Adverse Reactions to Biologic Medications Used in Allergy and Immunology Diseases

Biologics Used in Allergic DiseaseOmalizumab

Omalizumab, the first biologic approved specifically for an allergic disease, now holds approval for moderate to severe asthma, chronic spontaneous urticaria, and most recently nasal polyposis. Omalizumab is a humanized monoclonal antibody that binds IgE forming biologically inert complexes. This prevents IgE from binding and activating the FceR1 receptor on mast cells and basophils, leading to downregulation of FceR1 receptors and diminished reactivity to allergens.

Early studies reported anaphylaxis in 0.1–0.2% of patients with most events occurring within 2 h of the first 3 injections. This led to a black box warning and requirements for in-office administration and prescription of epinephrine autoinjectors for all patients. A retrospective review of anaphylaxis reports found that most cases occurred in women ages 18–44 years and life-threatening anaphylaxis was more common among patients with asthma than chronic urticaria. Fatal anaphylactic events were rare (0.28% of all reports) [46]. Limited access to in-office therapies during the COVID-19 pandemic led Shaker et al. to examine the cost-effectiveness of self-administration of omalizumab at home. They found the risk of automobile accidents en route to or from the office and cost of in-office injections outweighed the small reduction in anaphylaxis related mortality [47]. Subsequently, omalizumab’s manufacturer suggested that prescribers may consider self-administration at home in patients without history of anaphylaxis who had tolerated 3 doses in clinic and were able to recognize and treat anaphylaxis.

With regards to management of omalizumab-related anaphylaxis, omalizumab RDD procedures have been reported [48•, 49, 50]. For omalizumab RDD, the largest cohort reported 12 patients, 67% of whom had Brown grade 2 reactions, and 33% who had a Brown grade 3 reaction [48•]. Skin testing was not performed. These patients underwent 97 omalizumab desensitization procedures, beginning with a two-bag, 7 step protocol with subsequent consolidation if tolerated. Of these treatments, 96% were tolerated with either no reaction or mild cutaneous symptoms. Of the four patients who had a systemic reaction, 2 had Brown grade 3 reactions during desensitization, one of whom had airway concerns and documented vocal cord dysfunction, and the other who developed wheezing and hypotension and required multiple doses of intramuscular epinephrine [48•]. As discussed above, the role of skin testing in biologic reactions is not clearly defined and practically difficult in most practice settings. Omalizumab is the only biologic discussed in this section for which non-irritating skin prick concentrations have been defined [28]. These concentrations are exceptionally dilute (1:100,000), which raises the question of whether skin testing of other biologics using higher concentrations may be affected by false positivity from irritant effects.

Several other unusual ADRs have been reported in association with omalizumab, though the incidence of these is unknown. Methemoglobinemia occurred with repeated exposure to omalizumab after other potential causative agents had been stopped in a 50-year-old woman treated for CSU [51]. Transient hair loss (telogen effluvium) has been reported in the first 1–2 months after initiation of omalizumab for CSU [52, 53]. Four incidents of serum sickness like reactions occurred in the original preclinical trials and symptoms resolved despite continuation of therapy (3 omalizumab and 1 placebo). Case reports of serum-sickness like reactions involving arthralgias, fever, and malaise occurring within a week of administration have been reported [23, 54]. However, these are not common; a retrospective review involving 923 patient-years of omalizumab therapy from a single center found no cases of serum sickness [55].

Mepolizumab

Mepolizumab is a humanized IL-5 blocking monoclonal antibody, first approved in 2015 for severe eosinophilic asthma. It has subsequently gained approval for eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndromes, and chronic rhinosinusitis with nasal polyps. Multiple long-term open label studies have examined the safety of both in-clinic and at-home administration of mepolizumab [56, 57]. Adverse events were similar between mepolizumab and placebo. Nasopharyngitis, headache, upper respiratory tract infections, and injection site reactions were most common [56,57,58]. No anaphylactic reactions were reported. Mepolizumab was approved for self-administration in 2019.

