Dupilumab For Atopic Dermatitis Research Articles

Safety of dupilumab in patients with atopic dermatitis: expert opinion

ABSTRACT Introduction: Dupilumab, the first biologic drug to be approved for the treatment of moderate to severe atopic dermatitis in adolescents and adults, has shown efficacy and safety in clinical trials. Data on long-term safety is limited but crucial for pharmacovigilance. Therefore, we performed this review to evaluate available real-world data on the long-term safety of dupilumab in atopic dermatitis. Areas covered: PubMed and Google Scholar databases were searched for randomized controlled clinical trials (RCTs), observational studies, case series, and case reports regarding the use of dupilumab for the treatment of atopic dermatitis. Adverse events were summarized and critically evaluated. Expert opinion: Atopic dermatitis patients receiving dupilumab reported ocular surface disease more often than patients receiving placebo. Real-world data show previously unreported adverse events (blood eosinophilia, rosacea-like skin lesions, weight gain), but their mechanistic association to dupilumab treatment still requires clarification. Cutaneous T-cell lymphomas occurring under the therapy with dupilumab might be unrelated to the drug use itself but long-term follow-up data of large patient cohorts is necessary to rule out such possibility. Real-world data show that dupilumab is well tolerated in atopic dermatitis; however, ocular adverse events are not rare. Registries are needed to monitor future adverse events.

Association of Dupilumab with Intraocular Inflammation

ABSTRACT Purpose To report four cases of uveitis after treatment with dupilumab for atopic dermatitis. Methods Retrospective case series. Results Data was collected from four patients with inflammation that developed after treatment with dupilumab. The first patient was thought to have developed posterior scleritis or Harada’s-type disease related to her treatment with dupilumab, with recurrence of intraocular inflammation upon restarting treatment. The second patient developed anterior and intermediate uveitis as well as cystoid macular edema in her right eye about two years after starting dupilumab treatment. The third patient developed a distinct relentless placoid chorioretinitis while on therapy with dupilumab. The fourth patient developed bilateral cystoid macular edema while on treatment with dupilumab. Conclusion We report a case series of patients treated with dupilumab who developed intraocular manifestations of inflammatory disease.

Dupilumab‐associated hypereosinophilia in patients treated for moderate‐to‐severe atopic dermatitis

Trials assessing dupilumab in atopic dermatitis (AD) showed transient eosinophilia in less than 2% of patients (1). The frequency of hypereosinophilia (HE), defined as eosinophil blood count (EBC) ≥1500/mm3 (2), was higher (15.8%) in our previous real-life cohort of AD patients treated with dupilumab (3). Since symptomatic HE was reported in asthma trials, we aimed to assess the clinical impact of HE in AD patients receiving dupilumab.

Dupilumab-associated ocular surface disease: presentation, management and long-term sequelae

ObjectivesTo determine the presenting features of ocular surface disease in patients with atopic dermatitis (AD) treated with dupilumab at a tertiary, university hospital. To establish the need for treatment of dupilumab-associated ocular surface disease and report any long-term effects on the ocular surface.MethodsA retrospective analysis of consecutive patients treated with dupilumab for AD between January 2017 and August 2019 was undertaken. Data were collected on demographics, incidence and type of ocular disease features, natural history and treatment.ResultsA total of 50% (14/28) patients developed ocular symptoms with a mean time of onset of 6.75 (±6.1) weeks from starting dupilumab. Of these, 69% (9/13) were diagnosed with conjunctivitis associated with cicatrisation in two patients and periorbital skin changes in four. Of these nine, four had prior history of atopic keratoconjunctivitis. All were treated with topical steroids; two required additional ciclosporin drops. In all, 67% (6/9) patients went on to have on-going ocular inflammation requiring maintenance drops at a mean of 16 (±6.9) months of follow-up. All patients had improvement in their AD severity; only one patient discontinued dupilumab due to ocular side effects.ConclusionThe rate of dupilumab-associated ocular surface disease was 32%. Periorbital skin changes and conjunctival cicatrisation were noted in association with conjunctivitis. Ocular surface disease improved on topical steroids and ciclosporin but 67% of patients needed on-going treatment. Close liaison with an ophthalmologist should be considered in those patients who develop conjunctivitis or have a past history of severe ocular surface disease.

EAACI Biologicals Guidelines—dupilumab for children and adults with moderate‐to‐severe atopic dermatitis

Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based), its cost-effectiveness and long-term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.

