Severe asthma (SA), affecting 5–10% of asthmatic patients, is associated with a high socio-economic burden due to uncontrolled symptoms, recurrent exacerbations requiring hospitalizations or medical visits, absence from work, and costs for the management of adverse events related to frequent or long-term systemic corticosteroids (SCSs) use [1,2]. “Type 2-high” (T2) asthma, driven by interleukin (IL)-4, IL-5, and IL-13 with eosinophilic inflammation and/or increased fractional exhaled nitric oxide (FeNO) represents ∼80% of SA patients [3,4]. T2-inflammation extends beyond the lower airways and underlies a range of comorbidities affecting the upper airway, skin, and gastrointestinal tract, which share overlapping immunopathogenic mechanisms [5]. Fig. 1 summarizes the hypersensitivity reactions involved in T2-inflammatory diseases pathogenesis, while Fig. 2 represents detailed mechanisms of immune responses engaging immunoglobulin E (IgE) antibodies (A), mediated by T2-cells (B), and driven by dysfunctional epithelium following damage (C) [6].

Fig. 1.

Summary of hypersensitivity reactions involved in T2-inflammatory diseases. Hypersensitivity reaction is defined as an undesirable, uncomfortable or damaging response that arises from a tissue cell dysfunction or immune system overreaction [6]. T2: type 2 immune response; IgE: immunoglobulin E; Th: T helper lymphocytes; ILC2: innate lymphoid cells type 2; IL: interleukins; MC: mast cell; BAS: basophil; AR: allergic rhinitis; ARC: allergic rhinoconjunctivitis; AD: atopic dermatitis; FA: food allergy; Tc2: T cytotoxic lymphocyte type 2; NKT: natural killer T cell; CRS: chronic rhinosinusitis; EoE: eosinophilic esophagitis; AERD: aspirin-exacerbated respiratory diseases; SMC: smooth muscle cell.

Fig. 2.

Detailed mechanisms involved in type I, type IVb and type V hypersensitivity reactions. (A) Mechanisms of type I hypersensitivity in AR, asthma, AD, urticaria, and FA. Following the first contact with the allergen deposited on the epithelial cells, in the respiratory tract, gut or skin, the sensitization phase occurs. Dendritic cells (DCs) present the antigen to the naïve T cell inducing differentiation into T helper 2 (Th2) cell. Type 2 innate lymphoid cells (ILC2) are activated by epithelial alarmins, such as interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP). Upon activation, they produce large amounts of type 2 cytokines, including IL-5, IL-9 and IL-13, further supporting the T2-cell response. T follicular helper cells (Tfh) help B cells to maturate and produce allergen-specific immunoglobulin E (IgE). Mast cell (MC) and basophil (BAS) possess the high-affinity receptor for the Fc fragment of IgE (FcɛRI) and are coated with IgE, thus concluding the sensitization phase. The effector phase occurs upon subsequent exposure to the same allergen. The allergen crosslinks IgE fixed to MC and BAS, triggering degranulation. Preformed mediators inside MC and BAS like histamine, tryptase, leukotrienes (LTs), prostaglandins (PGs) are released into the microenvironment inducing vasodilation, bronchial muscle contraction and increased mucus secretion. Eosinophils (EOS) play a significant role in the delayed allergic response and the persistence of inflammation engaging mechanisms related to type IVb hypersensitivity. The mutual interaction between type I and IVb-related processes is vital to both the sensitization and the chronic phase. (B) Mechanisms of type IVb hypersensitivity in AR, asthma, AD, CRS with NP, FA and EoETh2 is the key player in type IVb sensitivity, driven by IL-4, IL-13, IL-5 and IL-31. These cytokines stimulate B cells to produce IgE (IL-4 and IL-13) and activate eosinophils (IL-5) inducing inflammation and tissue damage. IL-31 produced by Th2 activates receptors on sensory neurons with release of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) causing neurogenic inflammation and itch. Th9, which differentiate with IL-4 and tumor necrosis factor beta (TGF-β), contribute to this response by promoting IgE production and MC growth. The inflammatory response is enhanced by the ILC2, MC and alternatively activated macrophages (Mϕ). ILC2, DC and Th2 activated by epithelial alarmins cooperate producing cytokines that promote eosinophil and basophil recruitment, modulate DC function and affect epithelial barrier contributing to the chronicity of type IVb reactions. Invariant natural killer T cells-(i)NKT contribute to this response inducing alternative activation in Mϕ by IL-4 and IL-13 production. Migrated to inflammatory sites, eosinophils activate various cytokines and release cytotoxic granules contributing to tissue damage, cell apoptosis and chronic inflammation. At the final stage when IgE synthesis is triggered, type IVb and I hypersensitivity overlap. (C) Mechanisms of type V hypersensitivity in AR, asthma, CRS, AD, and EoE. The epithelial barrier damage and microbial dysbiosis lead to dysregulation of the immune response, including extensive activation of T1 (mediated by T helper 1 [Th1] cells), T2 (mediated by Th2) and T3 (mediated by T helper 17 [Th17]) responses combined with the loss of T regulatory cells (Treg), B regulatory cells (Breg) and innate regulatory lymphoid cells (ILCreg). Increased microbiome translocation induces aberrant immune response to opportunistic pathogens and commensals like Staphylococcus aureus with IgE antibody (Ab) production against them. Additionally, activation of Mϕ, EOS, innate lymphoid cells (ILC), MC and BAS by epithelial alarmins with release of proinflammatory cytokines and chemokines (e.g. histamine, LT, reactive oxygen species- ROS) enhances the local inflammatory response and tissue damage.

