Evolocumab, developed by Amgen Inc, is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby increasing low-density lipoprotein receptor recycling and enhancing the clearance of low-density lipoprotein cholesterol. PCSK9 inhibitors have revolutionized lipid management by achieving substantial low-density lipoprotein cholesterol reductions in patients who do not reach target levels with statins and ezetimibe.1Take-Home Message•Given the increased reliance in clinical medicine on biological pharmaceuticals, this is likely to become more commonplace, and the mechanisms of such reactions should be explored when feasible. Here, we have provided a framework for diagnosis, therapy, and advanced testing strategies to do just that.
The safety profile of evolocumab is generally favorable, with most adverse events being mild and transient. Common adverse reactions include nasopharyngitis, upper respiratory tract infections, back pain, and injection-site reactions.1,2 Severe hypersensitivity reactions, such as anaphylaxis, are rare but have been reported.1,2 The mechanism underlying these hypersensitivity reactions is not fully understood but may involve non-immunoglobulin E (IgE)-mediated pathways.3Visual SummaryEvolocumab-Induced Angioedema
Angioedema is a potentially life-threatening condition characterized by rapid-onset swelling of the deeper layers of the skin and mucous membranes, often affecting the face, lips, tongue, and airway. While angioedema is a well-known adverse effect of angiotensin-converting enzyme inhibitors (ACEi),3 its association with PCSK9 inhibitors, such as evolocumab, remains poorly documented.4 Previous literature has highlighted the potential for hypersensitivity reactions with PCSK9 inhibitors and underscores the importance of careful monitoring of patients receiving these therapies.4
To date, there have been no published case reports documenting evolocumab-induced angioedema. This case report describes the first known instance of acute-onset orofacial angioedema following evolocumab administration, highlighting the importance of clinical awareness and the need for further pharmacovigilance to elucidate the incidence, risk factors, and underlying mechanisms of this rare adverse event.
Case Presentation
A 64-year-old male with a medical history of familial hypercholesterolemia on biweekly subcutaneous evolocumab injections (last dose 6 days prior) presented with acute-onset face and tongue swelling associated with dysphagia, which developed after consuming rice and beans for dinner. He denied any known food allergies, use of herbal medications, or over-the-counter supplements. He had no prior history of angioedema and did not take ACEi, angiotensin II receptor blockers (ARBs), or nonsteroidal anti-inflammatory drugs (NSAIDs).
The patient also denied tobacco, alcohol, or illicit drug use. His family history was notable for premature cardiovascular disease in both his father and grandfather, occurring in their 40 to 50s.
Notably, he was initiated on biweekly evolocumab injections 4 months prior to his presentation after experiencing intolerance to the combined therapy of high-intensity statin and ezetimibe due to muscle aches.
Clinical Findings
Upon presentation to the emergency department, his vital signs were as follows: temperature, 37.2°C; blood pressure, 125/78 mm Hg; heart rate, 73 beats/min; respiratory rate, 18/min; and oxygen saturation, 98% on room air. Examination revealed a swollen face and edematous tongue with right submandibular prominence (Figure 1). Pulmonary assessment was unremarkable, with clear lung sounds and no stridor, wheezing, rales, or rhonchi.
The cardiovascular examination revealed a regular rate and rhythm without murmurs, and the abdominal examination showed a soft, nontender abdomen with active bowel sounds.Figure 1Marked Tongue Edema in a Patient With Evolocumab-Induced Angioedema
In the emergency department, the patient was initially treated with 0.3 mg intramuscular epinephrine, 25 mg intravenous diphenhydramine, and 10 mg intravenous dexamethasone.
Diagnostic Assessment
Laboratory results obtained on admission are demonstrated in Table 1.Table 1The Patient's Laboratory Data Obtained on AdmissionPatient's Values on AdmissionReference Range, AdultsHemoglobin, g/dL13.812.0-15.5Hematocrit, %39.734.9-44.5White cell count, per mm37,8003,500-10,500Platelet count, per mm3320,000150,000-450,000Sodium, mEq/dL140135-145Potassium, mEq/dL4.33.5-5.1BUN, mg/dL1412-21Creatinine, mg/dL1.10.72-1.25ALT, u/L249-29AST, u/L2912-31Alkaline phosphatase, U/L6540-150INR1TSH, mcIU/mL4.10.35-4.9A1C5.2≤6.5A1C = glycated hemoglobin; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; INR = international normalized ratio; TSH = thyroid-stimulating hormone.