The Use of Dupilumab in Atopic Dermatitis During Coronavirus Disease-19 Era – A Review

The global pandemic of coronavirus (CoV) d0isease 2019 (COVID-19), caused by severe acute respiratory syndrome CoV (SARS-CoV 2), has been a challenging event for every individual. It is known that COVID-19 may exhibit a vast range of symptoms ranging from mild to severe. Acute respiratory distress syndrome (ARDS) and multiple organ failure are the most common causes of death in COVID-19 cases [3]. Accumulating evidence shows that T-helper type (Th-1) inflammation cascade plays a major role in COVID-19 pathogenesis. It is proposed that aberrant immune reaction, or known as cytokine storm, is one of the main causals of ARDS in COVID-19 case, while dupilumab, the first Food and Drug Administration-approved immunomodulatory treatment for atopic dermatitis, is known for its effectiveness in suppressing the Th-2 inflammation pathway. It is postulated that both types of inflammation can cross-regulate each other. Therefore, some may believe that the regression of Th-2 cascade may upregulate the Th-1 cascade, leading to an exaggerated cytokine storm. This hypothesis leads to the uncertainty of the safety of continuing this modality during the pandemic.

RF-Conjuntivitis Associated With Dupilumab in Atopic Dermatitis

RF-Conjuntivitis Associated With Dupilumab in Atopic Dermatitis

Recognition of atopic keratoconjunctivitis during treatment with dupilumab for atopic dermatitis

To the Editor: Dupilumab, a monoclonal antibody that blocks T helper type 2 cytokines,1-4 is approved for the treatment of cutaneous manifestations of atopic dermatitis. Unfortunately, dupilumab use can result in ophthalmic complications. In the inaugural phase 3 clinical trials, 14% to 19% of patients reported dupilumab-associated conjunctivitis but were not examined by an ophthalmologist.1,4 Thus, it is possible that some of these patients could have experienced a more severe form of ocular surface disease than simple reactive conjunctivitis.

Higher baseline serum lactate dehydrogenase level is associated with poor effectiveness of dupilumab in the long term in patients with atopic dermatitis.

Dupilumab shows high efficacy and tolerable safety for the treatment of atopic dermatitis (AD). However, the extent of its effectiveness varies in individual patients. To date, practical predictors of later effectiveness of dupilumab in AD patients have not been reported. To explore practical predictors of later effectiveness of dupilumab in AD, we retrospectively investigated the correlation of baseline demographics and baseline laboratory results with the percentage reduction in Eczema Area and Severity Index (EASI) scores at 1, 3, 6 and 12months after initiating dupilumab. Furthermore, multiple regression analyses were conducted. Data were collected from patients' charts. Data on 54 Japanese adult patients (43 men and 11 women) with moderate to severe AD were analyzed. Baseline serum lactate dehydrogenase (LDH) level was negatively correlated with the percentage reduction in EASI score at 3, 6 and 12months after initiating dupilumab but not at 1month. Multiple regression analyses also revealed that effectiveness of dupilumab at 3 and 6months was associated with lower baseline serum LDH level. AD patients with allergic diseases tended to have lower percentage reduction in EASI at 1month, but had higher percentage reduction in EASI in the long term than patients without allergic diseases. In conclusion, higher baseline serum LDH level was associated with poor effectiveness of dupilumab in the long term in patients with AD. Furthermore, it tended to take a longer time for AD patients with allergic diseases to respond to dupilumab, and these patients responded better to dupilumab in the long term than patients without allergic diseases.

Efficacy and safety of dupilumab in atopic dermatitis in elderly patients: a retrospective study.

Atopic dermatitis (AD) is a common inflammatory skin disease with high prevalence in both children (15-30%) and adults (2-10%), but limited data are available for older people. Elderly patients form a challenging group, as multiple comorbidities, associated polypharmacy and failures with previous treatments are common. We performed a retrospective observational study on elderly (≥65years) patients treated with dupilumab, monoclonal antibody to the shared alpha subunit of the interleukin-4 and -13 receptor approved for the treatment of moderate-to-severe AD in adults.

Transitory Dissemination of Molluscum Contagiosum in a Patient Treated with Dupilumab for Atopic Dermatitis.

Transitory Dissemination of Molluscum Contagiosum in a Patient Treated with Dupilumab for Atopic Dermatitis.