The figure was reproduced with permission (License Number 6150051257285) from Ref. [6].

T2-comorbidities, common in SA, include allergic rhinitis-AR (49%), chronic rhinosinusitis-CRS (46%), nasal polyps-NP (21%), atopic dermatitis-AD (10%), chronic spontaneous urticaria-CSU (3.5%), food allergy-FA (3.3%), aspirin sensitivity (1.6%) and eosinophilic esophagitis-EoE (0.5%). Almost 70% of SA patients have at least one T2-comorbidity [7]. These comorbidities adversely affect asthma outcomes, contribute to disease persistence and corticosteroid dependence, increasing the disease burden [2,7–9]. The augmentation in number of comorbidities worsens this negative impact [7]. Therefore, systematic assessment and management of T2-comorbidities is critical for optimizing SA outcomes [10].

The development of biologics targeting key T2-mediators or their receptors has revolutionized the treatment of SA. Randomized controlled trials (RCTs) and real-world studies (RWSs) demonstrated the efficacy of these therapies in terms of exacerbation rate, SCSs use, asthma control, lung function and patients’ quality of life (QoL) [1,4]. Several biologics used for SA (e.g. omalizumab, mepolizumab, benralizumab, dupilumab, tezepelumab) proved also benefits on different T2-comorbidities [11–16]. This highlights the systemic nature of T2-inflammation and supports the concept of a unified multimorbidity therapeutic approach.

Despite advances, knowledge regarding the magnitude and consistency of biologics efficacy across SA comorbidities remain limited, whereas the optimal strategies for selecting biologics in multimorbid patients are still unknown [2,4]. The aim of this narrative review is to summarize current data concerning the efficacy of biologics available for SA on T2-comorbidities to help clinicians in choosing the “right treatment for the right patient”.

For this narrative review, we performed a literature search in PubMed and Medline databases up until November 30th, 2025. The search terms used were: “severe asthma”, “biologics” associated with “allergic rhinitis”, “chronic rhinosinusitis”, “nasal polyps”, “aspirin-exacerbated respiratory disease (AERD)”, “atopic dermatitis”, “eczema”, “chronic spontaneous urticaria”, “food allergy”, and “eosinophilic esophagitis”. We selected RCTs, RWSs, systematic reviews, meta-analyses, and case series. Case reports were excluded. A preference was given to more recent articles published in the last five years to have the most up-to-date evidence. Results were limited to publications in English.

AR is the most frequent comorbidity of asthma sharing common genetic background, similar epithelial structure and disease characteristics with chronic airway inflammation classically recognized as been mediated by IgE with symptoms related to allergen exposure, supporting the “one airway, one disease” hypothesis [17]. Increasing evidence exists for the involvement of hypersensitivity type IVb and V reactions in addition to type I hypersensitivity in AR and asthma pathogenesis [6,18] (Figs. 1 and 2). Asthmatic patients with AR have more severe symptoms, frequent exacerbations and medical visits [7,19,20]. In the association AR-asthma, treatment with nasal corticosteroids (NSs) and/or antihistamines for AR improves asthma control and decreases healthcare utilization whereas administration of montelukast or biologics for asthma ameliorates nasal symptoms and patients’ QoL [11,17,20–22].

