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Management of inadequate response and adverse effects to dupilumab in atopic dermatitis
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, skin-pain, and sleep disturbances. Currently, dupilumab is the only U.S. FDA approved systemic therapy and biologic medication for moderate-to-severe AD in adults and children. There is a sparsity of literature available on determining treatment failure with dupilumab and the next steps healthcare providers can take to treat AD. Individual goals and quality of life, and not just body surface area should be considered when defining treatment failure. Possible confounding dermatoses should also be ruled out. Early identification of dupilumab induced adverse-events is important, and for most, dupilumab can be continued while treatment for the adverse-event is initiated. Adjusting dupilumab dosing frequency may also be considered in some circumstances. Adjuvant therapies such as methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, or phototherapy can be added but the safety and efficacy of these combination treatments is not known at this time.
... Dupilumab-associated ocular surface disease (DAOSD) is a notable TEAE of dupilumab, and typically presents as conjunctivitis, blepharitis, or keratitis. Clinical signs include dry or itchy eyes, hyperemia, tearing, foreign body sensation or decreased visual acuity that develops weeks to months after starting dupilumab [12]. One review of phase II and phase III RCTs calculated an incidence of 3.6-31% in adult and pediatric (6-17 years old) cohorts on either tralokinumab or dupilumab, another meta-analysis of 22 observational studies found DAOSD reported in 26% of 3033 of adults on dupilumab [13,14]. ...
... One review of phase II and phase III RCTs calculated an incidence of 3.6-31% in adult and pediatric (6-17 years old) cohorts on either tralokinumab or dupilumab, another meta-analysis of 22 observational studies found DAOSD reported in 26% of 3033 of adults on dupilumab [13,14]. While the exact mechanism of DAOSD is unknown, inhibition of IL-4 is known to prevent conjunctival goblet cell activation in meibomian glands leading to hypoplasia and decreased mucin production, affecting tear film stability [12,13,15]. Conjunctival biopsies of DAOSD-patients exhibit T-cell and eosinophil infiltration, as well as a scarcity of goblet cells [16]. ...
... Initial management includes warm compresses, artificial tears, oral omega-3 supplementation, sodium hyaluronate drops, and mast-cell stabilizing drops [12,13]. Moderateto-severe conjunctivitis management may include corticosteroid or calcineurin inhibitor eyedrops or ointments [12,13]. ...
Purpose of review
Expansion of systemic therapies has improved atopic dermatitis (AD) management in pediatric cohorts, however guidelines for use of these medications in children remain limited. This review aims to guide decision-making for selection and substitution of systemic therapies as well as anticipation of potential adverse effects for pediatric AD patients.
Recent findings
Currently, high-dose abrocitinib and any-dose upadacitinib exhibit the best clinical outcomes followed by dupilumab. Administration of scheduled live vaccines in dupilumab-treated children outweighs risks of deferred immunization, however vaccine safety and efficacy in dupilumab and future systemic AD therapies should be included in clinical trials.
Summary
Dupilumab has the broadest age-approval and best safety-efficacy and is thus the best first-choice systemic option for pediatric AD. Risks of dupilumab use include provisional guidance for administration of scheduled live vaccines in children and conjunctivitis, which may be mitigated with topical treatments or switching to an IL-13 inhibiting MAB such as tralokinumab or lebrikizumab.
... 6 Rarer considerations include Netherton syndrome, primary immunodeficiency diseases, and acrodermatitis enteropathica. 7 Diagnosing AD in FIGURE 2. Physical examination showed several pink plaques with silvery scale and ill-defined hypopigmented patches on the scalp, and numerous scattered guttate patches and plaques on the face, elbows, and knees. ...
... 12 It is believed to trigger psoriasis via suppression of the Th2 (AD) pathway in patients with AD, shifting the balance toward Th1/Th17 (psoriasis pathway) predominance 3d. and the development of psoriasis. 7,13 The morphology of this patient's eruption and acute worsening with dupilumab allowed for a clinical diagnosis, precluding need for a biopsy. ...
Distinguishing between psoriasis and other inflammatory dermatoses in pediatric skin of color can pose challenges. As more topical and systemic treatments become available for pediatric patients, early and accurate diagnoses are needed to help guide treatments for those that progress to severe disease. Delays in diagnosis for this population often lead to worsening disease until a correct diagnosis is reached. The goal of this article is to improve the understanding of inflammatory dermatoses in skin of color and review differential diagnoses, by presenting a case of psoriasis in a pediatric patient who flared after receiving dupilumab for an incorrect diagnosis of atopic dermatitis.
... Given that a subset of atopic dermatitis patients fail dupilumab (anti-IL-4Rα monoclonal) therapy but respond to JAK inhibitors, this suggests that alternative pathways to IL-4Rα and JAK1 (ref. 37), such as IL-3Rα and JAK2, are new targets in atopic dermatitis and other itch disorders 38 . ...
In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response1,2. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch3–7. Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown. Here we describe a γδ T cell–IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal γδ T cell subset⁸, termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra-expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This γδ T cell–IL-3 signalling axis further acts by means of STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens on first exposure. This pathway may explain individual differences in allergic susceptibility and opens new therapeutic avenues for treating allergic diseases.
... However, some patients do not respond well to Dupilumab treatment, and relapse upon discontinuing the drug is common. 118,119 Although Janus Kinase Inhibitors improve symptoms in patients with poor efficacy of Dupilumab therapy, their inhibitory effect on the JAK/STAT pathway makes patients more susceptible to herpes, respiratory tract infections, and other adverse events. 120 In clinical trials of new biologics for AD treatment, IL-31Rα blockers have been shown to effectively improve dermatitis symptoms in patients with moderate-to-severe AD, and IL-22 monoclonal antibodies have been successful in treating patients with high baseline levels of IL-22. ...
Atopic dermatitis (AD) is a chronic and inflammatory skin disease with intense itchiness that is highly prevalent worldwide.The pathogenesis of AD is complex and closely related to genetic factors, immunopathogenic factors, environmental factors, and skin infections. Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells derived from the mesenchymal stroma. They have anti-inflammatory, anti-apoptotic, and regenerative properties. Numerous studies demonstrate that MSCs can play a therapeutic role in AD by regulating various immune cells, maintaining immune homeostasis, and promoting the repair of damaged tissues. The key mediators for their biological functions are extracellular vesicles (MSC-Evs) and soluble cytokines derived from MSCs. The safety and efficacy of MSCs have been demonstrated in clinical Phase I / IIa trials for AD. This paper provides a comprehensive review of the pathogenesis of AD and the currently published studies on the function of MSCs and MSC-Evs in AD, primarily including the pathogenesis and the immunomodulatory impacts of MSCs and MSC-Evs, along with advancements in clinical studies. It provides insights for comprehending AD pathogenesis and investigating treatments based on MSCs.
... Dupilumab is the only biologic drug approved to date by the U.S. Food and Drug Administration for the treatment of moderate-to-severe AD in adults and children [144]. It works by blocking IL-4/IL-13 signaling and inhibiting receptor signaling. ...
Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin condition characterized by a multifaceted pathophysiology that gives rise to diverse clinical manifestations. The management of AD remains challenging due to the suboptimal efficacy of existing treatment options. Nonetheless, recent progress in elucidating the underlying mechanisms of the disease has facilitated the identification of new potential therapeutic targets and promising drug candidates. In this review, we summarize the newest data, considering multiple connections between IL-22 and AD. The presence of circulating IL-22 has been found to correlate with the severity of AD and is identified as a critical factor driving the inflammatory response associated with the condition. Elevated levels of IL-22 in patients with AD are correlated with increased proliferation of keratinocytes, alterations in the skin microbiota, and impaired epidermal barrier function. Collectively, these factors contribute to the manifestation of the characteristic symptoms observed in AD.
... This trial also demonstrated substantial improvement in EASI-75 and peak pruritus numerical rating scale [41]. Side effects included paradoxical head and neck erythema, ocular complications, new-onset psoriasis, arthritis, and alopecia [42,43]. ...
Atopic dermatitis is a chronic inflammatory dermatosis characterized by pruritic, scaly, erythematous lesions. Its incidence varies but is estimated to be approximately 20% in children and between 7 and 14% in adults, with variation amongst countries. It is a multifactorial condition, with a complex interplay between genetic, immunological, and environmental factors. Research into the inflammatory response has identified new therapeutic targets that work to reduce inflammation and subsequently reduce flares. This study explores existing therapeutic agents for atopic dermatitis as well as newer therapies such as biologics and small molecules, drawing upon each agent’s mechanism of action, relevant landmark clinical trials, efficacy, and safety profile. Current therapies include emollients, corticosteroids, cyclosporine A, calcineurin inhibitors, phototherapy, and methotrexate. Biologics described include dupilumab, tralokinumab, lebrikizumab, nemolizumab, and rocatinlimab. Small molecules inhibitors include Janus kinase inhibitors, phosphodiesterase 4 inhibitors, transient receptor potential vanilloid subfamily V member 1 antagonist, and aryl hydrocarbon receptor antagonist.
... Dupilumab has demonstrated its good safety profile and efficacy over time in patients with moderate to severe atopic dermatitis (AD) in pivotal 1 and real-life studies. 2 Few real-life studies describe the management of patients with an inadequate response to on-label use of dupilumab, despite published algorithms propose to increase the dose, or to combine with immunosuppressive drugs, 3,4 or to switch for oral Janus Kinase inhibitors (JAKi). 5,6 We conducted a multicenter retrospective study to i) assess the response to increased dose of dupilumab or combination with other systemic agents and ii) analyze epidemiological and clinical factors associated with this response. ...
In patients with moderate to severe atopic dermatitis (AD) showing an inadequate response to dupilumab 300mg/2weeks, few real-life studies reported the response to alternative regimen maintaining dupilumab.
