Understanding Biologics in CRSwNP: Related Events and Insights

Abstract

Purpose of Review

This review examines the immunologic and clinical considerations surrounding biologic therapy for chronic rhinosinusitis with nasal polyps (CRSwNP), focusing on adverse events, hypersensitivity reactions, excipient-related reactions, and practical allergological evaluation. Importantly, the majority of adverse events reported with biologic therapies represent non-immune-mediated side effects rather than true hypersensitivity reactions. A structured diagnostic approach is essential to distinguish IgE-mediated, non-IgE-mediated, immune complex, excipient-driven, and paradoxical immune-mediated reactions to ensure safe continuation or appropriate switching of therapy. Consequently, we integrate excipient-related reactions within the broader framework of immunologic and non-immunologic adverse events.

Recent Findings

Recent published real-world studies and pharmacovigilance analyses show that dupilumab, mepolizumab, omalizumab, tezepelumab and depemokimab are highly effective but associated with distinct adverse profiles, including ocular inflammation, arthralgia, serum-sickness–like reactions, and rare anaphylaxis. Increasing attention has been given to polysorbates and polyethylene glycol (PEG), synthetic surfactants/stabilizers that can trigger immediate hypersensitivity in sensitized individuals. Updated EAACI/ENDA recommendations support structured testing, provocation, and selective desensitization.

Summary

Biologic therapy has transformed CRSwNP management. Most adverse reactions are non‑allergic; however, systematic allergological evaluation is essential to differentiate drug‑specific immune reactions from excipient hypersensitivity and paradoxical immune syndromes. Improved ingredient transparency, standardized testing, and vigilant pharmacovigilance will optimize long-term safety and guide future research.

Introduction

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a severe, debilitating inflammatory disorder that remains challenging to manage despite advances in medical and surgical therapy. The pathophysiology of CRSwNP is dominated by type 2 (T2) inflammation, which is characterized by the activation of T helper 2 (Th2) lymphocytes and the subsequent release of key cytokines, including interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). This inflammatory response is further amplified by thymic stromal lymphopoietin (TSLP), an alarmin released by epithelial cells in response to allergens or pathogens. TSLP activates dendritic cells, promoting the differentiation of naive CD4 + T cells into Th2 cells and enhancing the production of IgE by B cells, which perpetuates allergic responses. The heightened presence of eosinophils, driven by IL-5, along with IgE-mediated mast cell activation, results in significant tissue inflammation, leading to persistent inflammation, nasal mucosal edema, and ultimately the development of nasal polyps and the characteristic symptoms of CRSwNP [1].

Given the substantial burden of disease and the limitations of current treatment options for CRSwNP, there is a significant unmet clinical need for effective therapies that can address the underlying pathophysiology of T2 inflammation. Growing, high-quality scientific evidence indicates that biologics targeting pivotal inflammatory pathways provide substantial clinical benefit in CRSwNP. Agents directed against type 2 inflammation (specifically those targeting IL-4/IL-13, IgE, and IL-5/IL-5Rα) have shown robust, clinically meaningful efficacy in patients with severe, uncontrolled CRSwNP. These therapies consistently reduce nasal polyp size [2] and improve nasal obstruction, olfactory function, and disease-specific quality of life (QoL), while simultaneously reducing dependence on systemic corticosteroids and the need for endoscopic sinus surgery (ESS). Evidence supporting these outcomes derives from phase 3 [3–5] randomized controlled trials and corroborating real-world effectiveness studies [6]. Moreover, the rapidly evolving biologic landscape now includes recently approved or investigational agents, such as depemokimab [7] and tezepelumab [8], which hold promise for further expand in the therapeutic arsenal against CRSwNP.

Because biologics are immunologically active agents, they may be associated with diverse adverse reactions, including cytokine-release (infusion-related) reactions, serum sickness–like disease, and true hypersensitivity reactions, which may be immediate (including anaphylaxis) or delayed in onset.

The objective of this article is to review the allergological evaluation, under-discussed clinical impacts, and adverse reactions to biological agents used in CRSwNP, with the goal of improving current and long-term management of these agents.

Methodology: PRISMA Guidelines for Narrative Review

This narrative review was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) principles adapted for non-systematic reviews. A structured literature search was performed in PubMed, Embase, and the Cochrane Library to identify relevant publications up to December 2025. Eligible sources included randomized controlled trials, real-world observational studies, pharmacovigilance analyses, and EAACI/ENDA position papers addressing the efficacy, safety, immunogenicity, and hypersensitivity reactions associated with biologic therapies in CRSwNP.

Non–peer-reviewed sources and non-English manuscripts without available translation were excluded. The retrieved literature was synthesized using a narrative approach, with emphasis on clinically relevant safety data, mechanistic insights, and practical recommendations for allergological evaluation. This structured methodology was adopted to enhance transparency and reproducibility while allowing integration of emerging evidence and expert guidance.

