Acquired Angioedema Due to C1 Inhibitor Deficiency

Acquired angioedema (AAE) due to acquired C1-inhibitor (C1-INH) deficiency (C1-INH-AAE) is a rare disorder caused by acquired consumption of C1-INH. It is clinically characterized by recurrent episodes of nonpitting asymmetric edema of the face, lips, tongue, limbs, and genitals; severe abdominal pain due to edema of the gastrointestinal mucosa; and life-threatening edema of the upper respiratory tract. It is not associated with urticaria and is not an immunoglobulin E (IgE)‒mediated process.

Acquired angioedema was first described by Caldwell et al in 1972. The three key elements that initially characterized acquired angioedema were acquired deficiency of C1-INH, hyperactivation of the classic pathway of human complement, and recurrent angioedema symptoms.[1]

Two distinct syndromes are described below. Both types of acquired angioedema (AAE) without urticaria are characterized by painless, nonpruritic, nonpitting swelling of the skin. They are classified into 2 forms: acquired angioedema type I (AAE-I) and acquired angioedema type II (AAE-II).

Acquired angioedema type I is associated with other diseases, most commonly B-cell lymphoproliferative disorders. Acquired angioedema type II is an autoimmune process defined by the presence of an autoantibody directed against the C1 inhibitor molecule (C1-INH).

See the image below.

Angioedema secondary to ACE inhibitors.

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C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is primarily synthesized by hepatocytes. Its synthesis is up-regulated by interferon-gamma, interleukin 6, and interleukin 1. Androgens may also have a role in stimulating C1-INH synthesis. The major functions of C1-INH include inhibition of activated C1r and C1s, inhibition of activated Hageman factor (XIIa), and inhibition of activated kallikrein, the contact system protease that cleaves kininogen and releases bradykinin.[2]

Bradykinin is an important mediator involved in tissue permeability and vascular dilatation. Its biological effect is exerted through activation of bradykinin B2 receptors, which are expressed in the membranes of endothelial and smooth muscles cells. Elevated blood bradykinin levels are found during clinical flares in patients with angioedema.  Other kinins may also be pathogenic.[2]

The specific trigger responsible for inducing the release of these vasoactive peptides is unclear. Activation of factor XII (Hageman factor) may be secondary to phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation. This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin.

Supporting the importance of bradykinin in acquired angioedema, vascular permeability has been shown to increase in mice deficient in C1-INH, but not in mice with a deficiency in both C1-INH and the bradykinin B2 receptor.[3] The precise pathophysiology of acquired angioedema type I remains to be defined. C1-INH levels diminish as a result of its increased catabolism and excessive activation of the classic complement pathway.

Although the current classification of acquired angioedema is being readdressed, in acquired angioedema type I, the associated disorders (usually lymphoproliferative malignancies) produce complement-activating factors, idiotype/anti-idiotype antibodies, or other immune complexes that destroy C1-INH function. Neoplastic lymphatic tissue has been found to play an active role in the consumption of C1-INH and the complement components of the classic pathway.

The most commonly associated malignancy, B-cell lymphoma, has shown that anti-idiotypic antibody attached to immunoglobulin on the surface of B-cells causes C1-INH deficiency. Increased consumption of C1q followed by C2 and C4 results in subsequent release of vasoactive peptides that act on postcapillary venules.

In acquired angioedema type II, a normal 105-kd C1-INH molecule is synthesized in adequate amounts but, because of an unknown event, a subpopulation of B cells secretes autoantibodies to the C1-INH molecule. This autoantibody, which may be of any of the major immunoglobulin classes, binds to the reactive center of C1-INH. After binding to C1-INH and altering its structure, its regulatory capacity is diminished or abrogated.