To assess and analyze the response to an increased dose of dupilumab or its combination with cyclosporin A (CsA), methotrexate (MTX), or itraconazole (ITRA), all adult AD patients from 7 French University Hospitals were retrospectively included if they achieved an inadequate response to dupilumab 300mg/2weeks and were subsequently treated with an increased dose of dupilumab (300mg every 7 or 10 days), or a combination of dupilumab 300mg/2weeks with CsA, MTX or ITRA. The response after 3 months, along with epidemiological, clinical, and therapeutic baseline characteristics, were collected.
Overall, 68.75% of the 48 included patients achieved an improved response, including 45.8% of complete response (CR). No strategy proved significantly better. Patients showing an initial no response never achieved a further CR versus 52.4% of patients with an initial partial response (p = 0.025). Digestive intolerance and tachycardia led to MTX and ITRA discontinuation in 3 patients.
Increasing the dose of dupilumab or combining it with CsA, MTX, or ITRA could be alternative and safe options, to be evaluated in further medico-economic studies.
... However, the adverse effects like dermatitis after using dupilumab, psoriasis, some adverse ocular events, and alopecia are also high in those treatments Sometimes seronegative inflammatory arthritis is also reported. [12] Some known adverse effects of azathioprine are nausea, malaise, fatigue, lymphopenia, and neutropenia. [13] Topical corticosteroids, which are used in AD, have multiple adverse effects like telangiectasia, skin atrophy, hypertrichosis, hyperpigmentation, etc. [14] Here homoeopathy has a great scope to flourish. ...
Atopic Dermatitis (AD) is a very common dermatological disorder in children. It is chronic, intensely pruritic, and of a relapsing nature. There are several risk factors related to AD. However, family history and filaggrin (FLG) genes are leading among them. As per available data, Homoeopathy is very effective for the management of AD. This case is of a child 8 years of age who was suffering from AD for almost 7 months. He presented with pruritus with eczematous lesions and redness in the right axilla. There was oozing of sticky discharge from the affected area. After proper case-taking and repertorization, Graphites 30 was prescribed, followed by Graphites 200. After a few follow-ups gradual improvement was observed. This case study reveals a positive role of homoeopathic treatment in atopic dermatitis.
... Adverse reactions that have occurred during dupilumab treatment include: injection site reactions, eosinophilia, eczema of the head and neck, rosacea, psoriasis, ocular complications (dry eye, conjunctivitis, blepharitis, keratitis, and ocular pruritis), arthritis, alopecia, and serosurgelike reactions. [40][41][42][43] In the PRESCHOOL and PEDS phase III trials, most adverse events were reported at a higher rate in the placebo group than in the dupilumab group, whlie the incidence of treatment-emergent adverse events was similar across treatment groups in ADOL. In addition, the incidence of adverse reactions was higher with dupilumab q2w dosing group than with dupilumab q4w dosing group in PEDS and ADOL. ...
Atopic dermatitis (AD), a common pruritic and chronic inflammatory skin disease, has a major impact on a patient’s quality of life. It is characterized by dry, itchy, and eczema-like rashes. AD is more prevalent in young children and has been linked to a variety of other allergy disorders. Traditional drug therapy has certain limitations for treating young children with AD. However, biologics have good clinical application prospects in the medical treatment of young patients. Dupilumab, a fully human monoclonal antibody, specifically binds to the IL-4 Rα subunit, inhibiting IL-4 and IL-13 signaling and blocking the occurrence of type 2 inflammatory response. It has a good effect on treating infants and children with moderate-to-severe AD. This review explores the safety and efficacy of dupilumab in the treatment of AD in infants and children and the impact of early intervention on AD progression, with the aim of informing clinical practice in the use of dupilumab for the treatment of young patients with AD.
... Approved by the United States Food and Drug Administration for moderate/severe AD. Several clinical trials have demonstrated the efficacy in improving the severity of AD and quality of life and presents safety profile in adults and children [17]. ...
Atopic dermatitis (AD), also known as atopic eczema, is a chronic and inflammatory disease caused by an interaction of genetic, immunological, and environmental factors. It is characterized by skin lesions and itching and progresses with periods of improvement and worsening. Patients with AD often experience sleep disorders, which leads to a worsening of the quality of life of patients and their families and may be associated with poorer school performance, behavioral and mood dysfunction, risk of short stature, metabolic syndrome, mental illness, neurocognitive dysfunction, psychiatric comorbidities such as anxiety, stress, depression, attention deficit hyperactivity disorder (ADHD). Furthermore, sleep disturbances in children with AD have been associated with pruritus and greater severity of dermatitis. To this day, we do not have a curative treatment for this disease, but there is treatment, and it is possible to keep the disease under control. In these patients, controlling the condition is very important to improve the quality of sleep, at the same time, with better sleep there is greater control of AD. Despite being very common in AD, we currently have few studies on sleep disorders and their treatment in this disease, and there is no consensus on the therapeutic approach. We carried out a descriptive study with a narrative review of the literature. The research was based on studies published in English and Portuguese between January 2013 and October 2023, electronically in several databases, such as PubMed, Scientific Electronic Library Online, and Latin American and Caribbean Literature in Health Sciences. The objective of this review is to describe possible treatments for sleep disorders in AD, in order to contribute to a better understanding and clinical management of these cases, seeking to minimize the impact on the lives of these patients.
... AD is a chronic and recurrent intractable skin disease. While biological agents have been employed in AD treatment, their long-term efficacy and potential risks remain unknown [29]. Previous research has shown that oral administration of QRQS effectively treats AD patients [7]. ...
Accumulating evidence has highlighted a strong association between gut microbiota and the occurrence, development, prevention, and treatment of atopic dermatitis (AD). The regulation of gut microbial dysbiosis by oral traditional Chinese medicine (TCM) has garnered significant attention. In the treatment of AD, the TCM formula Qingre-Qushi Recipe (QRQS) has demonstrated clinical efficacy. However, both the therapeutic mechanisms of QRQS and its impact on gut microbiota remain unclear. Thus, our study aimed to assess the efficacy of QRQS and evaluate its influence on the composition and diversity of gut microbiota in AD animal models. First, we investigated the therapeutic effect of QRQS on AD using two animal models: filaggrin-deficient mice (Flaky tail, ft/ft) and MC903-induced AD-like mice. Subsequently, we explored its influence on the composition and diversity of gut microbiota. Our results demonstrated that QRQS treatment ameliorated the symptoms in both ft/ft mice and MC903-induced AD-like mice. It also reduced the levels of serum IgE and pro-inflammatory cytokines, including IL-1β, IL-4, IL-5, IL-9, IL-13, IL-17A, and TNF-α. Furthermore, QRQS remarkably regulated gut microbiota diversity by increasing Lactobacillaceae and decreasing Bacteroidales. The inflammatory factors in peripheral serum of ft/ft mice showed a close correlation with gut microbiota, as determined using the Spearman correlation coefficient. Additionally, PICRUSt analysis revealed an enrichment in ascorbate and aldarate metabolism, fatty acid metabolism and biosynthesis, and propanoate metabolism in the QRQS group compared to the ft/ft group. Finally, we identified liquiritin as the primary active ingredient of QRQS using ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). Our findings revealed that QRQS improved AD-like symptoms and alleviated skin inflammation in ft/ft and MC903-induced mice. This suggests that modulating the gut microbiota may help elucidate its anti-inflammation activation mechanism, highlighting a new therapeutic strategy that targets the intestinal flora to prevent and treat AD.
... 67 The most common side effects associated with dupilumab are conjunctivitis and paradoxical eczematous reactions on the head and neck regions, but developing these does not necessitate discontinuation of treatment; it has been suggested to augment dupilumab with a combination of other AD treatments in these nonsevere cases. 68 Dupilumab was prescribed to 2.83% of AD patients in 2018. 26 ...
Topical corticosteroids (TCSs) are the most widely used treatment for atopic dermatitis (AD), but they can have adverse effects such as skin atrophy, telangiectasias, and hypopigmentation, especially with prolonged use of higher potency steroids. Many patients also have a fear of using TCSs, known as ''corticophobia.'' With the development of biologics and Janus kinase inhibitors, a nonsteroidal approach to the treatment of AD may be possible and may be preferred by certain patients. Given what is known about these nonsteroidal therapies, we propose a structured treatment ladder and action plan that can guide clinicians and patients on the use of these therapies for the treatment of AD. The ladder divides nonsteroidal medication classes into treatments for exacerbation versus maintenance therapies in an escalating order of increasing potential for adverse effects, both real and perceived. This treatment algorithm proposal paves the way for a potential nonsteroidal approach to managing AD. Capsule Summary Nonsteroidal treatment options for atopic dermatitis have rapidly expanded with the development of phosphodiesterase-4 inhibitors, biologics, and Janus kinase inhibitors. Although topical corticosteroids are considered first line for the treatment of atopic dermatitis, adverse effects can occur especially with prolonged usage, and nonsteroidal approaches may be preferred. This article provides a focused review of nonsteroidal treatments for atopic dermatitis and suggests a structured therapeutic ladder and action plan format that can guide clinicians and patients on the usage of these therapies for the treatment of atopic dermatitis.
... Despite remarkable advances in our understanding of AD, there are still patients with uncontrolled, refractory AD. Moreover, current treatments have some side effects [1]; for example, the leading calcineurin inhibitor, tacrolimus, can cause side effects such as a burning sensation, while the biologic dupilumab has been linked with conjunctivitis and paradoxical head and neck erythema [2,3]. Recently, several Janus kinase (JAK) inhibitors have been introduced as treatments for refractory AD; however, baricitinib can cause nasopharyngitis, folliculitis, and herpes infection; abrocitinib can trigger headache and nausea; and upadacitinib can cause acne and AD exacerbation [3,4]. ...