Overview of Current Biologics, Mechanism of Action and Immunologic Targets

Origins and Development: Short Summary (Practical Information for Clinicians and Patient Counseling: Origin, Manufacturing, and Formulation Considerations)

A core element of patient-centered care is recognizing and incorporating each patient’s values and preferences into therapeutic decision-making. In the context of biologic therapy, this includes transparent communication about formulation components, particularly excipients and sourcing, which may have immunologic, cultural, ethical, or dietary implications. Despite growing awareness of these issues, healthcare systems have been slow to adopt standardized ingredient disclosure practices, limiting patients’ ability to make fully informed and value-aligned therapeutic choices [9]. This issue is increasingly relevant as many patients choose to avoid animal-derived ingredients for ethical, cultural, or health reasons. Millions identify as vegan or vegetarian, and large populations, particularly within Hindu and Muslim communities, hold religious dietary restrictions that extend to medications. From a clinical perspective, certain require strict avoidance of mammalian components; for example, patients with alpha-gal syndrome may experience severe allergic reactions even to trace amounts of mammalian-derived material. These considerations underscore the ethical, culture, and clinical importance of transparency labeling regarding the source and formulation of biologics [10].

• a. Dupilumab (Dupixent®)

  • Type/origin: Fully human IgG4 monoclonal antibody (mAb) that blocks IL-4Rα subunit, thereby inhibiting both IL-4 and IL-13 signaling pathways. It was developed using Regeneron’s VelocImmune transgenic-mouse platform, a genetically engineered (humanized) mouse system designed to generate fully human variable regions.
  • Production: Produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells, a mammalian cell expression commonly used for therapeutic antibodies. The commercial product undergoes purification to remove host cell proteins and other process-related impurities.
  • Other approved indications: severe asthma [11], severer atopic dermatitis, chronic obstructive pulmonary disease [12], eosinophilic esophagitis [13], nodular prurigo [14].
• b. Mepolizumab (Nucala®)

  • Type/origin: Humanized IgG1κ mAb directed against IL-5. The original antibody candidates were generated through rodent immunization, after which murine complementarity-determining regions (CDRs) were grafted onto human immunoglobulin framework regions to reduce immunogenicity and create a humanized therapeutic antibody.
  • Production: Manufactured by recombinant DNA expression in CHO cells, followed by purification to eliminate host-cell proteins and process-related impurities prior to formulation.
  • Other approved indications: severe asthma [11], chronic obstructive pulmonary disease [12], eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome [11].
• c. Omalizumab (Xolair®)

  • Type/origin: Humanized IgG1κ mAb that binds circulating IgE. The variable region was originally derived from the murine mAb MAE11 and subsequently humanized by grafting murine complementarity-determining regions (CDRs) onto human immunoglobulin framework regions to minimize immunogenicity and enable therapeutic use.
  • Production: Produced by recombinant DNA technology in CHO cell lines followed by purification.
  • Other approved indications: severe asthma [11], food allergy [15], chronic urticaria [16].
• d. Tezepelumab (Tezspire®)

  • Type/origin: Fully humanized IgG2 mAb targeting TSLP, a key upstream epithelial-derived cytokine involved in the pathogenesis of asthma and other allergic diseases. Tezepelumab was developed using a transgenic mouse platform to generate fully human antibodies, minimizing immunogenicity.
  • Production: The drug is produced using recombinant DNA technology in CHO cells, with extensive purification processes to ensure the removal of host-cell proteins and other impurities before formulation.
  • Other approved indications: severe asthma [17]
• e. Depemokimab

  • Type/origin: Fully human IgG1 mAb targeting IL-5. It is an ultra-long-acting biologic engineered with enhanced IL-5 binding affinity and high potency. Depemokimab was developed using advanced phage display technology, resulting in a highly specific therapeutic agent while minimizing immunogenicity.
  • Production: Depemokimab is manufactured via recombinant DNA technology in CHO cells. Its molecular engineering confers an extended half-life, allowing sustained inhibition of type 2 inflammation with a dosing regimen of twice yearly in individuals with CRSwNP [7].
  • Other approved indications: severe asthma [18]

Key Technical Points Clinicians Should Know

• “Fully human” vs “humanized” mAb

Fully Human (Dupilumab, Tezepelumab)

The antibody sequences of dupilumab and tezepelumab consist entirely of human sequences in both the variable and constant regions. Fully human antibodies are generally associated with a lower risk of anti-drug antibody (ADA) formation compared to murine or chimeric mAb. Dupilumab is produced using a human-immunoglobulin transgenic mouse model (VelocImmune), which enables the generation of fully human variable regions. Similarly, tezepelumab is developed using a transgenic mouse platform to ensure a fully human antibody structure.

