Management of Patients With Allergic Diseases in the Era of Biologics

Abstract

Biologics are increasingly becoming the treatment of choice for allergic diseases that are unresponsive to standard treatments, such as chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, allergic rhinitis (AR), atopic dermatitis (AD), and prurigo nodularis [1-3]. Key biologics targeting type 2 (T2) inflammation include dupilumab and stapokibart, both of which block interleukin 4 receptor alpha (IL-4Rα) at distinct binding epitopes. Omalizumab targets immunoglobulin E (IgE) and mepolizumab, reslizumab, and benralizumab neutralize IL-5 and IL-5 receptor alpha, respectively. In China, dupilumab, stapokibart, and mepolizumab have received regulatory approval for CRSwNP, while asthma patients have multiple treatment options, including omalizumab, dupilumab, stapokibart, mepolizumab, and benralizumab. For AD, available biologics include dupilumab, stapokibart, tralokinumab, lebrikizumab, and Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, and baricitinib). However, the Chinese National Medical Products Administration has specifically authorized only dupilumab and stapokibart for moderate-to-severe AD. Notably, omalizumab is the sole biologic approved for chronic spontaneous urticaria, and stapokibart is the only one approved for AR in China. Real-world evidence from a meta-analysis of 64 studies involving 3921 participants reveals that patients with CRSwNP receiving dupilumab, omalizumab, mepolizumab, and benralizumab exhibited superior outcomes compared to those in randomized controlled trials (RCTs), particularly in terms of nasal polyp score and Sino-nasal Outcome Test score reductions [4]. The low discontinuation rates due to adverse events support their favorable safety profile [4]. Given this, biologics are particularly recommended for patients with allergic disorders who exhibit inadequate responses to standard treatments and have an impaired quality of life.

Several international and regional consensuses regarding biologic therapy in CRSwNP have been released to guide clinical practice. In the current China issue, a position paper by Chinese scholars provides guidance on patient selection, treatment regimens, and efficacy assessment [5]. Nevertheless, considerable unmet research needs remain. As biologics become integral to standard care, a multidisciplinary approach is recommended. Identifying biomarkers to predict therapeutic responses to specific biologics is crucial for precision medicine, enabling clinicians to match patients with the most appropriate treatment. Additionally, understanding the mechanisms underlying nonresponsiveness to biologics is essential to develop effective interventions and improve patient outcomes. Current biologics target T2 pathways, but there are limited guidelines on switching biologics due to inadequate symptom control. Uncontrolled non-T2 responses are more prevalent in Asian countries than in Western countries, and it is essential to develop novel therapies to treat these patients with allergic diseases. The latest progress and contributions of Chinese scholars, as highlighted in this special China issue of Allergy, provide valuable insights and innovative directions for advancing the treatment of allergic diseases in the era of biologics (Figure 1).

The importance of the “epithelial barrier theory” in allergic diseases has been widely acknowledged over the past 20 years [6]. Recent studies further support this theory by reporting that downregulation of the tight junction protein membrane-associated guanylate kinase inverted 1 (MAGI-1) promoted epithelial barrier dysfunction in CRSwNP, which is linked to type 1 cytokine IFN-γ stimulation [7]. Under hypoxic conditions, hypoxia-inducible factor 1α mediates the abnormal basal cell proliferation and goblet cell differentiation in the epithelial layer, ultimately contributing to excessive Mucin5AC secretion and defective epithelial barrier function [8]. Furthermore, ongoing RCTs are exploring the efficacy of monoclonal antibodies that target cytokines associated with epithelial cells, aiming to improve allergic disease treatments. In asthma management, tezepelumab, which targets thymic stromal lymphopoietin (TSLP), prevents asthma exacerbations in both patients with high and low T2 inflammation [9]. Furthermore, CM326, an anti-TSLP antibody developed in China, is currently under investigation for its efficacy and safety in patients with uncontrolled CRSwNP [10].