The yes-associated protein (YAP) of the Hippo pathway regulates a variety of target genes involved in cell proliferation, survival, and inflammation. YAP and transcription activator with a PDZ-binding motif (TAZ) proteins act as mediators of the inflammatory response. Still, their role in atopic dermatitis (AD)—particularly, the association with the nuclear factor kappa-B and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways—is not fully understood. In this study, we found that YAP, is upregulated in AD patients and NC/Nga mouse model of AD. In addition, inhibition of YAP significantly reduced epidermal cell proliferation by 58% and mast cell numbers by 51% and attenuated the upregulation of both Th1- and Th2-associated cytokines. Among the JAK-STAT family proteins, the expressions of JAK1 and JAK2 and those of STAT1, STAT2, and STAT3 were also downregulated. These findings may explain the role of YAP in AD and suggest YAP inhibitors as promising therapeutic agents for AD.
... It must be emphasized that the combination of a traditional systemic immunosuppressant or phototherapy with dupilumab may represent an effective strategy to enhance drug retention in patients experiencing an inadequate response to dupilumab monotherapy (19,20). ...
Objectives
The purpose of this study was to analyze the drug survival rate of dupilumab up to 2 years in a large real-world cohort of adult patients affected by moderate/severe atopic dermatitis (AD), and to investigate the clinical, demographic and predictive factors influencing the patients’ treatment persistence.
Material and methods
This study included adult patients affected by moderate-to-severe AD treated with dupilumab for at least 16 weeks who visited 7 dermatologic outpatient clinics in Lazio, Italy, from January 2019 until August 2021.
Results
A total of 659 adult patients (345 male [52.3%], mean age: 42.8 years) with an average treatment duration of 23.3 months were enrolled in the study. Overall, 88.6% and 76.1% of patients were still on treatment after 12 and 24 months, respectively. The drug survival rate for discontinuation due to AEs and dupilumab ineffectiveness was 95.0% at 12 months and 90.0% at 24 months. The main reasons for drug discontinuation included inefficacy (29.6%), failed compliance (17.4%), persistent efficacy (20.4%) and adverse events (7.8%). Adult AD onset (≥18 years) and EASI score severity measured at the last follow-up visit were the only factors significantly associated with lower drug survival.
Conclusion
This study revealed an increased cumulative probability of dupilumab survival at 2 years, reflected by a sustained effectiveness and a favorable safety profile of the drug.
... In the current research study, various relevant indicators related to AD symptoms, signs, and quality of life, such as POEM, ESAI, v-IGA, NRS, and DLQI, were evaluated, and the patients receiving dupilumab achieved better treatment outcomes than those without dupilumab treatment. The findings of the current study were similar to previous findings 24,25 . During the treatment, 20.23% of patients in the study group reported treatment-related adverse events, with conjunctivitis and injection site reactions being the most common. ...
Objective:
The aim of this study was to evaluate the efficacy and safety of combining dupilumab with topical tacrolimus for the treatment of atopic dermatitis (AD) in children aged 6 to 12 years.
Patients and methods:
A total of 168 pediatric (aged 6 to 12 years) patients with severe AD admitted to our hospital between April 2022 and April 2023 were included in this retrospective study. These patients are grouped according to different medication methods, assigned them to receive either tacrolimus plus topical corticosteroids (control group) or dupilumab combined with tacrolimus and topical corticosteroids (study group), with 84 patients in each group. Clinical efficacy and adverse reactions were primary clinical endpoints.
Results:
The use of dupilumab significantly increased the total effective rate for the patients by 14.29%, from 77.38% (65/84) in the control group to 91.67% (77/84) in the study group. Following treatment, patients given dupilumab showed a more significantly decreased peripheral blood eosinophils (EOS) and immunoglobulin E (IgE) levels than those without dupilumab treatment. Patients administered with dupilumab exhibited markedly lower scores on the Patient-oriented Eczema Measure (POEM) at weeks 12 and 16 and lower Eczema Area and Severity Index (EASI) scores at weeks 8, 12, and 16 when compared to those patients who did not receive dupilumab therapy. At the 16-week, 37 patients in the study group obtained a score of 1/0 on the Verified Investigator's Global Assessment (v-IGA) scale, whereas the control group had 24 such cases, indicating a significantly higher response rate provided by the protocol incorporating dupilumab. After 16 weeks of treatment, both groups demonstrated a marked decrease in itch numeric rating scale (NRS) scores and Dermatology Life Quality Index (DLQI) scores, with lower scores observed in the study group than in the control group. The absence of a significant difference in the incidence of adverse reactions between the two groups suggested a high safety profile of dupilumab.
Conclusions:
The combination of dupilumab with topical tacrolimus demonstrated favorable efficacy in the management of AD in children aged 6 to 12 years. This treatment protocol effectively alleviates symptoms, enhances the quality of life of patients, and shows no increased risk of adverse reactions.
... Other relatively rare adverse events include ocular complications (e.g., dry eyes, conjunctivitis, blepharitis, keratitis, and pruritus), head and neck dermatitis, onset of psoriatic lesions, progression of cutaneous T-cell lymphoma, alopecia areata, hypereosinophilia, and arthritis. Most of these adverse effects can be controlled during continued treatment with dupilumab, but some (such as severe conjunctivitis) may result in discontinuation of treatment [53,54]. Above all, dupilumab, which targets the IL-4/IL-13 pathway, may provide a better treatment choice for keloid patients, especially those with concurrent AD, and is worthy of further large-scale clinical trials. ...
Keloids are a type of fibrotic disease characterized by excessive collagen production and extracellular matrix (ECM) deposition. The symptoms of pain and itching and frequent recurrence after treatment significantly impact the quality of life and mental health of patients. A deeper understanding of the pathogenesis of keloids is crucial for the development of an effective therapeutic approach. Fibroblasts play a central role in the pathogenesis of keloids by producing large amounts of collagen fibers. Recent evidence indicates that keloids exhibit high immune cell infiltration, and these cells secrete cytokines or growth factors to support keloid fibroblast proliferation. This article provides an update on the knowledge regarding the keloid microenvironment based on recent single-cell sequencing literature. Many inflammatory cells gathered in keloid lesions, such as macrophages, mast cells, and T lymphocytes, indicate that keloids may be an inflammatory skin disease. In this review, we focus on the communication from immune cells to the fibroblasts and the potential of immunotherapy for keloids. We hope that this review will trigger interest in investigating keloids as an inflammatory disease, which may open up new avenues for drug development by targeting immune mediators.
... Dupilumab is a monoclonal antibody that selectively blocks IL-4 and IL-13 signaling and received the first global approval for AD treatment in March 2017, representing a major advance in treating patients with moderate-to-severe AD (3,4). However, dupilumab is ineffective in some AD patients and might induce new regional dermatoses, ocular complications, alopecia, and other adverse effects (5). Although there is no accurate cure for AD, many novel and targeted therapies promise to slow the disease's progression considerably, especially in patients with refractory AD. ...
Atopic dermatitis (AD) is a common allergic inflammatory skin condition mainly caused by gene variants, immune disorders, and environmental risk factors. The T helper (Th) 2 immune response mediated by interleukin (IL)-4/13 is generally believed to be central in the pathogenesis of AD. It has been shown that innate lymphoid cells (ILCs) play a major effector cell role in the immune response in tissue homeostasis and inflammation and fascinating details about the interaction between innate and adaptive immunity. Changes in ILCs may contribute to the onset and progression of AD, and ILC2s especially have gained much attention. However, the role of ILCs in AD still needs to be further elucidated. This review summarizes the role of ILCs in skin homeostasis and highlights the signaling pathways in which ILCs may be involved in AD, thus providing valuable insights into the behavior of ILCs in skin homeostasis and inflammation, as well as new approaches to treating AD.
... Atopic dermatitis (AD) is a chronic and in ammatory skin disease that most often develops in infants and young children and can be associated with allergic diseases, and is a Th2 in ammatory disease, along with asthma, chronic sinusitis with nasal polyps and eosinophilic esophagitis [1][2][3] . Dupilumab is a fully humanised monoclonal antibody (IgG 4 ) targeting the IL 4 receptor alpha subunit (IL 4Rα) and IL 13, which inhibits IL 4/IL 13 signaling pathway [4,5] . Most clinical trials have shown that Dupilumab is safe and effective in children with AD aged 6 months to 18 years [6 9] . ...
Objective
To investigate the efficacy of Dupilumab in the treatment of Chinese children under 18 years of age with atopic dermatitis (AD) and to analyze the associated risk factors.
Methods
The clinical data of children under 18 years old diagnosed with AD and treated with Dupilumab in the dermatology department of our hospital from 2021 to 2022 were collected, and the changes of SCORAD, BSA, NRS and DLQI were compared before and 4 weeks after treatment. and adverse events during the treatment period were counted. A multifactorial logistic regression model was constructed to analyze the risk factors affecting the outcome of Dupilumab treatment in children with AD.
Results
A total of 144 children were included in the study. The SCORAD, NRS, DLQI and BSA scores all decreased significantly (P < 0.001) 4 weeks after Dupilumab treatment. No adverse events occurred during treatment in all children. logistic regression models showed that age, course of disease/age, comorbidity, pet ownership, and dietary bias were the main risk factors for improvement in SCORAD (P < 0.05) and eosinophilia, place of residence, sleep duration, and home renovation as the main risk factors for improvement in NRS (P < 0.05), household income and staying up late as the main risk factors for improvement in DLQI (P < 0.05), course The main risk factors for improvement in BSA were course of disease/age, family history, comorbidity, and place of residence (P < 0.05).
Conclusion
Dupilumab for 4 weeks significantly improved the severity of lesions (including lesion area) and pruritus in children under 18 years of age with AD, thus improving the quality of life of the children and their families with good efficacy and safety. Age, course of disease/age, comorbidity, pet ownership and dietary bias mainly influenced the improvement of lesion severity; eosinophils, place of residence, sleep duration, home renovation mainly influenced the improvement of lesion area; household income and staying up late mainly influenced the improvement of pruritus; course of disease/age, family history, comorbidity and place of residence mainly influenced the improvement of quality of life.
... So far in its clinical use, dupilumab has demonstrated efficacy in moderate-severe AD and is generally well tolerated [54][55][56]. Common side effects include skin-related events (head and neck erythema, psoriasis, and alopecia) and mild to moderate ocular adverse effects (conjunctivitis, blepharitis, and keratitis) [57,58]. ...