Reslizumab

Reslizumab is a humanized anti-IL-5 monoclonal antibody that is administered intravenously using weight-based dosing. A phase 3 trial including 492 patients found fewer overall adverse events with reslizumab compared to placebo (55% vs. 74%) and fewer treatment related AEs (7% vs. 16%). The most common AEs were asthma, URI, and sinusitis. Serious AEs occurred in 4% in both groups. One subject had anaphylaxis felt to be related to reslizumab, which responded to epinephrine [59]. A follow up long-term open label study found a similar safety profile with only 2% discontinuing due to treatment related AEs over 12–24 months [60]. A pooled analysis of multiple trials found a 0.3% risk of anaphylaxis with reslizumab leading to a black box warning [61]. Although only reslizumab and omalizumab carry this warning (Table 4), a retrospective review of biologic related anaphylaxis reports from 2004 to 2020 found increased rates of anaphylaxis with mepolizumab, benralizumab, omalizumab, and reslizumab (reporting odds ratios ranged from 4.65 to 24.19). Only dupilumab did not have an increased signal for anaphylaxis [46]. Most patients with biologic associated anaphylaxis were female and ages 18–64. Hospitalization occurred in 25% to 43% of cases and deaths were rare (0% to 1.92% of all events) [46].

Table 4 Common adverse drug reactions, anaphylaxis, and black box warnings for biologic agentsBenralizumab

Benralizumab is a humanized monoclonal antibody that binds to the α-subunit of the IL-5 receptor on eosinophils and basophils, leading to antibody dependent cell mediated cytotoxicity. It was approved for severe eosinophilic asthma in 2017. Adverse events, most commonly nasopharyngitis and worsening asthma, were not significantly different between placebo and treatment groups in phase 2b and phase 3 trials; drug related hypersensitivity reactions were also similar between groups, occurring in 3%, with no anaphylactic events [62,63,64]. A two-year extension study examining risks related to prolonged eosinophil depletion found no increase in parasitic infections [65, 66].

Dupilumab

Dupilumab is an anti-IL4Rα human monoclonal antibody approved for allergic asthma, nasal polyposis, and atopic dermatitis. It blocks signaling of both IL-4 and IL-13. Early studies and later meta-analyses found similar overall adverse event rates between dupilumab and placebo groups, while severe AEs were less common with dupilumab (2.6% vs. 6.3%) [67,68,69]. Increased severe AEs in the placebo group were primarily skin infections, such as eczema herpeticum, and felt to be related to uncontrolled atopic dermatitis. Three AEs have been found more commonly with dupilumab than placebo, including injection site reactions (15–18% vs. 5–10%), eosinophilia (4.1% vs. 0.6%), and conjunctivitis (5–28% vs. 2–11%) [67,68,69]. Eosinophilia peaks 16–20 weeks after initiating dupilumab with an average increase in the absolute eosinophil count of 10%. Of 52 patients on dupilumab who developed eosinophilia, only 4 had symptoms and 2 were reported as serious AEs (chronic eosinophilic pneumonia and hypereosinophilia) [67]. A subsequent retrospective review of 653 patients treated with dupilumab for atopic dermatitis found 9% had hypereosinophilia defined as 1500/mm3 or higher (mean 2600/mm3). This developed around 2.5 months after dupilumab initiation and although no clinical signs of organ involvement were detected, 25% of patients with hypereosinophilia discontinued therapy. Among those who continued, absolute eosinophil counts trended downwards with time [70].