Humanized (Mepolizumab, Omalizumab, Depemokimab)

Humanized antibodies, including mepolizumab, omalizumab, and depemokimab, are derived from mouse antibodies in which the antigen-binding complementarity-determining regions (CDRs) incorporated into human immunoglobulin framework regions. This humanization process significantly reduces immunogenicity compared to murine or chimeric mAb, although a limited number of non-human residues may still be present. This approach is widely used among many biologics approved by the FDA and EMA.

• Manufacturing host = CHO cells for all biologics

All currently approved biologics for CRSwNP are produced in CHO mammalian cell lines, which are widely used for recombinant mAb production because they perform human-like protein folding and glycosylation. The final commercial formulation contains no intact animal tissue; it consists of purified recombinant protein together with pharmaceutical excipients.

• A increasing number of patients and families express concern regarding the potential animal origins of therapeutic products, including biologics. Clear, accurate, and transparent regarding antibody engineering, manufacturing platforms, and excipient composition is important to support shared decision-making and respect for cultural or religious values. Clinicians should be prepared to address these concerns using factual, evidence-based information and to document discussions as part of the informed consent process [19].

¿What to do in Practice? (Recommended Clinician Checklist)

Although animal-derived systems may be used during early development, the marketed biologic is a purified recombinant monoclonal antibody produced under strict regulatory standards. Validated purification processes remove host-cell proteins and other process-related impurities, and the final product does not contain intact animal tissue. Clinicians should consult the official Summary of Product Characteristics (SmPC) for formulation details.

• a. Review the specific product label for excipients, including the package inserts, to verify the absence of porcine gelatin or other explicitly animal-derived excipients. Share this information with the patient.

• b. If a patient raises religious or ethical concerns, clinicians may:

  • Provide the excipient list and clear explanation of the manufacturing process in writing.
  • Contact the manufacturer’s medical information department for definitive manufacturing-process detail.
  • Facilitate discussion with the patient’s religious advisor, many traditions permit medical products under the principle of necessity. Refer to published cultural-acceptability framework when useful.

• c. Document the discussion and informed consent, including that excipients and manufacturing details were reviewed. If the patient declines treatment, discuss alternative therapeutic options (different biologic or ESS/medical approach) and outline potential clinical consequences.

• d. For concerns regarding the use of animals in drug development (e.g., mouse platforms), clarify the distinction between research tools and finished commercial product. Modern biologics often involve animal’s components in discovery or manufacturing history; but the finished drug is highly purified and undergoes testing to remove process-related impurities.

Excipients and their Clinical Relevance

Biologic formulations typically include sugars (sucrose), buffers (histidine, acetate), and surfactants (polysorbate PS80 or 20) to maintain stability and prevent aggregation. These components are generally synthetic, plant-derived, or chemically manufactured. Product labeling lists excipients explicitly, which allows clinicians to screen for potential allergenic concerns.

Dupixent®

• L-Arginine monohydrochloride

• L-Histidine

• L-Histidine monohydrochloride monohydrate

• Polysorbate 80 (E 433)

• Sodium acetate trihydrate

• Water for injections (vehicle)

Notes: the product label specifies the exact quantity of PS80 per dose and highlights that polysorbates may cause hypersensitivity reactions in susceptible patients.

Nucala®

• Sucrose

• Sodium phosphate dibasic heptahydrate

• Citric acid monohydrate

• Polysorbate 80

• Disodium edetate (EDTA disodium salt)

• Water for injections (vehicle)

Note: Depending on the presentation (pre-filled syringe, vial, or pre-filled pen) the product labeling lists the same excipients. Lyophilised vials list specifies sucrose and buffer components with the liquid formulation).

Xolair®

• For solution presentations (pre-filled syringe/pen):

  • Arginine hydrochloride
  • Histidine hydrochloride monohydrate
  • Histidine
  • Polysorbate 20
  • Water for injections
• For powder (lyophilized) and solvent presentations:

  • Powder: Sucrose, histidine, histidine hydrochloride monohydrate, Polysorbate 20
  • Solvent: Water for injections

Tezspire®

• For solution presentations (pre-filled syringe/pen):

  • Sodium hydroxide (E524)
  • L-proline
  • Polysorbate 80
  • Water for injection

Depemokimab (Commercial Designation Pending)

Provisional formulation and excipient data are currently based on publicly available regulatory and clinical trial disclosures; the final technical data sheet is pending formal publication by regulatory agencies.

• Sodium acetate trihydrate

• Sorbitol (E420)

• Polysorbate 80

• Water for injection

• a. Practical safety notes (clinically relevant).