Dupilumab, a monoclonal antibody targeting interleukin‐4 receptor alpha, has shown both robust efficacy and safety in pediatric atopic dermatitis (AD), but data on complete disease control (Eczema Area and Severity Index [EASI] 100) are scarce. A retrospective analysis of 25 pediatric patients at our institution with a median treatment duration of 20 months revealed a significant improvement in EASI scores, with 44.0% achieving EASI 100 at a median of 52 weeks of treatment. No significant differences were found between the group of patients achieving EASI 100 and those who did not. While this study provides additional insight into the efficacy and safety of dupilumab in pediatric AD, its limited sample size underscores the need for larger scale studies focusing on EASI 100 to better understand the factors influencing complete disease control and to optimize treatment strategies for pediatric patients with AD.
Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disorder characterized by dry skin, eczema-like lesions, and severe itching. The multifaceted etiology of AD, which is not yet fully understood, includes genetic predispositions, immune dysfunctions(such as an impaired skin barrier and abnormal immune regulation), imbalances in the skin microbiota, and environmental factors, among others. In the field of AD treatment, the combination of traditional Chinese medicine and modern medicine is becoming an emerging trend. Given the potential side effects and reduced efficacy of conventional therapeutic drugs, Chinese herbal medicines offer patients new treatment options because of their unique efficacy and low toxicity. Some saffron extracts derived from saffron and gardenia , such as crocin, crocetin, and safranal, have shown promising potential in the treatment of AD. These natural ingredients not only possess anti-inflammatory and immunomodulatory properties similar to those of traditional Chinese medicines but also demonstrate excellent effects in promoting the repair of damaged skin barriers. Therefore, this article reviews the therapeutic potential of saffron extract in the treatment of AD, with a special focus on its mechanisms and potential interventions, while emphasizing the importance of herbal medicines as alternatives to traditional treatments, providing AD patients with safer and more effective treatment options.
Atopic dermatitis (AD) presents with a wide range of clinical manifestations with variable distribution, morphology, chronicity, and severity that may differ across ethnic and racial groups. A scoping literature review was conducted and included all studies of the clinical manifestations of adult AD in diverse populations. Promoting awareness of the heterogeneous clinical manifestations of AD may benefit the diagnosis, treatment, and characterization of eczema.
Atopic dermatitis (AD) is a common inflammatory dermatitis of the skin and poses therapeutic challenges due to the adverse reactions and high costs associated with available treatments. In Eastern Asian countries, a plethora of herbal remedies is extensively employed for the alleviation of AD. Many of these botanicals are renowned for their formidable anti‐inflammatory properties, contributing to AD management. Chinese herbal medicine (CHM) and its active ingredients exhibit both prophylactic and therapeutic promise against AD by modulating inflammatory response, orchestrating immune system functions, and enhancing antioxidant activities. A comprehensive exploration of the underlying mechanisms involved in CHM treatment can enhance the comprehension of AD pathogenesis and facilitate the development of innovative drugs for AD. This study aims to elucidate the signaling pathways and potential targets implicated in CHM‐based treatment of AD, providing a systematic theoretical framework for its application in therapy while serving as a valuable reference for developing more effective and safer AD therapeutic agents.
Many patients do not respond to targeted pathway-specific biologic therapies but predicting such failure remains an outstanding challenge. Here, in a case of adult-onset hand dermatitis that did not respond to multiple targeted biologic therapies, we detected gene expression programs activated in both atopic dermatitis and psoriasis, via high-resolution genetic profiling. Broader, kinase-based immunosuppression elicited a near complete clinical response. Therefore, our data suggest that such cases harboring greater molecularly complexity might be identified prospectively, circumventing some failures of single pathway blockade.
Background
Moderate-to-severe atopic dermatitis (AD) can be difficult to manage in paediatric patients, with few licensed treatments in this age group. Dupilumab is approved for AD in children older than 6 months.
Objectives
To assess the effectiveness and safety of dupilumab in a real-life cohort of paediatric AD patients in Spain.
Methods
A multicentre, retrospective real-life study on the effectiveness and safety of dupilumab in patients aged 2 to 18 years old with moderate-to-severe AD was conducted. Demographic and clinical characteristics were analysed, and effectiveness (EASI, IGA, DLQI, NRS itch), safety, and drug survival measures were assessed. A comparison of our results with other real-world outcomes and with clinical trials was made.
Results
Data from 243 patients from 19 centres was collected, with a mean follow-up of 85 weeks. Dupilumab exhibited significant effectiveness, with marked reductions in severity scores from week 4. By week 16, 79.4% of patients reached EASI75 and 40.5% reached EASI90. Mean percentage reduction in EASI was 79.7%. Increasing improvements were observed until week 52, with 85.8% and 49.6% achieving EASI75 and EASI90, respectively. Forty-three patients developed adverse events (AE) (43/243, 17.7%), being the most frequent ocular surface diseases (20/243, 8.2%), injection site reactions (8/243, 3.3%) and facial redness (7/243, 2.9%). Drug survival was high (96.9% and 93.1% after 1 and 2 years of follow-up, respectively), with only 19 (19/243, 7.8%) patients interrupting treatment: 7 (7/243, 2.9%) due to AE, 2 (2/243, 0.82%) due to secondary failure, 5 (5/243, 2.1%) were lost to follow-up and 5 (5/243, 2.1%) entered remission and stopped treatment.
Conclusion
Real-life use of dupilumab in paediatric AD showcased sustained effectiveness, high drug survival, and acceptable safety profiles. Longer-term studies are crucial for AE surveillance and how to manage disease remission.
Dupilumab and tralokinumab are currently the only FDA-approved biologic therapies for the treatment of moderate-to-severe atopic dermatitis. Tralokinumab is approved for patients greater than 18 years old, and dupilumab is approved for patients as young as 6 months old. Both medications are effective in clinical trials at improving atopic dermatitis. With a good safety profile and low-risk adverse events, dupilumab and tralokinumab are generally excellent treatment options for patients with severe or refractory atopic dermatitis.
Background
Trials and real‐life studies demonstrated clinically meaningful improvements of disease activity in the majority of patients with moderate to severe atopic dermatitis (AD) treated with the anti‐IL‐4RA‐antibody dupilumab. However, misdiagnosis or confounding skin diseases in particular cutaneous T‐cell lymphoma (CTCL) may lead to inadequate response.
Objective
To investigate the clinical and pathological features of patients with AD who showed insufficient response to dupilumab.
Methods
We reviewed the medical records of 371 patients treated with dupilumab for severe AD. Insufficient response was defined as failure to achieve an improvement of the eczema area severity index (EASI) of at least 50% (EASI‐50) at Week 16 and of 75% (EASI‐75) at Week 52. Among 46 patients with insufficient response, 35 patients consented to a re‐evaluation including a full physical exam, biopsies and laboratory assessments including immunohistochemistry and T‐cell receptor gene rearrangement analysis to differentiate CTCL.
Results
Of the 371 patients treated with dupilumab, 46 (12.3%) patients showed insufficient response to dupilumab. Of these, 35 underwent further evaluation, and 19 (54.2% of inadequate responders) were finally diagnosed with mycosis fungoides (MF). In these patients, transition to or addition of conventional MF treatment led to clinical improvements.
Conclusion
Insufficient response to dupilumab treatment may help uncover early MF on an existing AD background.
Introduction: Dupilumab is a fully human monoclonal antibody therapy FDA-approved to treat moderate-to-severe atopic dermatitis (AD) by interrupting the pro-inflammatory signaling pathway of interleukins 4 and 13. Common side effects of dupilumab include injection-site reactions, ophthalmic complications, and upper respiratory infections. We discuss the necessity for early recognition and management of dupilumab-induced EAC which has not been previously reported as a potential adverse effect. Case Report: A 48-year-old woman began treatment with dupilumab for severe AD and subsequently presented with a 3-month history of erythematous annular plaques with trailing scale on the trunk and extremities. She failed treatment with topical corticosteroids as well as topical and oral antifungals prior to being diagnosed with biopsy-confirmed erythema annulare centrifugum (EAC). The condition worsened after replacing dupilumab with tralokinumab but resolved after discontinuation of the drugs and has remained clear since. Conclusion: EAC is a reactive erythema that typically presents as expanding annular papules and plaques with central clearing and in some cases, trailing scale at the rim of the lesions. There are currently no reports in the literature describing the development of EAC secondary to dupilumab. Clinicians should be aware that EAC may be a potential adverse effect of dupilumab.
Dupilumab is a monoclonal antibody that works by inhibiting the activity of interleukin-4 and interleukin-13, two cytokines that play an integral role in the T helper 2 (Th2) immune response. It is FDA approved for the treatment of atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. For AD treatment, it is recommended for patients ≥6 months of age with moderate-to-severe disease who have not responded to conventional topical therapies. Numerous randomized controlled trials have established dupilumab as one of the most efficacious and arguably the safest systemic therapy available for the treatment of AD. The most commonly reported side effects include conjunctivitis, facial erythema, and injection site reactions. Because of its superior efficacy and side effect profile, dupilumab has in recent years become a first-line option among systemic AD treatments.
Background: One of the primary flavonoids found in the Glycyrrhiza glabra is called glabridin, which has anti-inflammatory, anti-bacterial, and antineoplastic effects. However, the insolubility of glabridin in water limits its application. Liposomes can increase the solubility of insoluble drugs and improve their bioavailability.
Objective: We examined the potential for the treatment of glabridin liposomes on histamine-induced atopic dermatitis.
Materials and Methods: After GL treatment, histopathology, inflammatory cytokines, and atopic dermatitis-related proteins were used to evaluate the therapeutic effect of GL.
Results: Glabridin liposomes alleviated histamine-induced scratching behavior; reduced mast cell proliferation, infiltration, and degranulation; and restrained the expression of associated pro-inflammatory cytokines. Additionally, glabridin liposomes restored nerve growth factor to normal levels and enhanced the expression of filaggrin to promote cuticle growth and repair skin damage caused by atopic dermatitis.
