Dupilumab treatment in patients with atopic dermatitis: a comparative cohort study between the Netherlands and Japan shows a discrepancy in patient-reported outcome measures.
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ABSTRACT: Background
Dupilumab was equally effective among all racial subgroups in clinical trials, but a direct comparison in daily practice is lacking.Objectives
To investigate the effectiveness of dupilumab in patients with atopic dermatitis (AD) in the Netherlands and Japan over 80 weeks of treatment.Methods
A longitudinal comparative cohort study was conducted in patients with AD who were treated with dupilumab in daily practice. We used linear mixed-effects models to determine changes over time.Results
We found statistically significant differences in sex, disease onset, body mass index and therapeutic history between Dutch (n = 208) and Japanese (n = 153) patients. The baseline Eczema Area and Severity Index (EASI) score was higher in Japanese patients (23·8 vs. 14·8), while baseline Patient-Reported Outcome Measures (PROMs) were higher in Dutch patients. EASI scores decreased quickly to a level indicating 'mild disease' (EASI < 7), and remained low in both countries. However, PROMs showed different trajectories with better scores in Japan.Conclusions
Dupilumab showed significant, comparable and sustained improvement of EASI scores in Japanese and Dutch patients. However, we found striking differences in the effect on PROMs between the countries, with a better outcome in Japanese patients.
SUBMITTER: de Wijs LEM
PROVIDER: S-EPMC8453550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Patient-reported outcome measures (PROMs) provide an important complement to physician-assessed clinical outcome measures in dermatologic diseases such as atopic dermatitis (AD) and chronic hand eczema (CHE). AD and CHE are chronic and relapsing inflammatory skin conditions that often co-occur. While both diseases result in various signs and symptoms that are burdensome and can negatively affect patients' lives, there may be distinct differences in the signs, symptoms, burden, and health-related quality of life (HRQOL) impact of these diseases. The objective of this study was to identify and evaluate PROMs used in studies of AD and CHE. The aim was to explore the assessment of key symptoms and impacts, and identify any gaps in the measures in use. A structured review of the PubMed database was conducted to identify PROMs used or developed for use in AD or CHE. The Dermatology Life Quality Index (DLQI), the Pruritus/Itch Numeric Rating Scale (NRS), the Patient-Oriented Eczema Measure (POEM), and the Quality of Life in Hand Eczema Questionnaire (QOLHEQ) were identified and reviewed in detail. With these measures, the AD and CHE symptoms and impacts most commonly evaluated in the literature include dermatology-related HRQOL in the domains of symptoms and feelings, daily activities, leisure, work and school, personal relationships, and adverse effects; pruritus; sleep disturbance; AD-specific symptoms (dryness, itching, flaking, cracking, bleeding, and weeping/oozing); and CHE-specific symptoms (pain, itch, fissuring, redness, bleeding, and dryness). A review of regulatory labels of drugs approved for AD by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) found that, among the four measures reviewed, the Pruritus NRS was included in the FDA and EMA labels for dupilumab, the DLQI was included in the EMA labels for dupilumab and tacrolimus, and the POEM was included in the EMA label for dupilumab. Key symptoms of AD (e.g. itching, flaking, cracking) and CHE (e.g. pain, itching, fissuring) are increasingly being assessed with PROMs; however, primary endpoints in clinical trials are often based on clinician-reported outcome measures. As therapeutic strategies in dermatology are targeted at specific dermatologic symptoms and diseases affecting specific sites (e.g. CHE), future research should explore patients' experiences with these symptoms and sites and the changes with treatment that are most meaningful to them.
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Project description:IntroductionDupilumab is approved to treat moderate-to-severe atopic dermatitis (AD) in several countries in patients as young as 6 years of age. Since its approval, practical issues related to the use of dupilumab for AD have arisen, with particular interest in transitioning from current therapies and managing medication overlap, considerations for special populations of patients with AD, and management of potential adverse events.MethodsThis article aims to review the literature addressing several practical management issues related to dupilumab use for AD and to provide a framework for clinical decision-making in these circumstances and sub-populations. Each statement was reviewed, revised and voted on by authors to provide their level of agreement and degree of uncertainty for each statement.ResultsAn agreement level > 80% was achieved for all of the statements.ConclusionThe expert panel provides statements considering the practical management of patients with AD taking dupilumab to inform clinical decision-making in specific but frequently encountered clinical situations.
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Project description:Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double-blind, placebo-controlled, parallel-group, phase III trials in adolescents (12-17 years; LIBERTY AD ADOL) and children (6-11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure-response (E-R) relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate-to-severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w; 200 mg q2w, baseline weight < 60 kg; 300 mg q2w, ≥ 60 kg), dupilumab 300 mg every 4 weeks (q4w; non-weight tiered), or placebo; 367 children with severe AD were randomized to dupilumab q2w (100 mg q2w, baseline weight < 30 kg; 200 mg q2w, ≥ 30 kg), dupilumab 300 mg q4w, or placebo. Children received concomitant topical corticosteroids in addition to dupilumab, and loading doses were administered at the start of therapy. Mean dupilumab trough concentrations at week 16 for weight subcategories in each dosing regimen were compared with adult exposures for the approved dupilumab 300 mg q2w regimen. Positive E-R relationships were demonstrated between dupilumab trough concentrations and AD outcome measures across patient populations and regimens; no relationship was observed with treatment-emergent conjunctivitis. Based on these analyses, a weight-tiered posology was proposed for adolescents (200/300 mg q2w in patients 30-< 60 kg/≥ 60 kg) and children (300 mg q4w in patients 15-< 30 kg, 200 mg q2w in patients 30-< 60 kg) with moderate-to-severe AD.
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Project description:BackgroundPatients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma.ObjectiveThe aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD.MethodsThis analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates.ResultsOf 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab.ConclusionsDupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. CLINICALTRIALS.Gov identifiersNCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.
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Project description:BackgroundConjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo.ObjectiveThe objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma.MethodsWe evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo.ResultsIn ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation.ConclusionsDupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug-disease interaction. CLINICALTRIALS.Gov identifiersNCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb).
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