adverse drug reactions (AEs) related to systemic immunomodulating therapy in patients with AD and to compare the incidence rates of AEs with the Summaries of Product Characteristics (SmPCs). METHODS: We conducted an observational prospective multi-centre cohort study, using the TREAT NL registry. All severe AEs, AEs of special interest and serious AEs in adult and paediatric patients on systemic immunomodulating treatment (ciclosporin, methotrexate, azathioprine, mycophenolic acid, dupilumab, tralokinumab, baricitinib and upadacitinib) were assessed. Incidences rates of all (potentially) drug-related AEs were standardized in patient years and compared to the cumulative incidences in the associated SmPCs. RESULTS: We collected 422 patient years of safety data from 266 patients, of whom 129 (48.5%) reported a total of 224 (potentially) drug-related AEs. Compared to dupilumab's SmPC, higher incidence rates were found for four AEs (reported ≥5 times): eosinophilia, blepharitis, dry eyes and head and neck erythema (i.e. dupilumab facial redness). A higher incidence rate of fatigue was found in patients on oral methotrexate in our cohort compared to the SmPC. Two new drug-related AEs (reported ≥5 times) were found in patients on dupilumab, including non-infectious conjunctivitis and meibomian gland dysfunction. CONCLUSIONS: Real-world reported AEs captured in AD patient registries can add information on the estimated incidence of AEs and benefit clinical decision aids. Future studies using data derived from the TREAT NL registry combined with data from other registries within the TREAT Registry Taskforce will provide more information on (rare) AEs associated with immunomodulating therapy in AD patients.

Classifying atopic dermatitis: a systematic review of phenotypes and associated characteristics.

Atopic dermatitis is a heterogeneous disease, accompanied by a wide variation in disease presentation and the potential to identify many phenotypes that may be relevant for prognosis and treatment. We aimed to systematically review previously reported phenotypes of atopic dermatitis and any characteristics associated with them. Ovid EMBASE, Ovid MEDLINE and Web of Science were searched from inception till 12 February 2021 for studies attempting to classify atopic dermatitis. Primary outcomes are atopic dermatitis phenotypes and characteristics associated with them in subsequent analyses. A secondary outcome is the methodological approach used to derive them. In total, 8511 records were found. By focussing only on certain clinical phenotypes, 186 studies were eligible for inclusion. The majority of studies were hospital-based (59%, 109/186) and cross-sectional (76%, 141/186). The number of included patients ranged from seven to 526 808. Data-driven approaches to identify phenotypes were only used in a minority of studies (7%, 13/186). Ninety-one studies (49%) investigated a phenotype based on disease severity. A phenotype based on disease trajectory, morphology and eczema herpeticum was investigated in 56 (30%), 22 (12%) and 11 (6%) studies respectively. Thirty-six studies (19%) investigated morphological characteristics in other phenotypes. Investigated associated characteristics differed between studies. In conclusion, we present an overview of phenotype definitions used in literature for severity, trajectory, morphology and eczema herpeticum, including associated characteristics. There is a lack of uniform and consistent use of atopic dermatitis phenotypes across studies.

Paternal and maternal use of dupilumab in patients with atopic dermatitis: a case series.

Dupilumab is a relatively new treatment option for patients with moderate to severe atopic dermatitis. There is a lack of knowledge about the effects of treatment with dupilumab during conception for both men and women, as well as during pregnancy and lactation in women. We report four patients (two men, two women) who expressed a wish to conceive during treatment with dupilumab in daily practice. Both men conceived during dupilumab treatment, while the two women discontinued dupilumab because of anticipated pregnancy. Apart from disease flares in both of the patients who discontinued treatment, no complications were reported concerning the ability to conceive, the course of the pregnancy or the fetal outcome. We present an overview of the current available literature on dupilumab during conception, pregnancy and lactation, which can guide considerations for patients on dupilumab wishing to conceive a child. Until more data are available, preference should be given to treatment with topical corticosteroids, phototherapy, systemic corticosteroids and ciclosporin.

