The New Era of Biologics in Atopic Dermatitis: A Review.
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ABSTRACT:
SUBMITTER: Schneider S
PROVIDER: S-EPMC8648434 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease driven by immune dysregulation and skin barrier dysfunction. We are currently experiencing a new era of understanding of the pathogenesis of AD and, as a consequence, a new era of innovation in therapeutics, including small molecules and biologic therapy. Recently, advances in translational research have challenged the traditional AD pathogenesis paradigm of AD being solely a Th2-dominant disease. Other immune pathways seem to play a role in the complex AD pathophysiology, although the clinical relevance of these additional immune pathway abnormalities is unclear. Type 1, type 22, and type 17 pathway activation (with related cytokines/chemokines) have been demonstrated in the skin and blood of AD patients. Type 2 (interleukin [IL]-4, IL-13), IL-31, and type 22 (IL-22) pathway cytokines are increased in AD acute lesions. IL-22 induces both an epidermal hyperplasia at the onset of acute AD and a marked increase in the terminal differentiation S100 genes. This understanding of pathogenesis corresponds to a historic increase in therapeutic development in AD. The extreme clinical heterogeneity and the chronic progression of AD establish the need for newer, safer, and more effective treatments, control the disease, and improve the quality of life of affected patients.
| S-EPMC7875213 | biostudies-literature
Project description:The era of biologics for the treatment of moderate-to-severe atopic dermatitis (AD) began in 2017 with the approval of dupilumab, a monoclonal antibody that binds to the α-subunit of the interleukin IL-4 receptor. Until then, only conventional immunosuppressants were available for systemic treatment, of which only cyclosporine is approved for the treatment of severe AD. In the meantime, the therapeutic landscape of AD has been changing rapidly, and additional biologics have been developed which target IL-13, the IL-31 receptor, OX40, and OX40L, among others. Many of these substances have already shown promising results in phase 1, 2, and in some cases also phase 3 trials. In June 2021, tralokinumab, an IL-13 antibody, has been approved in Europe for the treatment of moderate-to-severe AD in adults. In addition to antibody-based therapies, "small molecules" that, e.g., inhibit Janus kinases enrich the armamentarium of systemic AD therapies. With all these agents, not only will many more targeted therapies become available, but also will the complex and heterogeneous pathophysiological processes of this disease be better understood.
| S-EPMC8439107 | biostudies-literature
Project description:Atopic dermatitis (AD) is a chronic, inflammatory skin disease with an eczematous rash and itching. Due to undesired adverse effects of traditional systemic treatment, there is still an unmet need for safe and effective long-term therapy for refractory AD. As our understanding of the pathogenesis underlying AD grows, novel treatments targeting specific molecules have been developed. Here, we discuss the efficacy and safety profiles of these drugs in recent clinical trials. Among their adverse effects, of particular note is AD acceleration. Although there is still debate about whether certain adverse reactions can be said to be paradoxical adverse events (PAEs), a wide range of PAEs have been reported during biological treatment for chronic immune-mediated diseases. Close surveillance of novel biologics is crucial to detect new undescribed paradoxical reactions and to shed light on the convoluted pathogenesis of AD.
| S-EPMC8181104 | biostudies-literature
Project description:Atopic dermatitis (AD) is a chronic, systemic, inflammatory disease that affects the skin and is characterized by persistent itch and marked redness. AD is associated with an increased risk of skin infections and a reduced quality of life. Most AD treatment options to date were not designed to selectively target disease-causing pathways that have been established for this indication. Topical therapies have limited efficacy in moderate-to-severe disease, and systemic agents such as corticosteroids and immunosuppressants present with tolerability issues. Advances in the understanding of AD pathobiology have made possible a new generation of more disease-specific AD therapies. AD is characterized by the inappropriate activation of type 2 T helper (Th2) cells and type 2 innate lymphoid (ILC2) cells, with a predominant increase in type 2 cytokines in the skin, including interleukin (IL)-13 and IL-4. Both cytokines are implicated in tissue inflammation and epidermal barrier dysfunction, and monoclonal antibodies targeting each of these interleukins or their receptors are in clinical development in AD. In March 2017, dupilumab, a human anti-IL-4R? antibody, became the first biologic to receive approval in the United States for the treatment of moderate-to-severe AD. The anti-IL-13 monoclonal antibodies lebrikizumab and tralokinumab, which bind different IL-13 epitopes with potentially different effects, are currently in advanced-stage trials. Here, we briefly review the underlying pathobiology of AD, the scientific basis for current AD targets, and summarize current clinical studies of these agents, including new research to develop both predictive and response biomarkers to further advance AD therapy in the era of precision medicine.
| S-EPMC6850480 | biostudies-literature
Project description:Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease driven by immune dysregulation and skin barrier dysfunction. Currently, we are experiencing a new era of understanding of the pathogenesis of AD and, as a consequence, a new era of innovation in therapeutics, including small molecules and biologic therapy. In contrast to biologics, small molecules are similar to conventional pharmacologic chemical agents used as drugs and are generally prepared by chemical synthesis. Unlike biologics, these drugs often are taken orally or formulated for topical use. The purpose of this review is to summarize the efficacy and safety of the current topical and systemic new therapies in AD by reviewing recently published papers on therapies currently in phase 2 or 3 clinical trials. In this review, it is important to note the characteristics of the study population, the primary endpoints, and whether or not there was concomitant topical therapy allowed. These study design elements may significantly alter the results of studies and should be taken into account. Targeted therapy help push AD treatment into a new era of personalized medicine.