162 Biomarkers CCL17/TARC and Total IgE Do Not Predict Clinical Response to Dupilumab in Atopic Dermatitis (AD): a Post hoc Analysis of Pooled Phase 3 Data (SOLO 1 & 2)

Dupilumab (DUP), a fully human IL-4Rα mAb, inhibits signaling of IL-4/IL-13, key drivers of Type 2/Th2 immune diseases such as AD/asthma. CCL17 (TARC) and IgE production are enhanced by IL-4/IL-13 and correlate with AD severity. This pooled post hoc analysis reports the relationship between baseline (BL) serum CCL17 and total IgE levels and DUP treatment effect in adults with moderate-to-severe AD in 2 identical double-blind, placebo (PBO)-controlled phase 3 trials (SOLO 1: NCT02277743, N=671; SOLO 2: NCT02277769, N=708). Patients (pts; N=1,379) were randomized (1:1:1) to subcutaneous 300 mg DUP weekly (qw), every 2 weeks (q2w), or PBO for 16 weeks (W). CCL17 and total IgE were measured in serum samples collected between BL and W16 using commercial assays. Efficacy analyses by BL CCL17 tertiles (≤1115; >1115 to ≤4300; and >4300 pg/mL) and total IgE subgroups (<150 kU/L and ≥150 kU/L) were performed for % changes from BL in Eczema Area and Severity Index (EASI) and peak pruritus Numerical Rating Scale (NRS). On study entry, pts with low BL CCL17 (≤1115 pg/mL; n=457) or IgE concentrations (<150 kU/L; n=220) had numerically lower BL EASI and pruritus NRS scores than pts with high CCL17 (>4300 pg/mL; n=457) or IgE levels (≥150 kU/L; n=1158). Both DUP dose regimens significantly reduced EASI and pruritus NRS scores from BL at W16 vs PBO in pts with high, mid, or low BL CCL17 or high or low IgE levels (all P<0.0001 vs PBO, except pruritus in the low IgE group [P=0.002/P=0.006; qw/q2w]). The most common adverse events with DUP vs PBO were injection-site reactions and conjunctivitis. BL levels of CCL17 and IgE did not predict DUP treatment response (% reductions in EASI and pruritus NRS), although the smaller n of the low IgE group and lower BL disease activity in the low CCL17 and IgE groups may affect the power of this analysis.

127 TREATGermany registry: “real-world effectiveness” of dupilumab in atopic dermatitis

127 TREATGermany registry: “real-world effectiveness” of dupilumab in atopic dermatitis

Dupilumab after the 2017 approval for the treatment of atopic dermatitis: what's new and what's next?

The IL-4/13 antagonist dupilumab was approved in 2017 as the first biologic for atopic dermatitis. Here, we comprehensively review compelling new data regarding dupilumab published following the approval. Daily clinical practice reports of dupilumab in atopic dermatitis are favorable and in line with the registration trials. Dupilumab does not appear to negatively affect pharmacokinetics of CYP450-metabolized drugs nor vaccination responses. Type 2 inflammation biomarkers in skin and serum are reduced following dupilumab treatment. Dupilumab increases the risk for conjunctivitis, especially with higher baseline atopic dermatitis severity and a history of conjunctivitis, but the underlying mechanisms are unknown. Favorable effects of dupilumab have been reported in treatment-recalcitrant hand eczema and prurigo nodularis cases; for allergic contact dermatitis and alopecia areata, there are conflicting responses to dupilumab, possible stemming from pathophysiological heterogeneity. Daily practice data support the continued use of dupilumab for atopic dermatitis. The only safety signal is an increased risk for conjunctivitis; mechanistic studies into dupilumab-associated conjunctivitis should lead to risk mitigation strategies. Prospective, controlled evaluations are needed for dupilumab in hand eczema and prurigo nodularis. A precision medicine-driven drug-development approach is essential to assess dupilumab for diseases with heterogeneous pathophysiologies, such as alopecia areata and allergic contact dermatitis.

Conjunctivitis in dupilumab clinical trials.

SummaryBackgroundDupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo.ObjectivesTo characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials.MethodsWe evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47).ResultsIn most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis.ConclusionsConjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD).In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo.Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare.Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials.Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation‐regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis.Patients who responded well to dupilumab had reduced incidence of conjunctivitis.Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab‐treated patients with AD.