Effectiveness of dupilumab treatment in 95 patients with atopic dermatitis: daily practice data.

BACKGROUND: Dupilumab is the first biologic registered for the treatment of moderate-to-severe atopic dermatitis (AD), and efficacy was shown in phase III clinical trials (primary outcome at week 16 was reached in 38% of patients). Currently, there are limited daily practice data available for dupilumab, especially when it is combined with systemic immunosuppressants. OBJECTIVES: To evaluate dupilumab treatment in daily practice in patients with AD. METHODS: In this observational cohort study, we prospectively included all adult patients with AD who had been treated with dupilumab in two university hospitals in the Netherlands. Concomitant systemic immunosuppressive treatment was monitored. Physician-reported outcome measures and patient-reported outcome measures (PROMs) after ≥ 12 weeks of follow-up were analysed. We used a linear mixed-effects model to determine changes in scores during follow-up. RESULTS: Ninety-five patients were included. Of these, 62 patients were using systemic immunosuppressants at baseline; the use of systemic immunosuppressants was continued during dupilumab treatment in 43 patients. From baseline to 16 weeks of treatment, the estimated mean Eczema Area and Severity Index score (0-72) decreased from 18·6 [95% confidence interval (CI) 16·0-21·4)] to 7·3 (95% CI 5·4-10·0), and the estimated mean PROMs showed a decrease of 41-66%. Investigator's Global Assessment 0 or 1 (clear/almost clear) was reached in 38% of the patients. Five patients discontinued dupilumab treatment due to side-effects or ineffectiveness. Eye symptoms and orofacial (nonocular) herpes simplex virus (HSV) reactivation were reported in 62% and 8% of the patients, respectively. CONCLUSIONS: Dupilumab treatment in daily practice shows a clinically relevant improvement of physician-reported outcome measures and PROMs, which is in line with efficacy data from clinical trials. Besides frequently reported eye symptoms and orofacial (nonocular) HSV reactivation, there were no apparent safety concerns. What's already known about this topic? Dupilumab has been shown to be an efficacious treatment for atopic dermatitis in several clinical trials. However, it is known that there may be considerable differences in patient characteristics and treatment responses between clinical trials and daily practice. What does this study add? This study presents the first experience with dupilumab treatment in 95 patients with atopic dermatitis in daily practice in two Dutch university hospitals. Less stringent inclusion and exclusion criteria and follow-up schedules, in contrast to those used in clinical trials, might better represent daily practice. Dupilumab treatment shows a clinically relevant improvement of physician- and patient-reported outcome measures; besides patient-reported eye symptoms (in 59 of 95 patients; 62%) and an apparent increase in orofacial (nonocular) herpes simplex virus reactivation (eight of 95 patients; 8%), there were no other safety concerns during follow-up up to 16 weeks of dupilumab treatment.

TREatment of ATopic eczema (TREAT) Registry Taskforce: protocol for a European safety study of dupilumab and other systemic therapies in patients with atopic eczema.

BACKGROUND: A long-term prospective observational safety study is essential to characterize fully the safety profile of systemic immunomodulating therapies for patients with atopic eczema. The TREatment of ATopic eczema (TREAT) Registry Taskforce offers a large platform to conduct such research using national registries that collect the same data using a predefined core dataset. OBJECTIVES: To present a protocol for a safety study comparing dupilumab with other systemic immunomodulating therapies in children and adults with moderate-to-severe atopic eczema, to assess the long-term safety risk of these therapies in a routine clinical care setting. METHODS: We describe a registry-embedded international observational prospective cohort study. Adult and paediatric patients who start treatment with dupilumab or another systemic immunomodulating agent for their atopic eczema will be included. The primary end point is the incidence of malignancies (excluding nonmelanoma skin cancer) compared between the treatment groups. Secondary end points include other serious adverse events and adverse events of special interest, such as eye disorders and eosinophilia. CONCLUSIONS: This protocol delineates a safety study for dupilumab in adult and paediatric patients with atopic eczema, using a standardized methodological approach across several national registries. The protocol could also be used for other novel systemic immunomodulating therapies, and could provide licensing and reimbursement authorities, pharmaceutical companies and clinicians with safety evidence from a routine clinical care setting. What's already known about this topic? There is a need for long-term data on the safety of systemic immunomodulating therapies in patients with atopic eczema. Regulatory bodies, such as the European Medicines Agency, increasingly stipulate the collection of such data as part of the licensing agreement for new treatments, to assess the new agent's long-term safety profile against established therapies. Large numbers of patients with a long duration of follow-up are necessary in order to detect rare events like malignancies. What does this study add? The TREAT Registry Taskforce offers a platform to conduct such research with a network of multiple national atopic eczema research registries. We present a protocol for an investigator-initiated multicentre safety study comparing dupilumab with other systemic immunomodulating therapies in adults and subsequently adolescents and children with moderate-to-severe atopic eczema. This protocol can be used as a framework for similar studies for other novel systemic immunomodulating therapies across both adult and paediatric populations.