Among biologics, more evidence regarding the impact on AR exists for omalizumab, the first agent approved as add-on therapy for moderate-to-severe allergic asthma. By binding circulating IgE, omalizumab reduces the inflammatory response related to allergen exposure. Both RCTs and RWSs demonstrated the efficacy of omalizumab in patients with seasonal and perennial AR by improving total nasal symptom score (TNSS), endoscopic score, Rhinitis QoL Questionnaire (RQLQ) score and decrease in rescue medication use with a favorable safety profile [11,23–33]. In patients with AR-SA, omalizumab improved sinonasal outcomes, asthma control, exacerbation rates, Asthma QoL Questionnaire (AQLQ) score, and forced expiratory volume in one second (FEV1), enhanced the efficacy and tolerability of specific allergen immunotherapy (SIT) [11,30–33]. Decreases in serum IgE, FeNO levels and blood eosinophil count (BEC) were reported following omalizumab treatment [23,24,34]. These findings have been confirmed by meta-analyses and systematic reviews [35–37].

More recently, the efficacy of dupilumab, an antibody blocking the receptor for IL-4 and IL-13 (IL-4Rα), has been investigated in AR. These cytokines play key role in allergen-specific T-cell responses; therefore, their inhibition may benefit AR outcomes [6,22]. A proof-of-concept study using transcriptome data from nasal brushing showed that 16 weeks of treatment with dupilumab repressed gene signatures of AR disease and after nasal allergen challenge (NAC) [38]. In patients with AR and asthma, dupilumab reduced TNSS and RQLQ score, improved asthma control, exacerbation rate, FEV1 and decreased FeNO and serum IgE levels [22,39]. In a RCT involving patients with AR, adding dupilumab to SIT did not confer superiority over SIT alone with regard to TNSS following NAC [40]. However, a RWS on patients with SA-AR reported improvements in symptom control, QoL, lung function, and airway remodeling on chest CT-scan, with a reduction of FeNO levels after 48 weeks of treatment [41].

The efficacy of anti-IL5 (mepolizumab, reslizumab) and anti-IL5R (benralizumab) antibodies on AR has not been specifically evaluated. A recent RCT involving patients with cat-allergy-related rhinitis showed that addition of tezepelumab, an anti-thymic stromal lymphopoietin antibody, to SIT achieved a greater reduction in TNSS at 52 weeks compared with SIT alone without significant difference when comparing tezepelumab monotherapy vs placebo [42]. Incoming study TEZARS (NCT06189742) evaluates the efficacy of tezepelumab in patients with AR and asthma. Subgroups analyses from large clinical studies showed comparable efficacy of tezepelumab and mepolizumab in improving asthma outcomes in SA patients with or without AR [43,44].

Overall, evidence supports a high level of efficacy for omalizumab and dupilumab on AR as comorbidity of SA. Findings from representative studies are summarized in Table 1.

CRS and asthma often coexist sharing the same immunological processes involved in their pathogenesis with epithelial barrier dysfunction and cell-mediated inflammation (hypersensitivity type IVb and V) [6,18,20] (Figs. 1, 2B and 2C). While T2-inflammation is predominant in patients with NP, T1 and T3 inflammatory signatures are more frequent in patients with CRS without NP (CRSsNP) [45]. Clinical characteristics of patients with asthma-CRS include older age at diagnosis, longer duration of nasal symptoms, poor symptom control, high risk of exacerbation requiring SCSs, airflow obstruction, worse sinus CT and endoscopy scores, increased frequency of sinonasal surgeries and impaired QoL. Treatment of CRS with NSs or surgery may improve asthma outcomes, whereas several asthma medications (e.g. montelukast, macrolides, biologics) demonstrated benefits on CRS scores [20].