In studies of atopic dermatitis but not other indications, dupilumab was associated with an increase in conjunctivitis compared to placebo. The original RCTs reported an incidence of 5% to 28% compared to 20% to 25% in subsequent open label studies [71•, 72, 73]. Symptoms develop in the first weeks to months after drug initiation (average 6 weeks). New terminology, dupilumab associated ocular surface disease (DAOSD), has been suggested to better capture the spectrum from mild, self-limited conjunctivitis and dry eye to more severe forms of keratitis, blepharitis, and cicatricial conjunctivitis, see Table 5. Proposed mechanisms for DAOSD include increased Th1 inflammation and goblet cell hypoplasia due to IL-13 blockade resulting in decreased mucin and epithelial barrier dysfunction. More severe atopic dermatitis at baseline and preexisting conjunctivitis appear to augment the risk of DAOSD [71•, 73]. Topical therapies, including artificial tears, corticosteroids, tacrolimus, and cyclosporine eyedrops, result in resolution or disease control in most cases. However, 3.6% to 15% of patients with DAOSD (less than 1% of all patients on dupilumab for atopic dermatitis) experience severe symptoms requiring discontinuation of dupilumab [71•, 73,74,75].

Table 5 Dupilumab associated ocular surface diseaseTezepelumab

Tezepelumab, the newest biologic in this field, was approved in 2021 for severe asthma of any endotype. It is a human monoclonal antibody directed against thymic stromal lymphoprotein (TSLP). TSLP is a cytokine released by respiratory epithelium in response to allergic and non-allergic stimuli. One case of Guillain–Barre syndrome was seen with Tezepelumab in the phase 2 trial [76]. None occurred in the phase 3 trial and both overall and serious AEs were similar between placebo and treatment groups. The most common AEs were nasopharyngitis, URI, headache, and asthma, the last of which was more frequent in the placebo group [77].

Biologics Used in Immunologic ConditionsRituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody used to achieve B cell depletion in a variety of inflammatory, autoimmune, and malignant conditions. It is associated with Pichler types α (cytokine release), β (hypersensitivity), and γ (immunomodulatory) adverse events.

Type α events include infusion reactions and, more rarely, cytokine release syndrome. While the pathophysiology is not fully understood, these are felt to be non-immunologic AEs and are associated with elevated levels of IL-6 and TNF-α. Infusion reactions are most common during the initial rituximab infusion, affecting up to 77% of patients [78]. Symptoms may include flushing, fever, chills, heart rate or blood pressure changes, nausea, dyspnea, and syncope. Infusion reactions tend to subside with subsequent infusions. They also respond to infusion rate reduction and various premedication regimens, including antihistamines, systemic steroids, antipyretics, and leukotriene receptor antagonists. Cytokine release syndrome results from target cell lysis and typically occurs in the context of lymphoma rather than autoimmune disease or immunodeficiency.

Allergy to rituximab (type β reactions) occur more rarely in roughly 3–10% of patients [45]. Both immediate IgE-mediate and delayed type hypersensitivity reactions may occur. The latter include serum sickness-like reactions, Steven Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS). A systematic review of rituximab induced serum sickness identified fever (78.8%), arthralgia (72.7%), and rash (69.7%) as the most common presenting symptoms, with 48.5% exhibiting the entire triad [20]. On average, symptoms developed 6–7 days after rituximab infusion. Most cases were treated with corticosteroids and mean time to resolution of symptoms was 2 days. Four patients were retreated with rituximab and all were premedicated with 100 mg prednisolone or methylprednisolone. Two of the 4 tolerated subsequent rituximab infusions, 1 had recurrent serum sickness, and 1 had angioedema. Although there is limited data on retreatment, this is emerging as an acceptable course in patients with SSLR who require further therapy [20, 31]. Patients should be informed of the potential risk of recurrence, which may be attenuated using premedication with steroids and/or a steroid taper following future infusions.

Immediate hypersensitivity reactions to rituximab have some similarity to and may coexist with infusion reactions. As these are often difficult to distinguish some authors suggest managing reactions according to severity rather than mechanism. A retrospective review of 67 patients with reactions to initial rituximab infusions found that 88% were NCI grade 1 or 2 [78]. This grading system does not account for etiology (e.g., IgE vs. non-IgE mediated). Reactions were treated with antihistamines, steroids, beta-agonists, and/or IV fluids. No patients required epinephrine. Fifty-one patients were rechallenged the same day using a 50% infusion rate reduction and 37 tolerated this without ADRs. Reactions to rechallenge increased with severity of initial reaction: none of the grade 1 patients reacted, 5 of 35 grade 2 patients, and all of grade 3 patients reacted. Reactions to same-day rechallenge were predominantly grade 1–2. This suggests that most patients with mild initial reactions can safely tolerate rituximab with premedication, rate reduction, and symptomatic treatment, whereas skin testing and desensitization procedures should be reserved for those with severe (grade 3 or 4) reactions.