In all reported cases of C1-INH deficiency caused by an autoantibody, C1-INH circulates in the blood in a form that has been cleaved by target proteases from its native molecule to a 95-kd fragment. Because of the higher affinity of the autoantibody for native C1-INH, the 95-kd antibody/C1-INH complex dissociates, and the freed antibody can bind to another native C1-INH molecule, further depleting C1-INH.

The distinction between acquired angioedema type I and acquired angioedema type II may be difficult to make at times, and it is imperative to stress that overlap does occur. For instance, cases of monoclonal gammopathy of undetermined significance (MGUS) have shown the monoclonal immunoglobulin itself to be the C1-INH antibody. Patients with acquired angioedema type I may initially present with autoantibodies to C1-INH, or the autoantibodies may develop as the disease progresses. While measuring antibodies against C1-INH is useful, groups have also developed assays that can measure the antibody against C1-INH in complex with C1-INH. In one study, anti–C1-INH antibodies were detected in 9 of 20 patients, while the complex between anti–C1-INH and C1-INH was found in 18 of 20, suggesting that there could be greater numbers of patients with anti–C1-INH antibodies than is seen when measuring antibody alone.[4]

Acquired angioedema type I is most frequently associated with B-cell lymphoproliferative disease. To date, only three reports of a T-cell lymphoma associated with acquired angioedema type I have been documented.[5]

Other associated disorders have included the following:

• Multiple myeloma

• Chronic lymphocytic leukemia

• Myelofibrosis

• Waldenström macroglobulinemia

• Non-Hodgkin lymphoma

• MGUS

• Rectal carcinoma

• Essential cryoglobulinemia

• Erythrocyte sensitization

• Livedo reticularis

• Cold urticaria

• Lupus anticoagulant

• Infection with Helicobacter pylori or Echinococcus granulosis

Acquired angioedema type II is not associated with any specific disorder but rather is characterized by the presence of autoantibody directed against C1-INH. Most of these antibodies work by binding the epitopes around the reactive center of INH.[6] However, the occasional existence of features of both acquired angioedema type I and acquired angioedema type-II has been noted, most notably with a MGUS.

A 2016 study reported that 33% of patients presenting with acquired angioedema had or would develop non-Hodgkin lymphoma, in particular marginal zone lymphoma. Of the studied patients, 62.5% were diagnosed with non-Hodgkin lymphoma at the onset of angioedema or up to 7 years later. Patients presenting with acquired angioedema and C1-INH deficiency should be monitored regularly for the development of malignancy.[7]

In addition to associations with MGUS, C1-INH–deficient AAE has also been reported in monoclonal gammopathy of renal significance (MGRS).[8] One case of acquired angioedema with C1-INH deficiency state was identified in association with liver transplantation. The status of the liver donor was unknown, but it is speculated that the donor may have been C1-INH deficient. Another case of acquired angioedema was reported with acute upper airway angioedema in association with the local anesthetic articaine.

Acquired angioedema is rare. Only approximately 150 cases have been reported in the medical literature worldwide.

Racial and sexual differences in incidence

Persons of any race can be affected by acquired angioedema. Men and women are equally affected.

Age-related differences in incidence

The onset of acquired angioedema is most common after the fourth decade of life, whereas the usual onset of hereditary acquired angioedema (HAE) is in the second decade.

The prognosis for patients with acquired angioedema is variable, and, in most cases, it depends on control of the underlying disorder. However, even with appropriate treatment of the underlying disease, patients may be free of symptoms only temporarily. Additionally, some patients who have had their underlying disease treated will be free of symptoms related to angioedema but will continue to have biochemical abnormalities.[9]

Compared with the general population, patients with acquired angioedema have a higher incidence of B-cell malignancies. Patients with acquired angioedema and a concurrent diagnosis of monoclonal gammopathy of undetermined significance (MGUS) do not have an increased risk for progression to malignancy compared with patients with a sole diagnosis of MGUS.

Although mortality may occur because of laryngeal edema, it is more likely due to the complications of the associated disorder.

For patient education information, see the Allergy Center and Hives and Angioedema.