  • PS80 or PS20 is present in all currently available biologic formulations for CRSwNP (PS80 in dupilumab, mepolizumab, depemokimab, and tezepelumab; PS20 in omalizumab). These nonionic surfactants are widely used in mAb formulations to enhance stability and prevent aggregation and are explicitly listed in product labeling because they may trigger hypersensitivity reactions or local injection-site reactions in susceptible individuals. Patients who have previously experienced severe reactions to injectable biologics should be closely monitored. There is documented cross-reactivity between polyethylene glycol (PEG) and PS80 in individuals who have confirmed hypersensitivity to excipients. This cross-reactivity occurs because IgE antibodies can recognize specific short sequences within PEG. In contrast, true monosensitization to PS80 seems to occur independently of PEG. In PEG-allergic patients, PS80 skin test positivity has been associated with more severe and persistent clinical phenotype, higher serum PEG-specific IgE levels, and enhanced basophil activation test (BAT) reactivity [20]. In such cases, an expanded allergological evaluation should be considered prior to re-exposure or switching biologic therapy.
  • Sucrose (present in mepolizumab and in lyophilized omalizumab powder) is a common stabilizer, it is not an animal-derived ingredient.
  • Disodium edetate (EDTA), buffers (histidine/acetate/phosphate) and amino acids (arginine) are standard excipients used to stabilize therapeutic proteins and prevent aggregation.

The finished drug products are highly purified recombinant proteins produced in CHO cell lines. The commercial vials/syringes do not contain whole animal tissue. If a patient is concerned about animal-derived excipients (like porcine gelatin, lactose from milk, beef gelatin), according to product labeling these common allergenic animal products are not present in these three biologics used for CRSwNP.

• b. Allergological work-up protocol for excipients in biologic therapies.

This assessment seeks to confirm or exclude excipient hypersensitivity, a rare occurrence in the general population but a critical consideration in high-risk patients with suspected biologic related reactions. This distinction is clinically essential, as adverse responses may result from:

1. Immunogenicity to the therapeutic mAb itself (ADA formation, IgE-mediated pathways).

2. Hypersensitivity to formulation components, including polysorbates, EDTA, sucrose, or buffering agents [21].

Accurate differentiation between these mechanisms allows a more precise interpretation of the reaction and guides safe, individualized management.

In some cases, confirming excipient hypersensitivity enables switching to a therapeutically equivalent biologic with a different excipient profile, thereby minimizing the risk of recurrence while preserving disease control.

A structured allergological assessment is essential when evaluating suspected hypersensitivity to a biologic formulation [22]. This approach aims to clarify the underlying immune mechanism, confirm causality, and ensure patient safety while preserving therapeutic options. The stepwise protocol integrates clinical observation with targeted laboratory and skin testing, following current EAACI (European Academy of Allergy and Clinical Immunology) and ENDA (European Network for Drug Allergy) recommendations [23]. When applied systematically, this approach increases diagnostic accuracy and supports evidence-based decisions on continuation, substitution, rechallenge, or desensitization (see Fig. 1).

Fig. 1.

Simplified algorithm for the management of adverse reactions to biologics (adapted from Yang BC, Castells M. Medical algorithm: Diagnosis and treatment of drug hypersensitivity reactions to biologicals, 2024 update. Allergy, 2025) [22]

Interpretation of allergological testing for suspected biologic or excipient hypersensitivity must integrate the clinical history, the temporal relationship between exposure and symptoms, and the results of in vivo and in vitro assays. A positive skin prick test (SPT), intradermal test (IDT), or BAT performed with appropriate, non-irritant concentrations provides strong evidence of sensitization, especially when the reaction reproduces the patient’s symptoms [24, 25]. permanent discontinuation of the implicated biologic is recommended, and clinicians should evaluate the risk of cross-reactivity with other products containing the same excipient [22].

When skin testing and in vitro assays are negative and the prior reaction was non-severe, a supervised re-exposure or graded provocation may be performed in a controlled hospital setting to confirm or exclude clinical tolerance [22]. A negative provocation indicates that the event was unlikely to be IgE-mediated and allows cautious re-initiation of therapy under monitoring. Conversely, a positive provocation confirms hypersensitivity and mandates avoidance of the culprit formulation.

For patients with essential therapeutic indication and no suitable alternative, desensitization may be considered, but only in specialized centers with full resuscitation capabilities and operating under strict pharmacovigilance supervision [22, 23]. In all scenarios, the reaction, test outcomes, and management decisions should be documented and reported to national pharmacovigilance systems to contribute to post-marketing safety data and refine future diagnostic algorithms [22] [26]. Table 1 with steps.

Table 1.

Tables 1, 2, and 3: Stepwise allergologic evaluation of reactions to biologics and their excipients [22–26] [39]

These recommendations for allergological assessment in relation to biologics and their excipients must be considered within the context of current knowledge. While interpreting allergological testing results, it is essential to integrate clinical history, temporal relationships between exposure and symptoms, and the outcomes of both in vivo and in vitro assays. However, it is important to note that there are currently no prevalence data regarding the results of skin tests for biologics, nor is there sufficient information on desensitization cases associated with these medications. This lack of data underscores the need for further research to understand the effectiveness and safety of desensitization protocols in patients requiring biologic treatments.