Lastly, rituximab can cause a secondary immunodeficiency, predispose to infections, or lead to reactivation of latent virus (type γ events). Some patients experience prolonged B cell depletion and secondary hypogammaglobulinemia (defined as low IgG levels) persisting beyond the expected duration of rituximab efficacy. The incidence is not clearly defined and hypogammaglobulinemia may or may not be associated with impaired specific antibody responses and a clinical syndrome of recurrent infections. A recent AAAAI work group statement on secondary hypogammaglobulinemia recommends checking immunoglobulin levels at baseline and 4–6 months after each infusion [79••]. Depending on infection history and plans for immunosuppression, B cell enumeration and vaccine responses can help further define the presence of immunodeficiency. Pre-treatment hypogammaglobulinemia is a predictor of more severe post-rituximab hypogammaglobulinemia and infection risk [80, 81]. Lower respiratory tract infections are most common, similar to primary hypogammaglobulinemia disorders. Immunoglobulin replacement therapy may be indicated in patients with significant infectious complications, particularly if they require ongoing rituximab therapy [79••]. Late onset neutropenia (ANC < 1000/mm3) has also been observed in 6.6% of patients receiving rituximab for autoimmune conditions. Most cases are reversible with filgastim and fewer than half are associated with fever or infection [82]. Finally, Hepatitis B reactivation is a well-known risk of rituximab therapy and screening prior to initiation is recommended.

Anti-TNF

Anti-tumor necrosis factor (TNF) biologics include both monoclonal antibodies infliximab, adalimumab, golimumab, and certolizumab, as well as etanercept, a soluble TNF receptor that competitively binds TNF. These medications are used to treat autoinflammatory conditions such as common variable immunodeficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome-associated enteropathies.

Type α events include infusion reactions and injection site reactions with intravenous and subcutaneous anti-TNF therapies, respectively. Infusion reactions occur immediately, and are generally rate-dependent and responsive to premedication. Injection site reactions are thought to be mediated by local binding of soluble antigen that aggregates near the injection site; these are typically self-limited [10].

Similar to rituximab, immediate, serum sickness-like, and delayed hypersensitivity (type β) reactions have been reported with anti-TNF biologics [18]. Immediate reactions can be IgE mediated via FceR1 activation as well as IgG mediated through FceγRIIA and generation of complement anaphylatoxins [10]. Non-irritating concentrations for skin prick and intradermal testing are reported for etanercept, infliximab, and adalimumab [18]. In addition to immediate reactions, neutralizing anti-drug antibodies may develop over time leading to loss of therapeutic efficacy. Anti-drug antibodies are detected in 10–50% of patients receiving infliximab and 25–30% receiving adalimumab. If patients lose response to a particular agent, switching to a different anti-TNF monoclonal antibody is often successful [83].

Type γ reactions include both predisposition to new infections as well as reactivation of latent tuberculosis, hepatitis B, and hepatitis C. Reactivation of tuberculosis often manifests as extrapulmonary disseminated disease. Screening for these infections and administration of age-appropriate vaccinations prior to initiating anti-TNF therapies are recommended. Opportunistic infections, particularly fungal, are increased with anti-TNF therapies. The risk of infections is greatest during the first 12 months of therapy and is higher with anti-TNF monoclonal antibodies compared to etanercept [83]. Anti-TNF therapies are also associated with an increased development of auto-antibodies, such as ANA and anti-double-stranded DNA. However, these infrequently lead to symptoms of autoimmunity, which usually present as a lupus-like syndrome or vasculitis [83].

留言 (0)

沒有登入
gif