PP81 Real World Data: The Early Access To Medicines Scheme Catches The Worm

IntroductionThe Early Access to Medicines Scheme (EAMS) aims to provide access to medicines prior to market authorization for patients with severe, life-threatening diseases who do not have adequate treatment options. An EAMS designation enables the potential collection of United Kingdom-specific real world evidence (RWE) prior to health technology assessment (HTA) by the National Institute for Health and Care Excellence (NICE). This research evaluates whether RWE is being gathered through the EAMS and utilized to support HTA submissions.MethodsAll EAMS designations as of 7 November 2018 were identified from the Medicines and Healthcare products Regulatory Agency website. For products with final NICE guidance, all publicly-available NICE documentation was reviewed.ResultsSixteen product and indication pairings with an EAMS designation were identified, with 12 having received final NICE guidance (11 were recommended, 3 were recommended for temporary reimbursement via the Cancer Drugs Fund, and 2 were not recommended). Of the 11 recommended products, seven had references to the number of patients or sites with product access through the EAMS, but only one (dupilumab for atopic dermatitis) had detailed data collected during the EAMS period. The manufacturer of dupilumab reported baseline demographics and disease characteristics from a cohort of 35 patients treated under the EAMS to inform the generalizability of trial populations for clinical practice. Follow-up results from this cohort demonstrated that real-world data on dupilumab effectiveness was comparable with the clinical trial data, despite a higher proportion of patients in the real-world cohort receiving immunosuppressant therapy, which makes improvements in efficacy harder to achieve. The committee also noted that the RWE presented supported the understanding of dupilumab's long-term clinical effectiveness and informed assumptions for the economic model.ConclusionsTo date, the majority of products receiving an EAMS designation have not presented RWE at NICE reappraisal. The case of dupilumab illustrated how RWE collected through the EAMS can be used to reduce uncertainty around how clinical trial data can be translated into clinical practice. In the future, RWE may increasingly be used to help inform NICE decisions.

Dupilumab in atopic dermatitis: rationale, latest evidence and place in therapy.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. The prevalence of AD is increasing and is currently estimated at 10-20% in adults worldwide. In the majority of patients, AD can be adequately controlled with topical treatment or ultraviolet light therapy, but there is a high unmet need for effective and safe therapeutics in patients with more severe or difficult to treat AD. During the past decade, new advances in the understanding of the underlying immune pathogenesis of AD have led to the development of new, more targeted therapies. Dupilumab, a fully human monoclonal antibody targeting the interleukin (IL)-4 receptor α, thereby blocking the IL-4 and IL-13 pathway, is one of the first biologics that has been developed for AD. Dupilumab has shown promising results in phase III trials and has recently been approved by the US Food and Drug Administration and the European Commission for the treatment of moderate to severe AD. With the approval of dupilumab, we are entering a new era of biological therapeutics in AD management. The place of dupilumab should be established in the current treatment standards. Based on current treatment guidelines and experts' opinions in the management of AD, we have built a proposal for a treatment algorithm for systemic treatment of AD in European countries.

1066 Biomarkers CCL17/TARC and total IgE do not predict clinical response to dupilumab in atopic dermatitis (AD): A post hoc analysis of pooled phase 3 data (SOLO 1 & 2)

1066 Biomarkers CCL17/TARC and total IgE do not predict clinical response to dupilumab in atopic dermatitis (AD): A post hoc analysis of pooled phase 3 data (SOLO 1 & 2)

282 Risk of skin infections with dupilumab for atopic dermatitis: Systematic review and meta-analysis of randomized controlled trials

282 Risk of skin infections with dupilumab for atopic dermatitis: Systematic review and meta-analysis of randomized controlled trials

Drug evaluation review: dupilumab in atopic dermatitis.

Atopic dermatitis (AD) is characterized by type 2 helper T (Th2) cell-driven inflammation. Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways. In Phase I and II studies of adults with moderate-to-severe AD, dupilumab administered as monotherapy or with topical corticosteroids resulted in rapid, significant improvements in clinical efficacy, patient-reported outcomes, and Th2-related serum and tissue biomarkers, and shifted the RNA expression profile of lesional skin to a more nonlesional signature. In all clinical studies to date, dupilumab has shown a favorable safety profile with no dose-limiting toxicity. The robust effects of dupilumab on skin inflammation and pruritus confirm the pathogenic role of IL-4 and IL-13 signaling in adult AD, and further support the application of Th2 cytokine antagonists in the treatment of this disease.