Apart from negative family history and age of onset, acquired angioedema cannot be distinguished clinically from hereditary angioedema.

Patients with acquired angioedema typically report no family history and onset is most commonly after the fourth decade.

Patients with acquired angioedema, similar to hereditary angioedema, report recurrent episodes of subcutaneous or submucosal edema at various locations, usually lasting 48-72 hours, but they can persist for up to 5 days in rare occasions. The edema is usually unresponsive to antihistamine therapy. The frequency of attacks is unpredictable and varies widely among affected individuals, as well as in the same individual.[10, 11]

Angioedema symptoms are referable to 3 prominent sites: subcutaneous tissues (eg, face, hands, arms, legs, genitals, buttocks); abdominal organs (eg, stomach, intestines, bladder), which may manifest as nausea, vomiting, and/or colicky pain and mimic a surgical emergency; and the upper airway (eg, larynx), which may result in laryngeal edema.

The most common reported symptom is nonpitting, nonpruritic cutaneous swelling of face and extremities.

Occasionally, acquired angioedema patients may experience heat and pain in the affected areas. Other symptoms of acquired angioedema may be related to underlying disorders, such as lymphoproliferative malignancies or connective tissue disease.

The clinical presentation is not distinguishable from hereditary angioedema. Physical signs include overt, noninflammatory swelling of the skin and mucous membranes. Although urticaria does not usually occur, occasionally, erythema or mild urticarial eruptions may precede the edema.

When looking at reports of different rates of recurrence at specific sites, hereditary angioedema has a tendency to present with more extremity involvement than does acquired angioedema, which presents more with face involvement than limb involvement. Acute abdominal pain due to edema of the gastrointestinal mucosa is less reported in acquired angioedema (30-50%) when compared with hereditary angioedema, in which it is reported in up to 80%.[10, 11]

Screening is conducted by determining the C4 level, which is decreased both during and in between clinical flares. If the C4 level is normal but clinical suspicion remains high, the C4 testing should be repeated, and, additionally, qualitative and functional values of C1 inhibitor (C1-INH) should be obtained. Antigenic levels of C1q are usually low and are useful to distinguish hereditary angioedema from acquired angioedema.[2]

Test results for acquired angioedema types I and II are as follows:

• Low C1-INH level

• Low C1q levels (except 1 reported case)

• Low C4 and C2 levels

Acquired angioedema type II shows positive immunoblot assay findings for the 95-kd C1-INH cleavage product.

An enzyme-linked immunosorbent assay (ELISA) has been developed that measures the neutralizing capacity of anti-C1-INH antibodies in plasma.[12]

Other laboratory findings are related to associated illnesses.

During attacks of gastrointestinal edema, abdominal ultrasonography or computed tomography scanning may show edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid.

Other findings may be referable to an associated illness.

Histologic findings are indistinguishable from other angioedema types. Features include sparse perivascular mononuclear cell infiltrate and reticular dermal, subcutaneous, or submucosal edema.

Vasodilation may be seen.

A variety of agents can be used for acute attacks of acquired angioedema (see Medication).[13] Depending on the symptoms and the site of the angioedema, intensive support may be necessary, including intravenous fluids. Intubation may be necessary in cases of laryngeal edema.

When possible, the underlying disorder should be treated. The resolution of angioedema has been reported with the treatment of underlying disease, although recurrences have occurred despite appropriate treatment of the disorder. In acquired angioedema type I (AAE-I), treatment of the associated lymphoproliferative process may result in correction of the abnormality.

Nonmyeloablative stem cell transplantation resulted in sustained remission in a patient with previously refractory acquired angioedema type I.[14]

Go to Angioedema, Pediatric Angioedema, Acute Angioedema, and Hereditary Angioedema for complete information on this topic.

The goals of pharmacotherapy for acquired angioedema are to reduce morbidity and to prevent complications. Medication may be used for acute or preventive treatment.