Rheumatic and not Drug-Specific Adverse Events

While the mechanism by which biologic therapy may induce rheumatic conditions is unknown, there is increasing evidence that suggest these biologic agents may paradoxically induce an autoimmune process which can lead to the induction of systemic lupus erythematosus, vasculitis, sarcoidosis, and antiphospholipid syndrome [27–29]. Dupilumab and mepolizumab exhibited distinct adverse events (AEs) profiles. The most common AEs for dupilumab were arthralgia (16%), rash (14%), and Dupilumab-associated ocular surface disease (DAOSD) (10%). For mepolizumab, the most frequent AEs were headache (6%) and fatigue (6%) [30]. Real-world data indicate that, although dupilumab is an effective treatment for uncontrolled CRSwNP, the incidence of AEs and discontinuation rates may be higher than reported in Phase III trials [31]. Ocular AEs were the most common, followed by injection site reactions, musculoskeletal, and non-injection site skin reactions, leading to discontinuation of the medication due to an AEs in these patients. A recent meta-analysis evaluated the risk and incidence of rheumatic AEs associated with biologics in CRSwNP. The analysis included 3,434 patients, of whom 2,763 (80%) received either dupilumab (n = 2,257; 82%), mepolizumab (n = 372; 13%), or omalizumab (n = 134; 5%) for the treatment of CRSwNP. The most frequently reported rheumatic AEs was arthralgia or joint pain (n = 94; 95%), followed by lupus-like syndrome or lupus erythematosus–like reactions (n = 2; 2.5%). Treatment discontinuation represented the most common management approach (n = 21; 39%). The authors concluded that biologic therapy increases the risk of rheumatic AEs in CRSwNP patients by more than twofold, highlighting the need for vigilant monitoring and individualized management strategies [32]. Additionally, a recent analysis spanning five years has been published, detailing the AEs of biologic treatments for CRSwNP [33], they identify potential predictors associated with AEs to FDA approved biologics including gender (male > female), age (increasing age), and prescription indication (asthma > asthma + CRSwNP > CRSwNP). This data is important to prescribers educating their patients to potential AEs.

Given that tezepelumab is a relatively new therapeutic agent with limited real-world clinical experience, post-marketing safety data have been evaluated using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). This study identified 1,699 AEs reports related to tezepelumab. The majority of reported events involved the respiratory, thoracic, and mediastinal systems. The most frequently reported AEs included arthralgia and back pain, while unexpected events such as chest pain and myalgia were also observed. The median time to onset of AEs was 7.5 days, with most events occurring within the first month of treatment [34].

By contrast, safety data for depemokimab is still limited. Available analyses indicate significantly lower risks for pneumonia, nasopharyngitis, rhinitis, and back pain. Additionally, an increased risk of allergic rhinitis has been reported [35].

Drug-Specific Reactions

Although most AEs associated with biologic therapy are mild to moderate, each agent has a characteristic safety profile. Dupilumab has been most strongly associated with ocular surface disease (including conjunctivitis, blepharitis, keratitis, and dry eye) which is thought to reflect disruption of IL-4/IL-13-mediated homeostasis at the ocular mucosa [36]. Transient eosinophilia and arthralgia are also reported in a subset of patients [37]. Mepolizumab is generally well tolerated, with headache and fatigue being the most documented symptoms; transient injection-site reactions, musculoskeletal complaints, and rare cases of systemic hypersensitivity have been described [33]. Omalizumab is effective and well-established in allergic diseases but carries a recognized risk of anaphylaxis [38], which typically occurs within the first few doses. However, it may occur after subsequent doses, even in patients who have been using it for an extended period.

For all three biologics, delayed cutaneous eruptions, serum-sickness–like reactions, and immune-mediated arthropathies have been reported in case series and pharmacovigilance databases [33]. Dupilumab and omalizumab, dermatologic AEs were most frequently reported (23% and 12%: including rash, pruritus, dermatitis, eczema, and urticaria). Unlike dupilumab and omalizumab, many reported AEs related to mepolizumab were pulmonary (17%) or administration/medical error related (18%) [33].

Drug-specific reactions may therefore reflect direct immune modulation (eosinophilia with IL-5 blockade, ocular surface inflammation with IL-4/IL-13 blockade), off-target immune activation, or true hypersensitivity to the molecule or its excipients. When clinically significant, management options include temporary interruption with close monitoring, switching to a biologic of a different class (or when no alternative exists) formal desensitization in a controlled setting [22].

