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 [27,28,29]. 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 ModelsImmunopathophysiological 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.

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.

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].