Autoimmune Angioedema - Causes, Diagnosis, and Treatment

Introduction

Autoimmune angioedema is an immune-mediated disorder presenting with a recurrent, well-demarcated, pitting type of edema (showing indentation when put under pressure) seen in the deep subcutaneous tissues. Angioedema primarily affects the face, lips, tongue, oropharynx, genitals, distal extremities, and gastrointestinal mucosa. The condition, if left untreated, can cause life-threatening airway compromise leading to death.

What Are the Types of Autoimmune Angioedema?

Based on the association with other conditions, autoimmune angioedema is categorized into two types:

• Type 1: Associated with other lymphoproliferative and autoimmune disorders.

• Type 2: Associated with autoantibodies against C1-INH (C1 esterase inhibitor) proteins in the blood.

Sometimes it might be difficult to differentiate between the two types of autoimmune angioedemas. Type-1-associated disorders may not be apparent till years after the presentation of angioedema.

Who Is Susceptible to Autoimmune Angioedema?

Autoimmune angioedema comprises less than one to two percent of all angioedemas. The true prevalence of the condition is difficult to estimate, but the same has been reported to be somewhere between 1 in 100,000 to 500,000 individuals. In the United States, less than 5000 cases have been reported to date. According to recorded medical literature, trauma, medical procedures, emotional stress, menstruation, oral contraceptives, infections, and drugs are some of the known triggers that induce autoimmune angioedema. In more than 90 % of the cases, people develop the condition after the age of 40, with 50 percent of the cases reporting abdominal pain, which is less than the hereditary variant that shows abdominal pain in more than 80 percent of cases.

What Causes Autoimmune Angioedema?

Possible causes of angioedema involve drug reaction, IgE-mediated allergy (immunoglobulin E mediated allergy), hereditary, protein deficiency, or in association with other autoimmune disorders.

Autoimmune angioedema is caused due to an acquired deficiency of C1-INH either due to consumption or inactivation. The deficiency increases the catabolism that may be associated with other autoimmune disorders or malignancies. The edema may recur spontaneously and last for not more than a week. Along with edematous conditions in various body parts, it may also cause severe abdominal pain from gastrointestinal mucosal edema. The condition has been known to occur alongside various lymphoproliferative disorders.

What Is the Pathophysiology of Autoimmune Angioedema?

The underlying pathophysiology of any kind of angioedema involves an increase in vascular permeability and vasodilation. This is mediated by histamine, bradykinin, or complement factors, resulting in fluid leakage into the interstitial space. Active C1-INH protein levels are decreased by catabolism or inactivating binding. The decrease in the protein levels leads to complement pathway dysregulation, which increases vascular permeability, mast cell degradation, and topping bradykinin levels. The majority of the patients also show autoantibodies against the concerned protein, C1-INH.

What Are the Clinical Features of Autoimmune Angioedema?

Edematous regions are seen throughout the body involving the lips, tongue, face, eyelids, larynx, genitals, and digits. The swellings are localized, well-demarcated, and non-pitting. The swelling develops rapidly, shows an unequal distribution, and the patient lacks any other symptoms that may be indicative of a different diagnosis.

The other clinical features are

• Urticaria (skin rashes).

• Abdominal pain (recurrent, severe, and mimicking surgical abdomen).

• Partial bowel resection.

How to Diagnose Autoimmune Angioedema?

Since pharynx involvement is common in this condition, the patients may present with a definitive compromised airway or with symptoms like voice change, hoarseness, stridor (high-pitched voice), or dyspnea (shortness of breath), all of which are indicative of possible airway involvement. This can be confirmed by fiber-optic-nasopharyngoscopy.

How to Manage Autoimmune Angioedema?

Oropharynx swelling makes emergent airway assessment and management a priority. Upon recognizing symptoms of potential airway compromise, the same must be confirmed by fiber-optic-nasopharyngoscopy. If the airway is already compromised, direct laryngoscopy may be out of scope, and fiberoptic intubation can be a viable alternative. Operators might opt for mild sedation (instead of complete) in order to preserve the patient’s respiratory effects since intubation carries a high degree of difficulty, especially in a compromised airway. Cricothyrotomy might be an ideal key to securing the airway.

After achieving airway clearance and access, supplemental medical oxygen, parental H1-blocker (antihistamines), parental steroid, and intramuscular Epinephrine are the primary management modes. These have shown limited success in managing autoimmune angioedema-associated swelling. Hence plasma-derived or recombinant C1-INH are recommended for acute attacks; even then, some patients are non-responsive.

Pharmacotherapy involves Icatibant, a bradykinin B2 receptor antagonist, which is well-tolerated and provides relief in autoimmune-associated swelling. Ecallantide, a bradykinin pathway inhibitor, has shown promising results and is recommended as an alternative to patients with C1-INH replacement. Other treatment modalities involve FFP (fresh frozen plasma), which is effective but may sometimes worsen symptoms. One of the most important aspects of treatment is to treat any underlying pathology or condition that triggers autoimmune angioedema.

The patients need constant re-evaluation as the attacks tend to recur, and the patients may suddenly deteriorate sans warning. Persistent involvement of intra-oral and throat components indicates a need for hospitalization and observation in the ER (emergency room) for at least four to six hours before discharging to a supportive environment.

What Is the Differential Diagnosis of Autoimmune Angioedema?

• Intestinal occlusion syndrome (blockage preventing food passage to the intestines).

• Hereditary angioedema (similar to autoimmune angioedema but hereditary in nature with differences in response to therapies and abdominal pain).

• Histamine-induced angioedema (swelling under the skin due to histamines).

What Are the Complications of Autoimmune Angioedema?

• Asphyxiation (oxygen deprivation).

• Fainting.

• Sudden or rapidly escalating breathing problems.

• Collapsing.

• Respiratory collapse.

• Brain damage.

• Death.

Conclusion

Autoimmune angioedema falls under a wider category of angioedemas. While other conditions occur as a result of various infections, traumas, allergies, genetic inheritance, or from medication side effects, the autoimmune variant is caused as a result of autoantibodies against certain vascular proteins. The disease is such that any kind of swelling in the head and neck region, any difficulty in breathing, change of voice, or abdominal pains should be referred to the concerned specialist so that preventive measures might be taken to prevent a full-fledged attack. The treatment requires an interdisciplinary approach involving ER physicians, anesthesiologists, rheumatologists, and allergists. New cases should be emergently managed, and when the patient is out of danger, underlying etiologies should be assessed and managed.