Previous data showed increased local production of IgE in NP independent of the presence of allergy [46]. In this context, the efficacy of omalizumab has been evaluated in NP. RCTs showed significant improvement in nasal polyps score (NPS), TNSS, sino-nasal outcome test-22 (SNOT-22) score, with decrease in needs for surgery after 24 weeks of treatment with omalizumab compared to placebo allowing for its approval as add-on therapy in patients with uncontrolled severe NP [46,47]. The benefits of treatment are also reported in patients with recurrent NP and maintained at one year [48,49]. The positive impact of omalizumab on NP and its favorable safety profile were confirmed by metanalyses and systematic reviews involving RCTs and RWSs [50,51]. Regarding the association SA-NP, RCTs and RWSs demonstrated omalizumab efficacy in improving both conditions outcomes from 16 weeks to 2 years of treatment, by increasing patients’ QoL, reducing T2-inflammation and therapeutic pressure [46,52–57]. In contrast, the effects of omalizumab in patients with CRSsNP were disappointing, with only modest improvement in SNOT-22 scores without significant differences compared to placebo concerning sinonasal symptoms and imaging after 6 months of treatment [58].

As most of NP in Caucasian population exhibit eosinophilic inflammation driven by IL-4, IL-5 and IL-13, biologics targeting these cytokines and their receptors have been extensively evaluated. The anti-IL5 antibody, mepolizumab reduced NPS, visual analog scale (VAS) symptom score, SCSs use and risk for sinus surgery in patients with refractory, recurrent NP compared to placebo allowing for its reimbursement for this indication [59–61]. Large metanalyses of RCTs and RWSs confirmed these findings and demonstrated good tolerability of the treatment [51,62,63]. Post-hoc analyses from RCTs showed similar benefits of mepolizumab on asthma outcomes in SA patients with and without NP [64]. Data from real-world cohort REDES suggested even higher efficacy of mepolizumab in improvement of asthma symptoms, annualized exacerbation rate (AAER), FEV1 and SCSs use in patients having this association compared to other SA patients after one year of treatment [65]. Multiple RWSs involving patients with SA and NP demonstrated the efficacy of mepolizumab on both conditions at 6 and 12 months of treatment with decrease in eosinophilic inflammation [66–69].

More limited data exists for the effects of reslizumab in the association SA-NP. Post-hoc analyses from RCT including 150 patients with SA-NP showed that reslizumab decreased AAER by 83% vs placebo with concomitant improvement in FEV1, asthma control and AQLQ score (all p<0.001) after 52 weeks of treatment [70]. In a subgroup analysis from RWS, including 14 patients with SA-NP, reslizumab reduced AAER, needs for surgery and BEC with increased asthma control and FEV1 (all p<0.02). Thirty-six percent of patients reported improvement in smell, although changes in NPS were not significant at one year of treatment [71].

The efficacy of benralizumab inducing eosinophil depletion, was also evaluated in patients with NP. A large RCT showed improvements in NPS, nasal blockage and sense-of-smell in patients receiving benralizumab compared to placebo at 40 weeks of treatment (all p≤0.003) without significant benefits on SNOT-22 score, time to first surgery and SCSs use. Patients with asthma experienced greater effects on NPS than the others [72]. A metanalysis including RWSs confirmed the positive impact of benralizumab on NP and its good tolerability [51]. In a subgroup analysis from a RCT involving 153 patients with SA-NP, significant improvements were found in the group benralizumab vs placebo after 24 weeks of treatment on SNOT-22 score (p=0.018), AAER, asthma control, FEV1 and St. George's Respiratory Questionnaire (SGRQ) score (all p<0.001) [73]. Numerous RWSs confirmed benralizumab efficacy in the association SA-NP regarding symptoms, AAER, lung function, SNOT-22 score, NPS, sinus imaging, eosinophilic inflammation, SCSs use and needs for surgery [69,74–78]. Despite benefits sustained up to 3 years [74], benralizumab is not currently approved as an add-on treatment of NP.

Very limited data exists concerning the impact of anti-IL5/R antibodies on CRSsNP. A RWS including 36 patients with SA-CRSsNP showed significant improvements on sinus imaging, BEC and serum IgE levels after treatment [79].