Dendritic cells (DCs), T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s), and macrophages are crucial immune cells beneath the epithelial barrier that participate in allergic diseases. Recent advances in single-cell RNA sequencing (scRNA-seq) have identified subsets of DCs in a house dust mite (HDM)-induced allergic asthma murine model, revealing that macrophage galactose-type C-type lectin 2 (Mgl2)⁺ DCs closely resemble human DC2 cells and amplify T2 inflammation [11]. A new subset of IL-9-producing macrophages was found in the lungs of ovalbumin (OVA)-sensitized mice. This subset exhibited strong antigen-presenting abilities, promoted Th9 proliferation, and expressed high levels of IL-5, IL-13, TGF-β, CCL6, CCL17, and CCL23 [12]. MiR-10b-5p inhibits the differentiation and activation of Th2 cells in the peripheral blood of the OVA-challenged AR mouse model by targeting Src homology 2 domain-containing phosphatase 2 [13]. Furthermore, regulating glucose metabolism using the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) in vitro can suppress ILC2s activation and function [14]. High wheat IgG4 levels in children with autism spectrum disorder are associated with altered gut microbiota, which may have clinical implications [15]. A recent RCT exploring the safety and efficacy of fecal microbiota transplantation from healthy candidates in 63 moderate-to-severe adult AD patients found no serious adverse reactions during the trial, and patients receiving fecal microbiota transplantation showed greater improvements in eczema area and severity index (EASI) scores and a higher percentage of patients achieving EASI 50 (a 50% reduction in EASI score) compared to those receiving a placebo [16]. These improvements were linked to reduced Th2 and Th17 cells, tumor necrosis factor-alpha (TNF-α) expression, and total IgE [16]. Similarly, abrocitinib, a Janus kinase 1 inhibitor, exhibited robust efficacy and a favorable safety profile in Chinese patients with moderate-to-severe AD, achieving its therapeutic effects through notable reductions in blood Th2, Th1, and Treg-related cytokines and chemokines after 4 weeks of treatment [17]. In drug allergy, TNF-α initiates a positive feedback loop in the early phase of drug-specific T-cell activation, whereas TNF-α antagonists inhibit the suppressive effect of regulatory T cells on drug-specific memory effector T cell [18]. Collectively, the regulatory mechanisms for T2 immune cells remain largely unexplored. Identifying novel therapeutic targets to modulate inflammatory cytokines or the function of immune cells could provide promising interventions in allergic diseases. However, bridging the gap between laboratory discoveries and real-world clinical applications remains complicated and requires extensive long-term studies to thoroughly assess safety, efficacy, and patient outcomes. Despite these challenges, it is undoubtedly a worthwhile pursuit.

The increasing prevalence of asthma has imposed a considerable socioeconomic burden. For instance, long-term exposure to air pollutants is associated with an increased risk of both initial and recurrent asthma hospitalizations [19], which might be attributed to particulate pollutants exacerbating the endotype of neutrophilic asthma by activating Th17 signaling [20]. Although subcutaneous immunotherapy (SCIT) is an effective treatment for asthma, a real-life, multicenter study involving Chinese patients with HDM-induced AR and/or asthma has recently demonstrated that asthma with a disease duration exceeding 5 years and high sensitization is an independent risk factor for systemic reaction to HDM SCIT [21]. Furthermore, the allergen extracts used in immunotherapy were identified as the second-highest drug-related trigger leading to anaphylaxis [22]. Various strategies are recommended for such patients, including adjusting allergen concentration, premedication, close postinjection supervision, and comprehensive contingency planning [21]. In addition, high-intensity interval training is recommended to improve lung capacity and alleviate symptoms among pediatric patients with asthma [23]. Thus far, a murine asthma model characterized by goblet cell metaplasia, inflammatory cell infiltration, and thickened airway smooth muscle has been widely used to investigate allergic disease pathogenesis and potential therapeutic interventions. With a growing focus on the role of neuroinflammation in allergic conditions, a canine asthma model has been developed to observe changes in neuronal markers and immune cells [24].

The authors declare no conflicts of interest.