Conclusion: Glabridin liposomes may relieve histamine-induced skin hypersensitivity and cortical hyperplasia by inhibiting the production of inflammatory cytokines, demonstrating their potential for the clinical treatment of atopic dermatitis.
Atopic dermatitis (AD) and psoriasis belong to the most common inflammatory dermatoses that we treat in everyday clinical practice. AD manifests in more than 70% of cases before the age of 5 years. Approximately one-third of psoriasis patients report on onset of disease in the first two decades of life. Here, we are going to review both disorders in the light of pediatric dermatology. We are going to discuss selected subtypes and present clues for further examination with respect to the differential diagnoses and comorbidities. The article provides insight into current therapeutic developments that are relevant for the treatment of children and adolescents.
Dupilumab is an interleukin‐4 receptor antagonist important in the treatment of refractory atopic dermatitis (AD), particularly among pediatric patients. Two boys with a history of AD and cardiac transplant who developed psoriasiform dermatitis in response to dupilumab therapy are reported. These patients paradoxically developed an immune‐mediated adverse drug reaction despite taking systemic immunosuppressive agents. While the literature suggests possible pathomechanisms for psoriasiform dermatitis despite immunosuppression, further research is necessary to better characterize this unique and unexpected phenomenon.
Background:
Spontaneous Adverse Event Reporting (SAER) databases play a crucial role in post-marketing drug surveillance. However, the traditional model-free disproportionality analysis has been challenged by the insufficiency in investigating subgroup and confounders. These issues result in significant low-precision and biases in data mining for SAER.
Methods:
The Model-Driven Reporting Odds Ratio (MD-ROR) was proposed to bridge the gap between SAER database and explainable models for exploring individual and confounding effects. MD-ROR is grounded in a well-designed model, rather than a 2 × 2cross table, for estimating AE-drug signals. Consequently, individual and confounding effects can be parameterized based on these models. We employed simulation data and the FDA Adverse Event Reporting System (FAERS) database.
Result:
The simulated data indicated the subgroup effects estimated by MD-ROR were unbiased and efficient. Moreover, the adjusted-MD-ROR demonstrated greater robustness against confounding biases than the crude ROR. Applying our method to the FAERS database suggested higher occurrences of drug interactions and cardiac adverse events induced by Midazolam in females compared to males.
Conclusion:
The study underscored that MD-ROR holds promise as a method for investigating individual and confounding effects in SAER databases.
Over the past years, eosinophils have become a focus of scientific interest, especially in the context of their recently uncovered functions (e.g. antiviral, anti‐inflammatory, regulatory). These versatile cells display both beneficial and detrimental activities under various physiological and pathological conditions. Eosinophils are involved in the pathogenesis of many diseases which can be classified into primary (clonal) and secondary (reactive) disorders and idiopathic (hyper)eosinophilic syndromes. Depending on the biological specimen, the eosinophil count in different body compartments may serve as a biomarker reflecting the underlying pathophysiology and/or activity of distinct diseases and as a therapy‐driving (predictive) and monitoring tool. Personalized selection of an appropriate therapeutic strategy directly or indirectly targeting the increased number and/or activity of eosinophils should be based on the understanding of eosinophil homeostasis including their interactions with other immune and non‐immune cells within different body compartments. Hence, restoring as well as maintaining homeostasis within an individual's eosinophil pool is a goal of both specific and non‐specific eosinophil‐targeting therapies. Despite the overall favourable safety profile of the currently available anti‐eosinophil biologics, the effect of eosinophil depletion should be monitored from the perspective of possible unwanted consequences.
Background: Dupilumab is an effective treatment for atopic dermatitis (AD) and it also restores skin barrier function. Nevertheless, early changes in epidermal barrier parameters related to sustained treatment response or treatment failure are not known. So, the objective of this study is to evaluate whether changes in skin barrier function after 16 weeks dupilumab treatment could predict sustained treatment response or treatment failure. Materials and Methods: A prospective observational study was conducted that included patients with AD starting dupilumab. Clinical scores, patient-reported outcome measures (PROMs), and skin barrier function parameters were assessed at baseline and after 16 weeks treatment. Patients were followed until they failed to dupilumab or until the end of the study period. Participants were divided into 2 groups: patients with treatment failure and those with sustained treatment response. Results: In total, 32 patients with AD were included in the study, with a mean age of 28.03 years (standard deviation 10.65), being 20 (60.6%) females. In total, 22 (66.7%) patients sustained dupilumab response during the study period and only 10 (33.3%) failed to treatment. After 16 weeks treatment, clinical scores were improved in both groups. Patients with sustained treatment response increased stratum corneum hydration (SCH) on noninvolved skin (34.25 arbitrary units [AU] vs 44.90AU, P = 0.001) and on eczematous lesions (20.71 AU vs 40.94 AU, P < 0.001) and also decreased transepidermal water loss (TEWL) on eczematous lesions (28.22 g/[m2·h] vs 14.83 g/[m2·h], P = 0.002). Patients with treatment failure did not change TEWL or SCH. SCH after 16 weeks treatment on noninvolved skin (odds ratio [OR] = 0.83, P = 0.018) and SCH after 16 weeks treatment on eczematous lesions (OR = 0.86, P = 0.028) were related to dupilumab failure. Conclusion: SCH could be used as a predictive biomarker of dupilumab response in patients with AD.
Purpose of review:
Many systemic medications have been observed to cause ocular toxicity. A subset of these reactions is thought to involve immunomodulation or a hypersensitivity reaction. As new medications are developed, ocular adverse effects are becoming increasingly prevalent. Herein we review immune-mediated drug reactions affecting they eye with special attention to the hypersensitivity mechanisms leading to ocular toxicity.
Recent findings:
Recent work has focused on mechanisms and risk of immune-mediated ocular adverse drug reactions including genetic susceptibility and loss of ocular immune privilege.
Summary:
Given the consequences of immune-mediated ocular adverse drug reactions, clinicians must be aware of these to facilitate early recognition and management. The prompt involvement of an ophthalmologist for diagnosis and management is often essential to preserve vision and avoid long-term morbidity.
Background
Spontaneous Adverse Event Reporting (SAER) databases play a crucial part in post-marketed drug surveillance. The reported odds ratio (ROR) is commonly used to detect the significant signal of AE-drug combinations. However, the typical ROR may be biased by heterogeneity from individual factors such as gender and age. In addition, confounding biases render the typical ROR far from indicative of causality. Therefore, these issues urgently require solutions.
Methods
Model driven ROR (MD-ROR) was proposed as an alternative to typical ROR to explore individual and confounding effects in SAER databases. Unlike the traditional 2*2 cross table approach, our method employed Poisson regression with two-way interactions to estimate the MD-ROR, which was shown to be equivalent to typical ROR. Subsequently, we introduce the MD-ROR under three-way interaction to reveal the heterogeneity behind pooled crude ROR and to identify subgroup effects on the signals of AE-drugs. We also introduce adjusted MD-ROR to address confounding biases by flexibly defining confound effects in the model. To test our methods, the simulation data and FDA Adverse Event Reporting System (FAERS) database were both used.
Result
The simulated data suggested the subgroup effects estimated by MD-ROR were unbiased and efficient. Additionally, the adjusted MD-ROR was more robust against confounding biases than crude ROR. Application of our method to FAERS database showed differences in drug interaction and cardiac adverse events between males and females for Midazolam existed. In addition, the AE-drug combinations, Midazolam-septic shock and Midazolam-depression, were found overestimated potentially due to confounding biases from gender.
Conclusion
Our study highlighted that MD-ROR is a promising method for exploring individual and confounding effects in SAER databases. Our method provides a bridge between SAER databases and flexibly customized models.
Atopic dermatitis (AD) is a common chronic skin disease caused by immune dysfunction, specifically the hyperactivation of Th2. AD is a complex disease with multiple factors contributing to its development; however, the interaction between these factors is not fully understood. In this study, we demonstrated that the conditional deletion of both the forkhead box p3 (Foxp3) and B-cell lymphoma 6 (Bcl6) genes induced the spontaneous development of AD-like skin inflammation with hyperactivation of type 2 immunity, skin barrier dysfunction, and pruritus, which were not induced by the single deletion of each gene. Furthermore, the development of AD-like skin inflammation was largely dependent on IL-4/13 signaling but not on immunoglobulin E (IgE). Interestingly, we found that the loss of Bcl6 alone increased the expression of thymic stromal lymphopoietin (TSLP) and IL-33 in the skin, suggesting that Bcl6 controls Th2 responses by suppressing TSLP and IL-33 expression in epithelial cells. Our results suggest that Foxp3 and Bcl6 cooperatively suppress the pathogenesis of AD. Furthermore, these results revealed an unexpected role of Bcl6 in suppressing Th2 responses in the skin.
FDA approval of dupilumab for moderate-to-severe AD shifted the paradigm from use of broad, systemic immunosuppressants to a safer, targeted treatment and led to the emergence of newer interleukin (IL)-4/IL-13 directed biologics and small molecule therapies, namely Janus kinase (JAK) inhibitors. Tralokinumab and emerging (not yet approved) lebrikizumab, which both target IL-13, are alternative biologics to dupilumab. Emerging anti-IL-31 receptor nemolizumab is likely to be used second-line to other biologics, primarily for pruritus. Three JAK inhibitors are currently in use for treating AD, two of which, abrocitinib and upadacitinib, are FDA-approved. This review provides an in-depth, practical discussion on use of these biologics and JAK inhibitors that are approved or have completed phase 3 clinical trials in pediatric patients and adults, comparing the groups of medications based on available efficacy and safety data.