Overview of Hypersensitivity Mechanisms (IgE-Mediated and Non-IgE)

Hypersensitivity reactions to biologics encompass a spectrum of immunologic mechanisms. Immediate IgE-mediated reactions are characterized by rapid onset (minutes to hours), often with urticaria, angioedema, bronchospasm, hypotension, or anaphylaxis.

Demonstration of specific IgE, positive SPT, or BAT supports this mechanism, and re-exposure is contraindicated unless desensitization is necessary for life-saving indications, particularly for certain medications such as antibiotics. While this is not typically applicable for biologics used in the treatment of CRSwNP, if desensitization is deemed strictly necessary, it should be personalized to the patient’s specific condition [22].

Non-IgE mechanisms include immune complex–mediated (Type III) reactions, such as serum-sickness–like presentations with fever, arthralgia, lymphadenopathy, and rash occurring days to weeks after exposure. CRR (also described as infusion-related reactions) present with flushing, fever, myalgia, or rigors and result from rapid immune activation rather than allergen-specific IgE. Delayed T-cell–mediated (Type IV) hypersensitivity can manifest as maculopapular eruptions or severe cutaneous adverse reactions, though the latter are rare with current mAb therapies.

Importantly, some reactions are driven by ADA formation, leading to reduced drug efficacy, complement activation, or inflammatory reactions despite the absence of classical IgE pathways [39]. Others arise from sensitization to excipients (most notably PS80 or 20, EDTA, or other stabilizers) [20]. A precise distinction between these mechanisms guides management: IgE-mediated events require avoidance or desensitization, immune complex reactions may warrant drug withdrawal or switching class, and excipient-specific allergy may permit safe use of an alternative biologic with a different formulation [23].

• Dupilumab: can lead to ocular inflammation [36], eosinophilia, and a psoriasis-like rash [40, 41]. The proposed mechanism for these side effects is that dupilumab inhibits interleukin-4 (IL-4), which normally helps to suppress Th1 and Th17 cell activation. By inhibiting IL-4, dupilumab may inadvertently promote the activation of these cells, both of which play a role in the development of psoriasis. Omalizumab: Anaphylaxis [38] was identified with a higher disproportionality index than in other biologics. Among the five biologic agents, only omalizumab carries an FDA black box warning for anaphylaxis. Although this requires monitored administration and patient education, it remains infrequent. Dupilumab, mepolizumab and tezepelumab have not been associated with black box warnings, but both can cause injection-site reactions, transient eosinophilia, conjunctivitis, upper respiratory infections (dupilumab), and serum-sickness–like reactions [42].

• Mepolizumab: local and systemic rare reactions. Reported events include headache, fatigue, arthralgia, and occasional serum-sickness–like reactions. Severe immediate hypersensitivity is uncommon [32].

• Tezepelumab recently was associated with elevated respiratory-related AEs (17.92%), with musculoskeletal disorders also prominently reported (10.02%) [43]. In comparative analyses, tezepelumab additionally demonstrated a relatively higher propensity for vascular disorders compared with the three previously discussed mAb [43].

• Depemokimab currently, detailed long-term safety data remain limited. Further post-approval clinical experience and systematic real-world monitoring are required to fully characterize its safety profile. The most frequently reported adverse events to date include upper respiratory tract infection and nasopharyngitis [7].

Immunopathophysiological Models

Immunopathophysiological Models of Adverse Events During Biologic Therapy

Although biologics for CRSwNP selectively inhibit key type 2 inflammatory pathways, immune modulation may alter the broader cytokine network and immune homeostasis. Blockade of dominant Th2 pathways can result in immune rebalancing phenomena, including relative upregulation of Th1- and Th17-driven responses, which have been associated with paradoxical inflammatory conditions [44, 45]. In addition, ADA formation may occur despite advanced humanization techniques and can influence both safety and therapeutic response [39]. Understanding these immunopathophysiological models is essential to distinguish paradoxical immune shifts from true hypersensitivity reactions and to guide appropriate management strategies.

• Cytokine network imbalance (Th2 → Th1/Th17 shift)

Blocking a dominant cytokine axis (e.g., IL-4/IL-13 with an anti-IL-4Rα biologic) can alter the homeostatic balance among T-helper lineages. In some patients this perturbation results in a relative loss of Th2-dominant signals and a compensatory or unmasked increase in Th1 and/or Th17 pathway activity (the so-called Th2 → Th1/Th17 shift). This is not a literal conversion of one cell into another in most cases, but a re-patterning of local and systemic cytokine networks that changes inflammatory phenotypes [44].

• Unmasking of eosinophilic syndromes: clinical correlates ¿what clinicians see?

• a. Paradoxical psoriasiform eruptions and new-onset psoriasis have been reported after IL-4/IL-13 blockade (dupilumab) and are hypothesized to reflect Th17/IL-17 upregulation. Case series and reviews document this emerging phenotype [40].