Dupilumab proved high efficacy in improving sinonasal outcomes in patients with NP in RCTs and RWSs. Analyses from RCTs showed decreases of NPS, nasal congestion, loss-of-smell, TNSS, SCSs use and needs for surgery with improvements of SNOT-22 score, sinus imaging and patients’ QoL after 24, respectively 52 weeks of treatment versus placebo with a favorable safety profile (all p<0.001) [80–83]. These results allowed to its approval as add-on therapy for adults with severe NP. Numerous RWSs confirmed sustained benefits up to 3 years [51,84–91]. In a metanalysis including RWSs, 90% of patients respond to treatment with at least three of five criteria defined in current guidelines [51]. Response appeared independent of the number of prior sinus surgery, comorbidities, or baseline levels of T2-inflammation [90]. Concerning the association SA-NP, dupilumab administered for ≥16 weeks, proved its efficacy on sinonasal outcomes with concomitant improvement of AAER, asthma control, lung function, patients’ QoL, FeNO and serum IgE levels, regardless of treatment indication, in RCTs and RWSs [15,80,91–95]. The benefits persist up to 30 months of treatment [94]. Regarding the impact of dupilumab on the association SA-CRS, an one-year study involving 50 patients showed similar efficacy of treatment in patients with and without NP in terms of exacerbations, hospitalizations, asthma control, anosmia, FEV1, BEC and SCSs use. A greater improvement in SNOT-22 scores was found in the group with NP compared to the group with CRSsNP (26.5±12.5 vs 15.1±9.4, p≤0.001) [96]. Dupilumab-induced blood eosinophilia probably represents the most feared effect for clinicians due to potential complications. Although nearly half of treated patients develop blood eosinophilia within six months of treatment, most of them are asymptomatic and BEC typically declines by 12 months [97–99]. Hypereosinophilia (BEC ≥1.5×109cells/L) occurs in 15% of patients, but the incidence of eosinophilic complications remains low (<1%) [97,99–101]. A practical algorithm was developed for the management of dupilumab-induced blood eosinophilia [101].

As thymic stromal lymphopoietin (TSLP) is an upstream key driver of multiple inflammatory cascades, the efficacy of tezepelumab targeting this alarmin has been assessed in patients with NP. In a large RCT, tezepelumab administered for 52 weeks improved NPS, nasal-congestion, loss-of-smell, TNSS, SNOT-22 score, and sinus imaging while reducing surgery and SCSs needs compared to placebo (all p<0.001) with good tolerability, supporting recent approval as add-on therapy in severe NP. Patients with comorbid asthma receiving tezepelumab had greater improvement in disease control vs placebo [15]. Subgroup analyses from RCTs and RWSs in SA-NP confirmed benefits of tezepelumab regarding AAER, asthma control, lung function, SNOT-22 score, and T2-biomarkers at weeks 24 and 52 [102–104]. In the PASSAGE RWS, patients with SA-NP had greater reduction in AAER than those with SA-CRSsNP (by 85% [65,93] vs 65% [52,75]) with higher improvement in SNOT-22 scores from baseline at 24 weeks (−26.1 [−34.6, −17.6] vs −12.6 [−16.1, −9.0]). The rate of response to treatment (improvement in the SNOT-22 score by ≥8.9) was 79% in the group NP and 55% in the group CRSsNP [104].

Indirect comparisons and metanalyses (mostly based on RCTs) assessing biologics efficacy on NP suggest a superiority of dupilumab (strongest evidence) and tezepelumab in improving sinonasal outcomes [105–111]. A RWS (n=85) showed greater efficacy of dupilumab compared to mepolizumab at 3 and 6 months of treatment in NPS, improving smell, peak nasal inspiratory flow (PNIF) and sniff-test with higher rate of response to treatment (70% vs 37%) [112]. The first head-to-head RCT comparing the efficacy of dupilumab and omalizumab in 360 patients with NP and asthma was recently published. Dupilumab was superior to omalizumab at 24 weeks of treatment across all endpoints including NPS, smell test score, nasal congestion, TNSS, SNOT-22 score, PNIF, rhinosinusitis severity, asthma control, FEV1, forced expiratory flow 25–75%, and AQLQ (all p≤0.013) [113]. A recent metanalysis of RCTs in SA-NP suggests greater efficacy of tezepelumab for AAER and asthma control, benralizumab for FEV1 and mepolizumab for SNOT-22 score [114]. RWSs in SA-NP reported comparable efficacy of anti-IgE, anti-IL5/R and anti-IL4R antibodies on asthma outcomes at 4–6 months of treatment with more benefits on sinonasal disease for dupilumab [15,69,115,116]. A systematic review showed that biologics use in patients with SA-NP is associated with significant improvements in lung function and QoL [117]. Analyses from the largest worldwide adult SA registry showed that patients with CRS±NP or NP alone may have greater benefits from biologics than those without these comorbidities [8,118].