Dupilumab is a monoclonal antibody that is used for the treatment of atopic dermatitis (AD) in adults. However, increasing reports of ocular complications including conjunctivitis and dry eye disease have been documented. In this report, we describe a case of a patient who developed limbal stem cell deficiency (LSCD) after prolonged Dupilumab use. A 56-year-old Caucasian male with a history of AD presented with gradual onset cloudy vision and extensive diffuse symblepharon resulting from Dupilumab treatment. He was diagnosed with cicatrizing blepharoconjunctivitis and secondary LSCD after slit lamp examination. In conclusion, LSCD secondary to cicatricial disease is a severe adverse ocular complication caused from long-term Dupilumab treatment.
Cutaneous T cell lymphoma (CTCL) encompasses a group of low-grade, non-Hodgkin lymphoma including mycosis fungoides (MF) and Sézary syndrome. Diagnosis of CTCL can be challenging given the prolonged, gradual onset and shared characteristics with many benign inflammatory skin diseases. In this case series, we describe four unique cases of patients with chronic, recalcitrant eczematous dermatitis who presented for patch test consultation and were ultimately diagnosed with CTCL. In particular, we highlight clinical pearls to aid in distinguishing CTCL from inflammatory dermatoses and describe the diagnostic strategy to help dermatologists arrive at the diagnosis of CTCL at earlier stages of the disease.
Background
Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms.
Objectives
To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate‐to‐severe AD who had an inadequate response to topical treatments.
Methods
In two, 52‐week, randomized, double‐blind, placebo‐controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate‐to‐severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W), or placebo. Primary endpoints were IGA score of 0 or 1 at week 16 and EASI 75 at week 16. Patient achieving an IGA score of 0/1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks.
Results
At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0/1: 15·8% vs. 7·1% in ECZTRA 1 [difference (95% CI) 8·6% (4·1–13·1); P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 [11·1% (5·8–16·4); P < 0·001] and EASI 75: 25·0% vs. 12·7% [12·1% (6·5–17·7); P < 0·001] and 33·2% vs. 11·4% [21·6% (15·8–27·3); P < 0·001]. Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient‐Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab‐responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab and in 77·0% and 66·0% of patients receiving placebo in the 16‐week initial period.
Conclusions
Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.
Background
Children with severe atopic dermatitis (AD) have limited treatment options.
Objective
We report efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6–11 years with severe AD inadequately controlled with topical therapies.
Methods
In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300mg dupilumab every 4 weeks (300mg-q4w), a weight-based regimen of dupilumab every 2 weeks (100mg-q2w, baseline weight <30kg; 200mg-q2w, ≥30kg), or placebo; with concomitant medium-potency TCS.
Results
Both the q4w and q2w dupilumab+TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QoL) versus placebo+TCS in all prespecified endpoints. For q4w/q2w/placebo, 32.8%/29.5%/11.4% of patients achieved Investigator’s Global Assessment scores of 0/1; 69.7%/67.2%/26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%/58.3%/12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300mg-q4w in children <30kg and 200mg-q2w in children ≥30kg. Conjunctivitis and injection-site reactions were more common with dupilumab+TCS than placebo+TCS.
Limitations
Short-term 16-week treatment period; severe AD only.
Conclusion
Dupilumab+TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QoL.
Atopic dermatitis is a chronic inflammatory condition of the skin affecting a large number of people worldwide. Historically, this condition has been managed by topical corticosteroids and general skincare measures. The inadequacy of these management strategies has always driven efforts to find better drugs. Dupilumab has been recently approved for the management of atopic dermatitis. It is a human monoclonal antibody that inhibits the binding of key interleukins involved in the pathogenesis of atopic dermatitis, thus blocking the signaling mechanisms and disrupting the disease progression. Dupilumab reduces the severity and associated symptoms of atopic dermatitis. It improves the life quality of patients and reduces the anxiety associated with the disease. Combination therapy of dupilumab and topical corticosteroids is more effective than dupilumab monotherapy. The treatment-related adverse events include headache, injection site reaction, conjunctivitis, nasopharyngitis, and herpes viral infections. Moreover, the simultaneous use of live vaccines with dupilumab is contraindicated. It is also beneficial in the management of asthma, chronic rhinosinusitis, and eosinophilic esophagitis. In this review, we have discussed the clinical efficacy and safety profile of dupilumab in the management of atopic dermatitis.
Background: Dupilumab is a biologic approved for treating moderate-to-severe atopic
dermatitis (AD) with efficacy in reducing pruritus. Cutaneous T-cell lymphoma (CTCL)
may resemble AD and have severe, debilitating pruritus.
Objective: To assess the effects of dupilumab on the disease course of patients
diagnosed with CTCL.
Methods: Retrospective chart review of 7 patients who were treated with dupilumab
and diagnosed with CTCL following initial diagnosis of AD, or experienced rapid
progression of previously diagnosed CTCL.
Results: Seven patients (3 female; median age=65.5 years [range 40-77]) who
received dupilumab were identified. Dupilumab was initiated for clinically presumed AD
in four patients and used off-label in CTCL (stages IB-IIIB) with pruritus in three
patients (median duration=4 months [range 3-27]). Six of seven experienced initial
improvement (median duration=2 months [range 1-8]), followed by worsening body
surface area (n=7), pruritus (n=5), lymphadenopathy (n=3), and systemic symptoms
(n=3). The four patients with clinically presumed AD were diagnosed with CTCL/MF.
The three patients with existing CTCL prior to dupilumab developed worsened blood
involvement on flow cytometry and were diagnosed with Sézary syndrome while on
treatment. Two of the three died of disease progression.
Limitations: Low number of cases.
Conclusion: Dupilumab should be avoided in patients with CTCL.
Dupilumab, a monoclonal antibody that inhibits both interleukin (IL)-4 and IL-13 signaling, is an effective treatment option in moderate-to-severe atopic dermatitis (AD). Patients with AD are already at increased risk of developing conjunctivitis, and clinical trials and case reports have shown a greater incidence of conjunctivitis in individuals with AD treated with dupilumab. As this is one of the more commonly reported side effects of this biologic agent, it is important that clinicians are aware of this association and advise patients receiving dupilumab to report signs of conjunctivitis. This review summarizes the risk factors, clinical features, and management options for patients with AD presenting with conjunctivitis after receiving dupilumab therapy.
Background:
The mechanisms underlying eye-related complications with dupilumab are poorly understood.
Objective:
This study aimed to determine the incidence and characteristics of ocular complications with dupilumab and the prevalence of comorbid allergic contact dermatitis in the same subpopulation.
Methods:
This is a retrospective chart review of 48 patients with atopic dermatitis who received dupilumab. For patients with eye involvement at first follow-up, we discuss the presence of eyelid dermatitis, blepharitis, or conjunctivitis and analyze available patch test findings in patients with ocular complications while treated with dupilumab.
Results:
A total of 14 patients (29.2%) showed eye involvement while on dupilumab, all of whom experienced eye involvement prior to dupilumab. The results of the patch test were most commonly positive for emulsifier/surfactants (42.5%) and fragrances (30.4%). Nine patients experienced improvement with allergen avoidance subsequent to patch testing, and four of nine patients' conditions cleared almost entirely. This is a non-randomized study in a small cohort of patients. Only 18 patients had their disease confirmed by an ophthalmologist.
Conclusion:
All patients with eye involvement while on dupilumab had a history of eye involvement prior to dupilumab, suggest that dupilumab may encourage rather than cause ocular surface inflammation. Significant improvement after patch testing in nearly half of patients suggests that allergic contact dermatitis contributes to some cases of dupilumab-associated eye complications.
Importance
Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population.
Objective
To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD.
Design, Setting, and Participants
A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included.
Interventions
Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85).
Main Outcomes and Measures
Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator’s Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.
Results
A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%).
Conclusions and Relevance
In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults.
Trial Registration
ClinicalTrials.gov identifier: NCT03054428
Background:
Dupilumab (monoclonal antibody blocking the shared receptor subunit for IL-4 and IL-13) is approved for patients aged ≥12 years with inadequately controlled, moderate-to-severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate-to-severe AD inadequately controlled with topical medications.
Objective:
To further characterise the safety of dupilumab by evaluating clinical laboratory findings from three randomised, double-blinded, placebo-controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS).
Methods:
Patients were randomised 1:1:1 (SOLO 1 & 2) or 3:1:3 (CHRONOS) for 16 and 52 weeks, respectively, to dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardised concomitant topical corticosteroid regimen. Laboratory outcomes were summarised descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS.
Results:
Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in dupilumab vs. placebo groups. Some dupilumab-treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of dupilumab-treated and placebo-treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters.
Conclusions:
There were no clinically important changes in routine laboratory parameters that could be attributed to dupilumab. This study supports use of dupilumab as a systemic treatment for moderate-to-severe AD that does not require laboratory monitoring. This article is protected by copyright. All rights reserved.
Background
Conjunctivitis is common in patients with atopic dermatitis (AD) in general and a commonly reported adverse event in AD clinical trials with dupilumab.
Objective
To survey opinions and experience about conjunctivitis occurring in AD, including those during dupilumab treatment in a group of AD experts from the International Eczema Council (IEC).
Methods
Electronic survey and in‐person discussion of management strategies.
Results
Forty‐six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new‐onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist.
Limitations
The study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey.
Conclusion
The IEC recommends that dermatologists address conjunctivitis in patients with AD, especially during treatment with dupilumab.
Dupilumab (Dupixent®, Sanofi), a fully human monoclonal antibody that blocks interleukin (IL)‐4 and IL‐13 signaling, is the first biologic approved in the UK for adult patients with moderate‐to‐severe atopic dermatitis (AD). In phase III studies, dupilumab was an effective treatment with 44–51% of patients achieving at least 75% improvement in Eczema Area and Severity Index (EASI).1–2 To date, dupilumab has been well tolerated; common adverse reactions reported from phase III data include injection‐site reactions (8–19%), allergic conjunctivitis (3–19%) and oral herpes (2–5%).
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Background
Two phase 3 trials with identical design, LIBERTY AD SOLO 1 (NCT02277743) and LIBERTY AD SOLO 2 (NCT02277769), confirmed dupilumab efficacy and safety versus placebo in adults with moderate-to-severe atopic dermatitis (AD).