Urinalysis was unremarkable, and urine toxicology was negative for methamphetamine, cocaine, opiates, phencyclidine, methadone, cannabinoids, barbiturates, and benzodiazepines. Chest radiography showed no acute cardiopulmonary abnormalities (Figure 2).Figure 2Posteroanterior Chest Radiograph Demonstrating No Acute Cardiopulmonary Abnormality
Contrast-enhanced computed tomography of the soft tissues of the neck revealed facial and scalp edema with prominent inflammatory changes centered around the submandibular gland, extending into the right glossotonsillar fossa. A mild mass effect on the oropharynx was observed, resulting in slight narrowing from the right side (Figure 3).Figure 3Contrast-Enhanced Computed Tomography (CT) of the Soft Tissues of the Neck Demonstrating Angioedema(A) Axial CT image showing facial edema (arrows 1 and 2) and scalp edema (arrows 3 and 4). (B) Sagittal and (C) axial CT images demonstrating edema in the right glossotonsillar fossa with mild mass effect on the oropharynx (arrows 5 and 6).
The patient was admitted to the intensive care unit for close airway observation. Laboratory evaluation of angioedema is demonstrated in Table 2.Table 2Laboratory Studies Assessing Potential Etiologies of AngioedemaPatient's ValuesReference Range, AdultsC1 esterase inhibitor level, mg/dL3421-39C1 esterase inhibitor function, %104>67C1q binding immune complex, μg Eq/mL<1.2<4.4Tryptase level, μg/L2.82.2–3.2
Decision-Making
The absence of ACEi, ARB, or NSAID use, along with normal complement, C1-INH, C1q-binding complex, and tryptase levels, helped exclude alternative etiologies of angioedema. Additionally, no other potential triggers were identified on verbal screening, making evolocumab the most likely causative agent.
Management
The patient's airway was closely monitored, and he was maintained on intravenous fluids, dexamethasone, and diphenhydramine during hospitalization. An Ear, Nose, and Throat specialist evaluated him and recommended continued conservative management. By hospital day 2, his facial and tongue swelling had markedly improved.
He successfully passed a swallow evaluation and tolerated a general diet without difficulty. The patient was advised to discontinue evolocumab and to follow up with his primary care physician and cardiologist to discuss the potential use of inclisiran as an alternative lipid-lowering therapy.
For a clinical timeline of evolocumab-induced angioedema, see Table 3.Table 3Clinical Timeline of Evolocumab-Induced AngioedemaTimeEvent/Clinical Course0 moEvolocumab InitiationStarted biweekly evolocumab injections for familial hypercholesterolemia after intolerance to statin and ezetimibe therapy.4 moSymptom onsetDeveloped acute orofacial swelling and dysphagia within 6 d of the last evolocumab injection.Emergency departmentClinical findings:•Facial and tongue swelling•No airway compromise•Normal vital signs and laboratory resultsTreatmentAcute management:•Intramuscular epinephrine 0.3 mg•Intravenous diphenhydramine 25 mg•Intravenous dexamethasone 10 mg•Admitted to intensive care unit for airway monitoring48 hClinical improvement:Marked reduction in swelling; passed swallow evaluation; transitioned to regular diet.Outcome/Follow-upResolution:Complete symptom resolution after discontinuing evolocumab.No recurrence during follow-up.Alternative lipid-lowering therapy (inclisiran) discussed with cardiology
Discussion
Evolocumab is generally well tolerated; however, according to the Food and Drug Administration reviewer summary, 5 cases of angioedema were reported among evolocumab-treated participants during clinical trials and their extension phases, though causality remained uncertain due to multiple confounding factors.4 In contrast, the lack of alternative triggers in our patient supports evolocumab as the most probable cause of angioedema.