In Europe, purified C1 inhibitor (C1-INH) has been available for the treatment of acute attacks of angioedema in hereditary angioedema (HAE) patients for decades, and it is now available in the United States. In October 2008, the US Food and Drug Administration (FDA) approved the use of C1-INH (Cinryze) at a dose of 1000 units IV 2-3 times/wk for prophylaxis to prevent HAE attacks. In October 2009, the FDA approved C1-INH (Berinert) at a dose of 20 units/kg IV for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE. Berinert was also approved for acute treatment of laryngeal attacks in January 2012.

In acquired angioedema, therapy for acute attacks may also be aborted with C1-INH concentrates.[15, 16] In one study of 44 patients with C1-INH–deficient AAE, treatment with plasma-derived C1-INH concentrate consistently decreased the duration of attacks compared with nontreatment.[15] Although there is wide variability in the degree of responsiveness, the findings are true even when a patient has autoantibodies against C1-INH. Rapid catabolism of C1-INH occurs in acquired angioedema and may require higher doses of C1-INH plasma concentrate compared with HAE. If C1-INH concentrate is unavailable, fresh-frozen plasma can be used.

In June 2017, the FDA approved the first subcutaneous C1 esterase inhibitor (Haegarda) for prevention of HAE attacks in patients aged 12-72 years. Approval was based on the phase 3 COMPACT trial (n=90), which showed C1-INH 60 IU twice weekly SC reduced the median number of HAE attacks by 90% compared with placebo. The study also showed use of rescue medication was reduced by greater than 99% versus placebo.[17]

In December 2009, ecallantide (Kalbitor), a kallikrein inhibitor, at a dose of 30 mg SC was approved for the treatment of acute attacks.

In August 2011, icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved for treatment of acute attacks of HAE in adults at a dose of 30 mg SC in the abdominal area. It is highly effective in decreasing the duration of attacks of acquired angioedema and was reported to successfully treat 26 of 26 patients.[16]

Androgens, such as danazol, may be beneficial in acquired angioedema type I, with one study reporting effective treatment of 23 (75%) of 31 patients.[16] Androgens are of no value in acquired angioedema type II. Prostate cancer and pregnancy preclude the use of androgens.

Antifibrinolytics, such as epsilon-aminocaproic acid and tranexamic acid, have been found to be more effective for long-term prophylaxis in those with acquired angioedema, although tranexamic acid has moderate efficacy as an abortive as well.[16]

Immunosuppressive therapy directed toward decreasing autoantibody production may be of value in patients with acquired angioedema type II, which may be accomplished by the use of plasmapheresis with cyclophosphamide.

In 2004 and 2006, two papers reported effective treatment of acquired angioedema cases with a series of 4 weekly injections with rituximab (a chimeric monoclonal antibody to CD20). In one study, rituximab treatment resulted in normalization of C1-INH and C4 levels and long-term remission of angioedema attacks in 3 patients with severe acquired angioedema.[18] In the second study, a patient with acquired angioedema type II refractory to standard treatment experienced a 6-month attack-free interval after treatment with rituximab.[19] Several other reports have supported the efficacy of rituximab in achieving remission of acquired angioedema in patients with either an underlying B-cell lymphoproliferative disorder or autoimmune disease.[20, 21, 22, 23] A long-term study of 10 patients over 10 years showed that rituximab decreased the number of attacks and increased the amount of C1-INH in patients with C1-INH–deficient acquired angioedema.[24]

Another immunosuppressant drug, etanercept, was reported to control angioedema in a 57-year old man with psoriatic arthritis. This man was treated with 25 mg of etanercept administered subcutaneously twice per week for recalcitrant psoriatic arthritis. The treatment also resulted in improvement of the patient's angioedema. The authors hypothesized that etanercept may have improved the angioedema by decreasing inflammation and vascular permeability.[25]

Class Summary

These agents are used to improve the clinical aspects of the disease.