Strong evidence supports the efficacy of dupilumab, tezepelumab, mepolizumab and omalizumab in NP as a comorbidity of SA, with currently greater benefits reported for dupilumab and tezepelumab. Results from key studies are summarized in Table 2. Limited data is currently available regarding the efficacy of biologics in the SA-CRSsNP association.

AERD associates asthma, NP and sensitivity to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). A prevalence of 14.9% is reported in SA [119]. Disease course is typically severe with numerous exacerbations requiring intubation, treatment-refractory NP, frequent needs for SCSs and sinus surgery [20,120]. In patients with AERD, ingestion of aspirin or NSAIDs increases production of cysteinyl leukotrienes (LT) and prostaglandin D2 (PGD2) inducing bronchoconstriction, mucosal oedema and T2-airway inflammation (hypersensitivity type VII reactions) [6,119,120]. Traditional management includes optimized treatment of SA and NP, along with as aspirin desensitization [17,20]. Biologics targeting T2-inflammation represent a promising therapeutic option for AERD.

Omalizumab administration for at least 16 weeks in patients with AERD suppresses LTE4 and PGD2 overproduction with improvement in sinonasal and respiratory symptoms, AAER, hospitalization rates, NPS, FEV1, SNOT-22 scores, SCSs and asthma rescue medication use in RCTs and RWSs [121–124]. Omalizumab pretreatment increased the tolerability during aspirin desensitization compared with placebo [121,125]. No significant differences in sinonasal and asthma outcomes were observed between patients with AERD and those aspirin-tolerant with SA-NP receiving omalizumab for 24 weeks [47,54].

Treatment with mepolizumab for 3 months decreased IL5-mediated signaling in mast cells, eosinophils and nasal epithelial cells in patients with AERD resulting in reductions of BEC and urinary LTE4 levels (all p<0.04) [126]. Subgroup analysis of the SYNAPSE RCT showed decrease in NPS and nasal congestion in patients with AERD receiving mepolizumab compared to placebo at week 52 without significant benefits on olfaction [127]. Improvements in SNOT-22 scores, asthma control and BEC were also reported after 3 months of treatment with mepolizumab in patients with AERD in a RWS [128]. Small series suggest that mepolizumab may not prevent NP recurrence or aspirin-induced reactions during desensitization [129,130]. Post-hoc analyses of RCT showed similar efficacy of reslizumab administered 52 weeks on asthma outcomes in patients with SA-NP with or without aspirin sensitivity [70]. Data from RCT and RWS demonstrated comparable efficacy of benralizumab in patients with AERD and those with NP or SA after at least 4 months of treatment in terms of sinonasal and asthma outcomes [72,131].

In patients with AERD, dupilumab improves nasal symptoms (particularly olfaction), asthma control, NPS, PNIF, sinus imaging, lung function, SCSs use and patients’ QoL in RCTs and RWSs [132–137]. The benefits, evident after one month of treatment, are attributed to reduced IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells, leading to decreased nasal and urinary LTE4 levels, even in patients with inadequate response to anti-IL5/R antibodies [134,138]. As perioperative treatment, dupilumab reduces the risk of NP recurrence [139]. Pretreatment with dupilumab for 6 months increases aspirin tolerance in more than half of patients [140]. In a RWS, greater perceived efficacy was reported by patients with AERD receiving dupilumab compared to other biologics [141].

NP tissues from patients with AERD expressed high levels of TSLP, which induces PGD2 production by mast cells suggesting its involvement in disease pathogenesis [142]. In a subgroup analysis of the WAYPOINT RCT, tezepelumab demonstrated similar efficacy regarding NPS and nasal congestion vs placebo at 52 weeks in patients with NP±AERD [16]. A post-hoc analysis of the NAVIGATOR trial, including 43 patients with AERD, showed a 79% decrease in AAER in patients receiving tezepelumab for 52 weeks compared to placebo, with improvement in asthma control, patients’ QoL and FEV1. A complete response was achieved in 71.4% of patients treated with tezepelumab [143].