| S-EPMC8082001 | biostudies-literature
Project description:Genomic imprinting is a genetic process where only one allele of a particular gene is expressed in a parent-of-origin dependent manner. Epigenetic changes in the DNA, such as methylation or acetylation of histones, are primarily thought to be responsible for silencing of the imprinted allele. Recently, global CpG methylation changes have been identified in psoriatic skin in comparison to normal skin, particularly near genes known to be upregulated in psoriasis such as KYNU, OAS2, and SERPINB3. Furthermore, imprinting has been associated with multi-chromosomal human disease, including diabetes and multiple sclerosis. This paper is the first to review the clinical and genetic evidence that exists in the literature for the association between imprinting and general skin disorders, including atopic dermatitis and psoriatic disease. Atopy was found to have evidence of imprinting on chromosomes 6, 11, 14, and 13. The ? subunit of the IgE receptor on chromosome 11q12-13 may be imprinted. Psoriatic disease may be related to imprinting effects on chromosome 6 for psoriasis and 16 for psoriatic arthritis.
| S-EPMC4679559 | biostudies-other
Project description:Atopic dermatitis (AD) is among the most frequent inflammatory skin diseases in humans, affecting up to 20% of children and 10% of adults in higher income countries. Chronic pruritus is a disease-defining symptom of AD, representing the most burdensome symptom for patients. Severe chronic pruritus causes significant sleep disturbances and impaired quality of life, as well as increased anxiety, depression and suicidal behavior. Until recently, skin care, topical corticosteroids, and calcineurin-inhibitors were primarily used to treat mild to moderate AD, while phototherapy and immunosuppressive agents such as corticosteroids, cyclosporine, and methotrexate were used to treat patients with moderate to severe AD. The potential short- and long-term adverse events associated with these treatments or their insufficient therapeutic efficacy limited their use in controlling pruritus and eczema in AD patients over longer periods of time. As our understanding of AD pathophysiology has improved and new systemic and topical treatments have appeared on the market, targeting specific cytokines, receptors, or their intracellular signaling, a new era in atopic dermatitis and pruritus therapy has begun. This review highlights new developments in AD treatment, placing a specific focus on their anti-pruritic effects.
| S-EPMC8137993 | biostudies-literature
Project description:Atopic dermatitis (AD) is a chronic inflammatory skin condition that can have tremendous impact on quality of life for affected children and adults. First-line therapy for acute management of AD includes topical therapies such as corticosteroids, calcineurin inhibitors, and, more recently, the phosphodiesterase inhibitor crisaborole. Topical agents have remained the mainstay therapy for decades; however, there has been a longstanding need for topical therapies with high efficacy and low risk of adverse effects with long-term use. Given the ongoing advances in understanding the pathogenesis of AD, there are novel targets for pharmacological intervention. We are now in an unprecedented time with more than 40 topical treatments in the pipeline for AD in addition to many developments and treatments on the horizon. This review summarizes selected therapeutic topical agents in later phases of development that target various aspects in the pathogenesis of AD such as Janus kinase inhibition (ruxolitinib and delgocitinib), phosphodiesterase-4 inhibition (roflumilast and difamilast), aryl hydrocarbon modulation (tapinarof), and modulation of the microbiome. We also review novel targeted therapies that are in early phase clinical trials, including AMTX-100, BEN-2293, and PRN473. Preliminary findings on efficacy and tolerability of most of these agents are promising, but further studies are warranted to evaluate the long-term safety and efficacy of these novel agents against the current standard of care.
| S-EPMC9464760 | biostudies-literature
Project description:The lack of standardized nomenclature for atopic dermatitis (AD) creates unnecessary confusion for patients, healthcare providers, and researchers. It also negatively impacts accurate communication of research in the scientific literature. We sought to determine the most commonly used terms for AD.A systematic review of the MEDLINE, EMBASE, and LILACS (1945-2016) for the terms AD, atopic eczema (AE), and multiple other eczematous disorders.In MEDLINE, 33 060 were identified, of which 21 299 (64.4%) publications used the term 'AD', 15 510 (46.9%) 'eczema', and only 2471 (7.5%) AE. Most of these publications used the term AD (82.0%) or eczema (70.8%) without additional nomenclature; only 1.2% used AE alone. Few publications used the terminology 'childhood eczema', 'flexural eczema', 'infantile eczema', 'atopic neurodermatitis', or 'Besnier's prurigo'. AD was rarely used until the late 1970s, after which it became the most commonly used of the three terms and continuously increased until 2015. Atopic eczema decreased between 2008 and 2015. Atopic dermatitis was the most commonly used term in studies across almost all publication types, languages, and journals.Atopic dermatitis is the most commonly used term and appears to be increasing in popularity. Given that eczema is a nonspecific term that describes the morphological appearance of several forms of dermatitis, we strongly suggest the use of a more specific term, AD, in publications, healthcare clinician training, and patient education. Support from researchers, reviewers, and editors is key to success.
| S-EPMC5228598 | biostudies-literature
Project description:Atopic dermatitis (AD) is a prevalent inflammatory skin condition that, depending on its severity, can cause enormous morbidity. Corticosteroids and systemic immunosuppression, traditionally standard of care for difficult-to-treat disease, have many undesirable side effects. The desire for targeted treatments along with an improved understanding of the pathophysiology of AD has spurred the development of novel treatments. In this article, we review promising new treatments and discuss how their targets-IL-13, IL-31, OX40 (CD134), and the Janus kinase family of proteins-participate in the pathogenesis of AD. We review the published phase II and III data for dupilumab, tralokinumab, lebrikizumab, nemolizumab, anti-OX40 antibody, baricitinib, abrocitinib, and upadacitinib. The introduction of new agents may offer new options, but it remains to be seen how narrow-acting agents, like single interleukin inhibitors, will compare in safety and efficacy to broad-acting agents such as JAK inhibitors.
| S-EPMC7281689 | biostudies-literature