Objectives
To report a pooled analysis of these trials to further explore dupilumab’s effects on AD clinical parameters, patient-reported outcomes (PROs), symptoms of anxiety/depression, health-related quality of life (HRQoL), and safety.
Methods
A pooled analysis of two 16-week phase 3 studies in adults with moderate-to-severe AD (N = 1379) inadequately controlled with/inadvisable for topical medications, randomized to dupilumab 300 mg once weekly (qw), every 2 weeks (q2w), or placebo.
Results
Dupilumab significantly improved all pre-specified efficacy endpoints versus placebo (P < 0.0001), including clinical severity outcomes and PROs, symptoms of anxiety/depression, and HRQoL, consistent with previously published results. In post-hoc analyses, among patients reporting at least some baseline pain/discomfort on the EuroQoL-5D, no pain/discomfort at Week 16 was reported by 43%/46%/14% of dupilumab qw/q2w/placebo-treated patients (P < 0.0001). The distribution of dupilumab-treated patients within pre-defined score categories on the Investigator’s Global Assessment (0–1/2/3/4) and Eczema Area and Severity Index (≥90%/≥75–<90%/≥50–<75%/<50%) steadily and consistently improved over time versus marginal changes with placebo. Dupilumab significantly improved pruritus within 1–3 days of treatment initiation. No new safety signals were observed. Injection-site reactions and conjunctivitis were more common with dupilumab; AD exacerbation and non-herpetic skin infections more frequent with placebo.
Conclusions
Dupilumab versus placebo significantly improved objective AD signs, subjective PROs, symptoms of anxiety/depression, and HRQoL, with a favorable benefit-risk profile in adults with moderate-to-severe AD.
Background
Dupilumab, which blocks the shared receptor component for interleukin (IL)‐4 and IL‐13, is approved for inadequately‐controlled moderate‐to‐severe atopic dermatitis (AD) and moderate‐to‐severe eosinophilic or oral corticosteroid‐dependent asthma. AD trials reported increased conjunctivitis incidence for dupilumab vs. placebo.
Objectives
To further characterise conjunctivitis occurrence and risk factors in dupilumab clinical trials.
Methods We evaluated randomised placebo‐controlled trials of dupilumab in AD (n=2629), asthma (n=2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n=60), and eosinophilic esophagitis (EoE) (n=47).
Results
In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous conjunctivitis history were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered/resolved during the treatment period; 2 patients permanently discontinued dupilumab due to conjunctivitis/keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and anti‐histamines/mast cell stabilisers. Most cases were diagnosed by investigators. In asthma and CRSwNP trials, conjunctivitis incidence was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase incidence vs. placebo. In the EoE trial, no patients had conjunctivitis.
Conclusions
Conjunctivitis 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, conjunctivitis incidence was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study.
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Purpose
Generalized dermatitis (defined as histological spongiotic dermatitis affecting more than three anatomical areas of the skin surface) has many potential causes that mimic atopic dermatitis and contact dermatitis. If a treatable cause is missed, the patient may be treated with chronic immunosuppressive therapy that carries more risk than specific treatment for a disease mimicking dermatitis. Checklists have been shown to improve patient safety, primarily in procedural contexts. This work assessed the utility of a diagnostic checklist for subacute and chronic generalized dermatitis in patients who had not improved after at least 1 month of avoidance of contact allergens identified by comprehensive patch testing, if indicated.
Patients and methods
Designed as a quality improvement project using Standards for Quality Improvement Reporting Excellence (SQUIRE) guidelines, a diagnostic checklist was used by the principal investigator for 1 year in a tertiary referral dermatitis clinic for patients without a confirmed cause for the dermatitis after two to three visits with the investigator. All patients had had diagnostic patch testing if indicated. Almost all had undergone skin biopsy by their referring provider. Fifteen patients met the criteria for inclusion in this study. Outcome measures included provider and patient perception of efficiency and/or confusion caused by the checklist. Length of time from the initiation of use of the checklist to final diagnosis was recorded. Additional diagnoses considered that were not included in the initial checklist were added to the checklist during the course of the study.
Results
The checklist was useful in improving diagnostic efficiency (prompting consideration of diagnoses not otherwise considered upon initiation of the visit that resulted in a final plan of care) in these complex cases of recalcitrant dermatitis. Open utilization of the checklist by the investigator during the clinical encounter was well accepted by patients and families.
Conclusion
Checklists can be useful for complex cognitive diagnostic work.
IRB approval status
University Hospitals Cleveland Medical Center Institutional Review Board # 11-15-34.
In the eye, goblet cells responsible for secreting mucins are found in the conjunctiva. When mucin production is not tightly regulated several ocular surface disorders may occur. In this study, the effect of the T helper (Th) 2-type cytokines IL4, IL5, and IL13 on conjunctival goblet cell function was explored. Goblet cells from rat conjunctiva were cultured and characterized. The presence of cytokine receptors was confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Changes in intracellular [Ca2+], high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with Th2 cytokines with or without the allergic mediator histamine. We found that IL4 and IL13 enhance cell proliferation and, along with histamine, stimulate goblet cell secretion. We conclude that the high levels of IL4, IL5, and IL13 that characterize allergic conjunctivitis could be the reason for higher numbers of goblet cells and mucin overproduction found in this condition.
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.
Background:
Atopic dermatitis (AD) is a chronic inflammatory skin disease that may require systemic therapy. Ciclosporin A (CsA) is a widely-used, potent immunosuppressant for AD. CsA is not effective in all patients, and side effects limit its use. Dupilumab, a fully human anti-interleukin (IL)-4 receptor-alpha monoclonal antibody, inhibits signaling of IL-4 and IL-13, key drivers of type 2/Th2-mediated inflammation, and is approved in the U.S.A. and the E.U. for the treatment of adults with moderate-to-severe AD.
Objectives:
To evaluate efficacy and safety of dupilumab with concomitant topical corticosteroids (TCS) in adults with AD with inadequate response to/intolerance of CsA, or for whom CsA was medically inadvisable.
Methods:
In this 16-week, double-blind, randomized, placebo-controlled, phase 3 trial, patients were randomized 1:1:1 to subcutaneous dupilumab 300 mg weekly (qw):every two weeks (q2w):placebo. All received concomitant medium-potency TCS from Week -2 through Week 16; dosage could be tapered if lesions cleared, or stopped for adverse reactions to TCS.
Results:
390 patients were screened; 325 were randomized and 318 completed the trial. Treatment groups had similar baseline characteristics. Significantly more patients on dupilumab qw+TCS/q2w+TCS achieved ≥75% improvement from baseline in Eczema Area and Severity Index at Week 16 vs placebo+TCS (primary endpoint) (59.1%/62.6% vs 29.6%; P<0.0001 vs placebo+TCS, both doses). Dupilumab qw+TCS/q2w+TCS significantly improved other clinical outcomes and AD symptoms, including pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and quality of life (QOL). Treatment groups had similar overall rates of adverse events (69.1%/72.0%/69.4%; qw+TCS/q2w+TCS/placebo+TCS) and serious adverse events (1.8%/1.9%/1.9%). Conjunctivitis was more frequent with dupilumab+TCS; skin infections were more frequent with placebo+TCS.
Conclusions:
Dupilumab+TCS significantly improved signs and symptoms of AD and QOL in adults with history of inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable. No new safety signals were identified. This article is protected by copyright. All rights reserved.
Background:
Since the best clinical response to dupilumab is achieved after 12-16 weeks, a combination therapy at the beginning of the treatment could be a helpful strategy to reach a faster response in patients with severe atopic dermatitis (AD).
Objectives:
To quantify the benefit of a combination of dupilumab treatment with a short course of narrow-band ultraviolet B (NB-UVB) phototherapy.
Methods:
In the present pilot study adult patients suffering from severe AD were enrolled with a 2:1 ratio to receive treatment with dupilumab alone or dupilumab plus NB-UVB phototherapy, for 12 weeks. After the twelfth week, all patients received dupilumab only. A follow-up visit took place after 16 weeks. Both clinician-oriented and patient-oriented scores were assessed at baseline (T0) and after 4 (T1), 12 (T2) and 16 (T3) weeks.
Results:
Forty-five adult patients were enrolled in the study. Both treatment regimens were well tolerated and very effective on all measured scores (EASI, SCORAD, BSA, NRS of itching, NRS of sleep loss, DLQI, POEM and HADS), but the combined regimen led to a more robust clinical improvement of lesions and relief of symptoms after 4 weeks. However, after 12 and 16 weeks, the additional therapeutic effect of phototherapy weakened.
Conclusion:
NB-UVB phototherapy can provide a faster remission of severe AD in the first few weeks of dupilumab therapy.
Background
Antibody-based therapies that inhibit pro-inflammatory cytokine signaling are commonly used in dermatology. Paradoxically, these medications may induce or exacerbate inflammatory disorders.
Objective
To summarize the spectrum of manifestations, incidence, timing, potential mechanisms, and general management approaches to paradoxical cutaneous reactions induced by cytokine-targeted antibodies in dermatology.
Methods
We performed a systematic review and analysis of published cases of cutaneous paradoxical reactions reported in association with TNF-α, IL-12/23 (p40), IL-17A/17R, IL-23 (p19), and IL-4Rα inhibitors.
Results
We identified 313 articles reporting 2049 cases of paradoxical reactions. TNF-α inhibitors resulted in 91.2% (1869/2049) of all cases, followed by IL-17/17R (3.5%), IL-4Rα (2.7%), IL-12/23 (2.4%), and IL-23 (0.01%) inhibitors. Psoriasiform and eczematous eruptions were the most commonly reported, but a wide spectrum of patterns are described. Phenotypically overlapping reaction patterns were common. Time to onset typically ranges from weeks to months, but can occur up to 1-2 years later. Improvement or resolution upon discontinuation of the inciting drug is common.