Overall, biologics targeting T2-inflammation are effective in AERD, with more evidence for dupilumab, tezepelumab and omalizumab. Some subgroup analyses from studies on patients with SA and/or NP suggest also benefits of reslizumab and benralizumab in this population. The key findings from relevant studies are summarized in Table 3.

CSU, characterized by wheals, angio-oedema, or both ≥6 weeks, is considered a T2-disease, at least the endotype driven by IgE autoantibodies (half of cases). CSU is associated with impaired QoL and performance at work/school, comorbidities and substantial economic burden. Other T2-conditions (e.g. AR, AD, asthma) are present in up to 20-30% of patients with CSU. One quarter of patients have uncontrolled disease despite up-dosing of antihistamines [144].

Omalizumab was approved as add-on treatment for CSU following RCTs showing significant improvement in symptoms and QoL vs placebo with a favorable safety profile [12,145–148]. These findings were confirmed in RWSs [149–151]. Dupilumab also showed benefits on CSU activity and symptoms in RCTs and RWSs [152,153]. The effects of other T2-biologics on CSU have been disappointing [154–157].

AD is the most common chronic inflammatory skin disease, characterized by eczematous lesions with intense pruritus, causing important socioeconomic burden, particularly in patients with moderate-to-severe disease. Its pathogenesis is complex involving skin barrier dysfunction and immune-mediated inflammation [158]. As part of the “atopic march”, AD is frequently associated with AR, asthma, and FA [159]. For long time, treatment options were limited to topical and systemic immunosuppressive agents but recently developed biologics revolutionized AD management [158].

In patients with AD aged ≥6 months, dupilumab improved symptoms and QoL with favorable tolerability in RCTs and RWSs, allowing for its approval as add-on medication to topical treatment in this indication [14,160–163]. Its effects are rapid and persist over time [163,164]. Post-hoc analyses of RCTs including adult patients with asthma, NP and both conditions associated with AD demonstrated concomitant improvements in asthma control, sinonasal and AD outcomes [165]. Dupilumab proved similar effects on AD in children aged 6 months to 5 years with and without T2-comorbidities such as asthma, AR, and FA [166]. Positive impact on AD was also reported for omalizumab in pediatric population [167]. In SA adult patients receiving omalizumab for one year, benefits on AD and CSU were observed in >80% of cases alongside improvement of asthma outcomes [168]. Other T2-biologics showed disappointing results on AD [169–171].

Currently omalizumab and dupilumab are the most effective biologics for CSU. Dupilumab is probably the best therapy for the association AD-SA and should be the first therapeutic choice, while omalizumab represents a good option for treating these patients. Key study results are summarized in Table 4.

FAs are hypersensitivity reactions to food allergens that may be IgE-mediated, non-IgE mediated (e.g. EoE) or mixed types (I, IVb and V). Common food allergens include milk, eggs, peanuts, soy, wheat, fish and shellfish [159,172]. In IgE-mediated FA, symptoms occur during the first 2h after exposure including cutaneous, gastrointestinal, respiratory manifestations and, in severe cases, anaphylaxis [172]. Patients with EoE experience dysphagia, regurgitation, vomiting, food impactions and abdominal pain between 1 and 24h after ingestion [159,173]. The gold standard for diagnosis of IgE-mediated FA is the oral food challenge (OFC) test and for EoE – the biopsy. Dietary elimination is recommended in both conditions with oral immunotherapy (OIT) for the first one, proton pomp inhibitors and SCSs for the EoE [172]. As FA and asthma frequently coexist and share common pathogenic mechanisms, T2-biologics were tested for FA treatment [159,172].

In patients with IgE-mediated FA, omalizumab significantly increased the tolerated dose of multiple foods and reduced allergic reactions during ingestion in RCTs and RWSs [174–178]. Improvements in FA-related symptoms, food tolerance, and QoL were reported in patients with SA-FA receiving omalizumab in RWSs [179,180]. In association with OIT, omalizumab raises the tolerated dose and the chances for successful desensitization [178,181,182]. Based on these results, the FDA approved omalizumab as add-on therapy for FA. A large post-hoc analysis of RCTs and RWSs showed a comparable efficacy of omalizumab on asthma outcomes in patients with and without FAs [183]. In contrast, dupilumab provided only modest increase in OIT efficacy in children with peanut allergy without any protection against OIT-related anaphylaxis [184,185].