Angioedema can arise from several biological pathways. The most common is histamine-mediated angioedema, caused by mast-cell or basophil degranulation and the release of histamine and other inflammatory mediators. This form develops rapidly, is often pruritic, and typically responds to antihistamines, corticosteroids, or epinephrine.3 In contrast, bradykinin-mediated angioedema results from excess bradykinin activity within the kallikrein–kinin system, leading to vasodilation and increased vascular permeability.
It occurs in hereditary or acquired C1 esterase inhibitor deficiencies and with ACEi therapy. These episodes evolve slowly, lack itching or urticaria, and do not respond to antihistamines or corticosteroids.3
With the expanding use of biologic therapies, monoclonal antibody–induced angioedema has emerged as a rare but clinically significant adverse effect. Reviews of antibody-based treatments for chronic diseases have documented angioedema associated with agents such as infliximab, cetuximab, rituximab, adalimumab, golimumab, and certolizumab.5, 6, 7, 8 Although hypersensitivity reactions, including angioedema, have been reported with evolocumab in postmarketing data,4 no published case reports have specifically described evolocumab-induced angioedema, and its underlying mechanism remains undefined.
Proposed mechanisms for angioedema associated with other monoclonal antibodies include:1.IgE-mediated reactions, in which patients develop specific IgE antibodies against the therapeutic antibody. Upon re-exposure, these antibodies cross-link on mast cells, triggering degranulation and histamine release that cause rapid swelling and urticaria. This mechanism is well described with older antibodies such as infliximab.5 In cetuximab, severe angioedema and anaphylaxis have been linked to pre-existing IgE antibodies targeting a galactose-α-1,3-galactose epitope on the Fab portion (Figure 4A).6Figure 4Mechanism of Monoclonal Antibody-Induced Angioedema(A) IgE-mediated reaction.
(B) Non-IgE-mediated reaction. (C) Immune complex-mediated reaction. This figure is generated from references.7, 8, 9 ADA = anti-drug antibody; CARPA = complement activation–related pseudoallergy.2.Non-IgE-mediated reactions, collectively referred to as complement activation–related pseudoallergy (CARPA), occur when the therapeutic antibody or immune complexes activate the complement system, generating anaphylatoxins (C3a and C5a).
These trigger mast-cell degranulation and increase vascular permeability, resulting in angioedema even after the first dose, as observed with rituximab (Figure 4B).73.Immune complex–mediated reactions, involving immune complex formation between the therapeutic monoclonal antibody and antidrug antibodies. These complexes activate the classical complement pathway, releasing inflammatory mediators that contribute to swelling and tissue edema (Figure 4C). This mechanism has been described with several biologics, including adalimumab, golimumab, and certolizumab.8
In this case, the patient developed acute orofacial swelling consistent with angioedema, without exposure to common triggers such as ACEis, ARBs, or NSAIDs or reported new environmental triggers. Laboratory evaluation showed normal C1-INH levels and function, normal C1q-binding immune complexes, and an unremarkable serum tryptase, effectively excluding hereditary, immune complex–mediated, or IgE-mediated mechanisms. Given the above factors, as well as the time between evolocumab administration and symptom onset, a non-IgE-mediated process—CARPA—is considered the most plausible etiology.
Although CARPA reactions typically occur with first or early exposures, delayed-onset responses have been reported with repeated or chronic biologic therapy.9 This may reflect gradual immune priming or cumulative complement activation over time.9 In this patient, angioedema developed after approximately 4 months of therapy, suggesting an idiosyncratic, exposure-dependent complement response. Thus, despite the delayed onset, a CARPA-like mechanism remains the most consistent explanation for this presentation.
Conclusions
Given that this is the first case report of suspected evolocumab-induced angioedema, future cases can be approached with a focus on mechanism exploration while pursuing the effective acute symptom treatment strategy outlined above.
We suggest evaluating the immune profile of any future affected patients to elucidate any specific antigenic variants that can predispose to angioedema or a similar-immune-mediated adverse event. In addition, testing for IgE, non-IgE, or immune-complex-mediated reactions using pathology-guided blood and/or tissue biopsy examinations can help shed light on the underlying immune process responsible for this reaction. Treatment with steroid and antihistamine therapies is an effective management strategy.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors declare that this manuscript is original, has not been previously published, and is not under consideration for publication elsewhere.