Limitations
This is a retrospective analysis.
Conclusions
Dermatologists should be familiar with the clinical features of paradoxical reactions from cytokine blocking antibodies to facilitate efficient recognition and management.
Background
Dupilumab, the first biological drug to be approved for the treatment of moderate-to-severe atopic dermatitis (AD) in adolescents and adults has shown good efficacy and safety in clinical trials.
Objective
To evaluate real-world data on the efficacy and safety of dupilumab in AD.
Methods
Pubmed and Embase were searched for observational studies with data on efficacy, drug survival and safety of dupilumab for the treatment of AD. Primary outcomes were mean percentage change in Eczema Area and Severity Index (EASI), and proportion of AD patients achieving 50%, 75% and 90% improvement in EASI (EASI-50, 75 and 90) following dupilumab therapy.
Results
22 unique studies encompassing 3,303 AD patients were included. After 16 weeks of dupilumab therapy, the pooled proportion of patients achieving EASI-50, EASI-75 and EASI-90 was 85.1%, 59.8% and 26.8%, and the weighted mean reduction in EASI was 69.6%. Conjunctivitis was the most common adverse event, reported in a pooled proportion of 26.1%.
Limitations
Limited data in terms of size and follow-up time was available.
Conclusion
Real-world data show that dupilumab is a successful and well-tolerated therapy for AD, but ocular adverse events commonly occur. Registries are needed to monitor for adverse events.
Dupilumab is a fully humanized Immunoglobulin‐(Ig)‐G4 antibody against the interleukin (IL)‐4α subunit of the IL‐4‐ and the IL‐13‐receptor.1 In patients with atopic eczema (AE), most frequent adverse reactions include injection site reactions and conjunctivitis/blepharitis.1,2 Recently, a case with suspicion of an IgE‐mediated hypersensitivity was reported.3 We herein report upon a patient who developed serum sickness like reaction (SSLR) under therapy with dupilumab.
Purpose
This study was performed to investigate the effects of interleukin (IL)-4 on adipogenesis and the underlying molecular mechanisms in human meibomian gland epithelial cells (HMGECs).
Methods
HMGECs and human white preadipocytes (HWPs) were cultured and differentiated with or without IL-4. Oil-red O staining, Adipored assay, and LipidTox immunostaining were performed to examine the extent of lipid droplet formation. The expression of signal transducer and activator of transcription 6 (STAT6), phospho-STAT6, peroxisome proliferator activator receptor (PPAR)γ, and sterol regulatory element-binding protein (SREBP)-1 was measured through immunoblotting. Cells were treated with STAT6 inhibitor, which prevents the phosphorylation of STAT6 by IL-4, to determine whether the effects of IL-4 on lipogenesis were altered.
Results
Treatment with IL-4 significantly facilitated lipid production in differentiated HMGECs. Phosphorylation of STAT6 and expression of key adipogenesis-related molecules PPARγ and SREBP-1 were increased after IL-4 treatment. Inhibition of STAT6 phosphorylation suppressed IL-4-mediated lipid synthesis in HMGECs. In contrast, the lipid synthetic effects of IL-4 were not observed in differentiated HWPs.
Conclusions
IL-4 appears to promote lipid synthesis in meibomian gland epithelial cells through the STAT6/PPARγ signaling pathway. This mechanism can serve as a potential therapeutic target for meibomian gland dysfunction.
Atopic dermatitis (AD) is a chronic, multifactorial, inflammatory skin disease which can have a negative impact on the quality of life (QoL). The moderate‐to‐severe forms frequently require systemic treatment. Dupilumab is a human monoclonal antibody directed against the alpha subunit of the IL‐4 receptor. It has been the first biologic drug that approved for the treatment of moderate to severe AD.
In this case series, the authors report three patients with severe atopic dermatitis who presented with epiphora and conjunctivitis while undergoing dupilumab therapy. On clinical examination, all patients were found to have punctal stenosis, with one case having progressed to punctal obstruction. An assortment of strategies was elected, including discontinuation of dupilumab, treatment of conjunctivitis, and surgical intervention with probing, punctoplasty, and silicone intubation. This report spotlights punctal stenosis as an important new side effect of dupilumab and suggests that additional cases of dupilumab-associated lacrimal drainage impairment will continue to emerge.
Background:
It is unclear whether the Th2-specific immunosuppressive action of dupilumab interferes with patch testing.
Objectives:
Evaluate the reliability of patch testing on dupilumab and the contribution of allergic contact dermatitis (ACD) to complex dermatitis in patients with residual dermatitis on dupilumab.
Methods:
This is a retrospective chart review of 48 patients with atopic dermatitis (AD) treated with dupilumab. We compare results of patch tests performed before and after initiation of dupilumab and the prevalence of comorbid ACD in patch tested individuals.
Results:
A minority of patch test reactions were "lost" on dupilumab (13/125 or 10.4%). 5 of 13 lost reaction occurred in individuals with documented immunodeficiency. 32 of 35 patch tested patients (91.4%) had comorbid ACD; 92.3% of individuals patch tested on dupilumab experienced further clinical improvement with allergen avoidance.
Limitations:
This is a non-randomized study in a small cohort of patients. Clearance of dupilumab was assessed by subjective patient reports.
Conclusions:
Dupilumab does not appear to exert a dampening effect on patch test results. AD with comorbid ACD was highly prevalent and allergen avoidance resulted in significant improvement in residual dermatitis that had not resolved with not dupilumab therapy.
Dupilumab is the first biologic registered for the treatment of atopic dermatitis (AD). We report a case of an acute onset monoarthritis of the ankle and generalized polyarthralgia in a 38‐year‐old female AD patient, shortly after starting dupilumab. Methotrexate therapy for AD was discontinued one week before start of dupilumab treatment because of decreasing effectiveness. Four weeks after starting dupilumab our patient reported improvement of her eczema. However, she also reported severe joint pain and morning stiffness in one ankle which gradually spread to her knees, hips and elbows. This article is protected by copyright. All rights reserved.
Dupilumab targets the interleukin-4 receptor (IL-4Rα) and is used for moderate-to-severe atopic dermatitis (AD). Some patients treated with this therapy develop new regional dermatoses (NRDs),¹⁻³ of which the etiopathogenesis and prevalence are unclear. We conducted a retrospective cohort study to describe the epidemiology, clinical features, and treatment of patients with AD developing NRDs while being treated with dupilumab.
Background:
Previous case reports and series suggested that dupilumab may be an effective treatment for allergic contact dermatitis (ACD). Little is known about the impact of dupilumab on patch test results and comorbid ACD in patients with atopic dermatitis (AD).
Objective:
Determine the impact of dupilumab on patch testing results and improvement of ACD in patients with AD.
Methods:
A retrospective study of patients with AD treated with dupilumab who underwent patch testing (n = 7) or had concomitant ACD (n = 6).
Results:
In all, 7 patients with AD were patch tested while taking dupilumab; in all of these patients, at least 1 positive patch test reaction was observed, with a total of 25 different allergens having a reaction graded as 1+ or stronger and few irritant reactions. In 1 patient, multiple previously positive relevant patch test results were not duplicated upon repeat patch testing. In the 6 patients with AD and concomitant ACD, dupilumab and allergen avoidance resulted in substantial or complete resolution of AD signs and symptoms but resolution of ACD in only 3 patients. However, 3 patients had at least 1 flare of ACD upon re-exposure to relevant allergens.
Limitations:
Retrospective and uncontrolled study.
Conclusions:
Dupilumab had variable impact on patch testing results and resolution of comorbid ACD in adult patients with AD.
Dupilumab is a fully human monoclonal IgG4 antibody directed against the alpha subunit of the IL-4 receptor and prevents the signaling of IL-4 and IL-13, two type 2 cytokines known to be important drivers of atopic diseases. In March of 2017, the United States Food and Drug Administration (FDA) approved dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults that is uncontrolled with topical medications, becoming the first biologic agent approved to treat this chronic skin condition. In October of 2018, Dupilumab received approval by the FDA as an add-on maintenance therapy in patients with moderate-to-severe asthma aged 12 years or older with an eosinophilic phenotype or with oral corticosteroid-dependent asthma. This review summarizes the characteristics of dupilumab and the clinical research that has been published to date, including treatment efficacy and adverse events.
Importance
Clinical trials of dupilumab for atopic dermatitis (AD) have reported an increased incidence of conjunctivitis in patients who received dupilumab compared with those who received placebo.
Objective
To describe the characteristics of patients who develop conjunctivitis secondary to dupilumab treatment for AD.
Design, Setting, and Participants
Case series of 12 patients who reported development of conjunctivitis from a cohort of 142 patients treated with dupilumab for AD at a secondary care center from March 14, 2017, to March 29, 2018.
Exposures
Patients received a 600-mg injection of dupilumab as a loading dose and a 300-mg injection every 2 weeks thereafter.
Main Outcomes and Measures
Primary outcome measures were severity of AD as measured by the Investigator Global Assessment (IGA) score, a 5-point scale from 0 (clear) to 4 (severe), at the time of dupilumab initiation and at conjunctivitis onset.
Results
Of the 12 patients included in this series, 7 (58%) were male. The mean (SD) age of patients was 30 (8.1) years at the time conjunctivitis developed. All patients showed improvement of their AD at the time of conjunctivitis diagnosis, with a mean (SD) 1.9 (0.8)–point decrease in IGA score and 47.8% (11.2%) decrease in body surface area affected. Nine of the 12 patients (75%) had severe baseline AD with an IGA score of 4. All patients who discontinued treatment had severe AD at the time of initial dupilumab administration and had at least 1 atopic condition in addition to AD.
Conclusions and Relevance
Conjunctivitis that develops after administration of dupilumab to treat AD may be severe enough to necessitate stopping therapy. Severe conjunctivitis was more likely to develop in patients with more severe baseline AD who had a good response to dupilumab and an increased atopic phenotype. Studies are needed to confirm risk factors associated with development of conjunctivitis and to determine effective treatment.