In EoE, dupilumab improved symptoms, endoscopic scores, histology and QoL in RCTs and RWSs, leading to its approval for children and adults in this indication [13,186–190]. In patients with asthma-EoE, improvements in both diseases’ outcomes were found after 6 months of treatment with dupilumab [191]. Omalizumab showed limited efficacy in patients with EoE while other biologics showed disappointing results [192–197].

Current evidence suggests that omalizumab should be the preferred treatment for SA patients with IgE-mediated FA and dupilumab for those with EoE. Findings from relevant studies are summarized in Table 5.

Fig. 3 represents the current knowledge on the efficacy of biologics on T2-conditions associated with SA.

Fig. 3.

Current evidence regarding the efficacy of biologics on T2-conditions associated with SA. AR: allergic rhinitis; NP: nasal polyps; AERD: aspirin-exacerbated respiratory disease; CSU: chronic spontaneous urticaria; AD: atopic dermatitis; FA: food allergy; EoE: eosinophilic esophagitis; green (+): undeniable benefits; red (−): absence of benefits; orange (+/−): some benefits; light blue (?): unknown.

Systematic reviews and analyses using VigiBase, the World Health Organization global pharmacovigilance database, confirmed the good safety of biologics currently available as treatment for SA in children and adults [198–200]. The most frequently reported drug-related adverse events are injection-site reactions, hypersensitivity, headache, fatigue, upper respiratory tract infections, and pyrexia [199,200]. These are well-known adverse effects related to biologic therapies but other associations, such as malignancies or cardiovascular events, are also reported requiring further assessment and investigation [199]. More limited data is available for tezepelumab as it is the most recently developed. Table 6 summarizes current evidence on safety and tolerability of biologics currently used as add-on treatment for SA.

T2-comorbidities are frequent in SA patients and have negative impacts on asthma outcomes, so their management is mandatory to reduce disease burden. Biologics available for the SA treatment proved benefits on T2-comorbidities, and the presence of CRS±NP, or NP alone may enhance their efficacy on asthma outcomes. This underscores the importance of systematic assessment of comorbidities before initiating biologic therapy. The spectrum of biologics efficacy on T2-comorbidities varies according to their mechanisms of action and should be considered in the choice of biologic for each patient. While choosing the most appropriate therapy in SA patients with a comorbidity for which one biologic proved superior efficacy (e.g. omalizumab for FA, dupilumab for EoE or AD) is evident, the decision-making process becomes more complex in multimorbid patients or those having a comorbidity with multiple treatment options (e.g. NP). Discussion by multidisciplinary team of these cases may be useful. More comparative analyses currently exist for the association SA-NP. Future directions should include more head-to-head trials to better assess the efficacy of biologics across T2-disease outcomes in other associations and SA patients with multiple comorbidities, but also studies evaluating socio-economic burden and patient-reported satisfaction to help physicians in their clinical practice.

AT was the promoter of the project. All the authors contributed to the writing and reviewing the manuscript. All the authors approved the submission.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

None declared.

AT reports honoraria for lectures, presentations, speakers’ bureaus, educational events from AstraZeneca, BMS, Chiesi, Roche; support for attending meetings and/or travel from AstraZeneca, Chiesi; consulting fees from AstraZeneca, Chiesi, Sanofi. GGF reports honoraria from Reprints Unlimited. HCG and PN have no conflict of interest to declare. DN reports honoraria for presentations from AstraZeneca, Berlin Chemie, Sanofi; support for attending meetings from AstraZeneca, Sanofi, Stallergen. KK reports licenses for UpToDate; honoraria for presentations from ALK, Aurovitas Pharma, Berlin Chemie, Emma MDT, Stallergenes; support for attending meetings from Berlin Chemie. DB reports honoraria for participation on Advisory Board from GSK, Sanofi, AstraZeneca. PS reports consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, GSK, Guidotti, Menarini, Specialty Therapeutics; honoraria for presentations from AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, GSK, Guidotti, Menarini, Novartis, Pfizer, ResMed, Specialty Therapeutics; support for attending meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, GSK, Guidotti, Menarini, Pfizer.