• b. Seronegative inflammatory arthritis/enthesitis and other Th1/Th17-mediated syndromes have been described as uncommon paradoxical events post-biologic therapy. IL-4/13 axis also plays a role in homeostatic tissue repair, and evidence for a link with ocular and arterial pathology [45].

• c. Eosinophilic complications refer to the development of peripheral or tissue eosinophilia temporally associated with biologic therapy, sometimes accompanied by systemic manifestations. These events may include transient peripheral eosinophilia, eosinophilic pneumonia, or eosinophilic granulomatosis with polyangiitis (EGPA)-like presentations.

Clinically, transient blood eosinophilia is the most frequently observed finding and is often asymptomatic, particularly during the first months of IL-4/IL-13 pathway blockade [37]. In rare cases, organ-specific involvement such as pulmonary infiltrates or vasculitic features has been reported [37, 46]. Proposed mechanisms include redistribution of eosinophils from tissue to circulation, effects related to corticosteroid tapering or unmasking of previously suppressed eosinophilic disease rather than direct drug-induced eosinophilic toxicity [37]. Careful clinical evaluation is required to differentiate these events from primary vasculitis, infection, or progression of underlying eosinophilic disorders.

• –Anti-drug antibody formation (ADA)

Although advances in antibody engineering and humanization have markedly reduced immunogenic potential, substantial evidence indicates that ADA may still develop, even against fully humanized biologics [39]. Approximately 2.9% of individuals in the studies included in the metanalysis by Chen et al., developed ADA over course of follow-up period. The ADA incidence was highest in the dupilumab (7.6%) studies, followed by mepolizumab (3.6%) group and lowest in the omalizumab (0%) group. The subcutaneous route and longer dosing intervals were associated with higher ADA development [39]. In the clinical trial of depemokimab was also assessed through the presence of ADA bit specific data are not available [7].

Key Considerations for Biologic Therapy in CRSwNP Patients with Previous Neoplastic or Hematological Conditions

In patients considered for biologic therapy for CRSwNP with a history of serious neoplastic or hematological conditions, it is crucial to thoroughly evaluate concomitant treatments that may influence safety, efficacy, or the potential for drug interactions [47, 48].

The Following Outlines the Medications to be Considered

• a. Oncologic drugs and immunosuppressants: they induce bone marrow aplasia and neutropenia.

  • Classical chemotherapy (platins, taxanes, anthracyclines, cyclophosphamide): risk of myelosuppression, increased susceptibility to infections.
  • Immunomodulatory agents (lenalidomide, pomalidomide, thalidomide).
  • Tyrosine kinase inhibitors (imatinib, dasatinib, ibrutinib).
  • Oncologic monoclonal antibodies (rituximab, trastuzumab, anti-PD1/PDL1, CTLA-4).

Commentary: No direct pharmacokinetic interactions with biologics for CRSwNP have been described. However, there is a potential cumulative risk of immunosuppression or hematologic effects.

• b. Systemic corticosteroids: decreased T and B lymphocyte activation, reduced cytokine production, and impaired neutrophil and monocyte function. Consequently, both cellular and humoral immunity are suppressed

  • Chronic use of prednisone or equivalents in allergic disease [49].

Added risk: immunosuppression, opportunistic infections, osteoporosis. It is important to consider progressive reduction upon initiating effective biologic therapy.

• c. Non-oncologic Immunosuppressants:

  • Azathioprine, methotrexate, mycophenolate, cyclosporine, tacrolimus (used in autoimmune diseases). Possible immunosuppressive synergy, increased risk of infections and secondary neoplasms.
• d. Targeted therapies in allergology and dermatology

  • Cyclosporine, methotrexate (in atopic dermatitis prior to biologics).
  • Phototherapy and history of cutaneous cancer should be considered.
• e. Anti-IL therapies or concomitant biologics.

  • Combining two immunomodulatory biologics: while generally not recommended due to a lack of robust evidence and the risk of excessive immunosuppression, combining two immunomodulatory biologics appears to be safe in limited, highly selective cases, though further clinical experience and rigorous monitoring are essential [50].
• f. Other relevant drugs

  • Anticoagulants and antiplatelet agents (warfarin, aspirin): risk if the patient has thrombocytopenia associated with a hematologic disease. Prolonged antivirals and antibiotics in prophylaxis (in transplants, hematology).
  • Hormonal therapies (tamoxifen, GNRh analogs): While no direct interactions with CRSwNP biologics have been described, overall comorbidity burden, including thrombotic and bone health risk, should be considered in patients receiving concomitant oncologic or endocrine therapies [47–49].