TREatment of ATopic eczema (TREAT) Registry Taskforce: consensus on how and when to measure the core dataset for atopic eczema treatment research registries.

BACKGROUND: Comparative, real-life and long-term evidence on the effectiveness and safety of phototherapy and systemic therapy in moderate-to-severe atopic eczema (AE) is limited. Such data must come from well-designed prospective patient registries. Standardization of data collection is needed for direct comparisons and data pooling. OBJECTIVES: To reach a consensus on how and when to measure the previously defined domain items of the TREatment of ATopic eczema (TREAT) Registry Taskforce core dataset for research registries for paediatric and adult patients with AE. METHODS: Proposals for the measurement instruments were based on recommendations of the Harmonising Outcome Measures for Eczema (HOME) initiative, the existing AE database of TREATgermany, systematic reviews of the literature and expert opinions. The proposals were discussed at three face-to-face consensus meetings, one teleconference and via e-mail. The frequency of follow-up visits was determined by an expert survey. RESULTS: A total of 16 experts from seven countries participated in the 'how to measure' consensus process and 12 external experts were consulted. A consensus was reached for all domain items on how they should be measured by assigning measurement instruments. A minimum follow-up frequency of initially 4 weeks after commencing treatment, then every 3 months while on treatment and every 6 months while off treatment was defined. CONCLUSIONS: This core dataset for national AE research registries will aid in the comparability and pooling of data across centres and country borders, and enables international collaboration to assess the long-term effectiveness and safety of phototherapy and systemic therapy used in patients with AE. What's already known about this topic? Comparable, real-life and long-term data on the effectiveness and safety of phototherapy and systemic therapy in patients with atopic eczema (AE) are needed. There is a high diversity of outcomes and instruments used in AE research, which require harmonization to enhance comparability and allow data pooling. What does this study add? Our taskforce has reached international consensus on how and when to measure core domain items for national AE research registries. This core dataset is now available for use by researchers worldwide and will aid in the collection of unified data. What are the clinical implications of this work? The data collected through this core dataset will help to gain better insights into the long-term effectiveness and safety of phototherapy and systemic therapy in AE and will provide important information for clinical practice. Standardization of such data collection at the national level will also allow direct data comparisons and pooling across country borders (e.g. in the analysis of treatment-related adverse events that require large patient numbers).

[Erythema nodosum as a reaction pattern: a broad spectrum of underlying causes]. / Erythema nodosum als reactiepatroon.

Erythema nodosum is a skin disorder that is characterised by the presence of painful erythematous nodules and plaques, mainly located on the shins. This disorder is associated with comorbidities and can be considered as an aspecific reaction pattern to a broad range of causes. However, an idiopathic variant also exists, which occurs in 22-72% of cases. Erythema nodosum is pre-eminently a skin disease which, due to its multifactorial pathogenesis, occurs in a wider field than dermatology alone. Therefore, knowledge of this disorder is important for all practicing physicians. To illustrate this we describe three patients with erythema nodosum attributable to different causes.