Immunological Recommendations for Biologic Use in Clinical Practice

A comprehensive review of concomitant medications is imperative in oncologic/hematologic patients to mitigate the cumulative risk of immunosuppression. The combination of immunomodulatory biologics should be avoided, except in exceptional cases occurring within the framework of structured research protocols. The pathophysiology of cumulative risk does not stem from the biologic agent alone, but rather from the combination of non-specific immunosuppression (corticosteroids, chemotherapy, immunomodulators) with selective blockade of immune pathways by biologics. Diligent monitoring for opportunistic infections (herpes, latent tuberculosis, helminths) [48] is crucial, particularly in patients receiving systemic corticosteroids or concurrent immunosuppressants. Consultation with oncology/hematology specialists is essential prior to initiating biologic therapy, especially in individuals with active disease or those undergoing antineoplastic treatment.

Conclusions

Given the increasing evidence supporting the effectiveness of biologics in managing chronic CRSwNP, clinicians must prioritize vigilance in monitoring and mitigating potential adverse events, despite the fact that these medications are considered safe. A thorough understanding of each agent’s unique safety profile, coupled with individualized risk assessment considering patient specific factors, preexisting conditions, and concomitant medications, is paramount. In this context, a comprehensive allergology evaluation plays a critical role in identifying preexisting sensitivities and guiding safer therapeutic choices. Moreover, a multidisciplinary approach, involving close collaboration between allergists, otolaryngologists, and potentially other specialists like immunologists, is essential for holistic patient management. Careful attention to ethical considerations, transparent communication regarding drug origins, and proactive management of excipient related hypersensitivity are also key components of optimizing patient care. While biologics have revolutionized CRSwNP treatment, their safe and effective implementation requires a nuanced and collaborative approach that prioritizes both efficacy and patient well-being. Moving forward, further research focused on identifying predictive biomarkers for AEs, refining desensitization protocols, and exploring novel therapeutic targets remains crucial for advancing the field and improving long-term outcomes for individuals with CRSwNP.

Key References

• Ieven T, Coorevits L, Vandebotermet M, Tuyls S, Vanneste H, Santy L, et. al. Endotyping of IgE-Mediated Polyethylene Glycol and/or Polysorbate 80 Allergy. J Allergy Clin Immunol Pract. 2023 Oct;11(10):3146-3160. 10.1016/j.jaip.2023.06.031. Epub 2023 Jun 26. PMID: 37380070; PMCID: PMC10291891.

  • This is the most mechanistically advanced paper on PEG/PS80 allergy, which is one of our manuscript’s key novel themes. It provides: Molecular endotyping, correlation between PEG-IgE, PS80 skin tests, and BAT, and direct clinical implications for biologic switching.
• Yang BC, Castells M. Medical algorithm: Diagnosis and treatment of drug hypersensitivity reactions to biologicals, 2024 update. Allergy. 2025 May;80(5):1534-1539. 10.1111/all.16353. Epub 2024 Oct 14. PMID: 39400368.

  • This is a state-of-the-art EAACI-endorsed clinical algorithm, exactly aligned with Current Allergy and Asthma Reports (CAAR)’s mission of educational, practice-ready reviews. It provides: A stepwise diagnostic pathway, clear criteria for rechallenge vs desensitization, and integration of skin testing, BAT, provocation, and desensitization.

Funding

Without financial support.

Declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest

Author AID: has received speaker fees from GlaxoSmithKline, Sanofi and Regeneron Pharmaceuticals Inc., AstraZeneca, Viatris, Loafarma, Menarini, Organon, Uriach, Inmunotek, Leti, Diater and Optinose.

Author ZA: she has no conflict of interest.

Author MV: received remuneration for scientific advisory in the REAL Project from LETI Pharma and in the FARO Project from Astra-Zeneca, for participating in studies conducted by Orion Pharma and Pharmore Research and has also received honoraria as a speaker from LETI Pharma, Astra-Zeneca, GSK and Sanofi.

Author IA declares to have received honoraria for consultancy and conferences from AstraZeneca, Viatris, Roche, Sanofi, GSK, MSD, Menarini, Salvat, Galenus Health, Olympus, Medtronic, and Novartis.

Author JM: has received speaker fees from GlaxoSmithKline, Menarini, Merck Sharp & Dohme, Mylan-Meda Pharmaceuticals (Viatris), Novartis, Regeneron Pharmaceuticals Inc., Sanofi, UCB Pharma, and Uriach; clinical trial funding from Genentech-Roche, Regeneron Pharmaceuticals Inc., and Sanofi; research grants from Mylan-Meda Pharmaceuticals (Viatris) and Uriach; and advisory board fees from Genentech-Roche, Mylan-Meda Pharmaceuticals (Viatris), Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Uriach.

Permissions

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Competing interest

JM is a Section Editor for the journal Current Allergy and Asthma Reports. He was not involved in the peer-review or handling of the manuscript. The authors have no other competing interests to disclose.