Fresh Frozen Plasma

Infuse prior to airway manipulation (eg, dental extraction) to prevent angioedema. Administering 2 units of fresh frozen plasma (FFP) sustains complement control and prevents the development of angioedema. Improved screening programs greatly reduce risk of hepatitis. FFP is not recommended for treatment of acute attacks.

Class Summary

Some agents in this class have potent immunosuppressive activity.

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Class Summary

C1-INH is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). It regulates activation of the pathway for complement and intrinsic coagulation, and it regulates the fibrinolytic system. Depending on the particular brand, these concentrates are used in the acute treatment of angioedema. They are approved by the US FDA for routine prophylaxis against angioedema attacks and as treatment for acute attacks.

C1 esterase inhibitor, human (Berinert)

This agent is a serine proteinase inhibitor found in human blood that regulates activation of the kinin system, complement pathway, intrinsic coagulation system, and fibrinolytic system. It binds to and neutralizes substrates that activate these systems, thereby suppressing activity. It is available as a pasteurized, lyophilized preparation derived from purified human plasma. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. C1 esterase inhibitor is indicated for acute laryngeal, abdominal, and facial angioedema attacks in adolescents and adults with HAE.

C1 inhibitor human (Berinert, Cinryze, Haegarda)

This agent is aerine proteinase inhibitor that increases the plasma concentration of C1 inhibitor activity. Berinert is indicated for the treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults and children. Cinryze and Haegarda are indicated for routine prophylaxis in adults and adolescents. Berinert and Cinryze are administered as an intravenous infusion, whereas Haegarda is administered as a subcutaneous injection.

C1 esterase inhibitor recombinant (Ruconest)

This agent is a human recombinant C1 esterase inhibitor purified from the milk of genetically modified (transgenic) rabbits; it restores the level of functional C1 esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling. It is indicated for the treatment of acute HAE attacks in adults and adolescents. It is administered as an intravenous infusion over 5 minutes.

Class Summary

These agents have specific kallikrein inhibitor activity, resulting in bradykinin reduction. They are useful for treating acute episodic attacks. The package insert carries a black box warning because a small subset of patients may have anaphylactic reactions to the drugs. They must be administered by medical personnel capable of treating anaphylaxis.

Ecallantide (Kalbitor)

A human plasma kallikrein inhibitor, ecallantide binds to plasma kallikrein and blocks its binding site. It reduces the conversion of kininogen to bradykinin. This agent is indicated for acute attacks of HAE. It is available as an injectable solution; 10 mg/mL per single-use vial.

Class Summary

Bradykinin receptor antagonists such as icatibant inhibit bradykinin from binding the B2 receptor and thereby treat the clinical symptoms of an acute attack. Recommended dose of icatibant is 30 mg SC in the abdominal area. It is available as a single-use, prefilled syringe, which delivers a dose of 30 mg (10 mg/mL).

Icatibant (Firazyr)

Icatibant is a bradykinin B2 receptor antagonist indicated for acute attacks of hereditary angioedema (HAE).

Class Summary

These agents have immunosuppressive properties.

Danazol

Danazol increases levels of the C4 component of complement and prevents attacks associated with angioedema.

Class Summary

Antifibrinolytic agents act through the inhibition of plasmin. They tend to be more effective than androgens for prophylaxis.

Aminocaproic acid (Amicar)

Aminocaproic acid is a lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity.

This agent is widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal. It can be used PO or IV.

Tranexamic acid (Cyklokapron, Lysteda)

An alternative to aminocaproic acid, tranexamic acid inhibits fibrinolysis by displacing plasminogen from fibrin.

Class Summary

The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.

Rituximab (Rituxan)

Rituximab is a humanized monoclonal antibody. It binds to the CD20 antigen, inducing complement- or antibody-mediated cytolysis. Variable treatment regimens have been used to treat acquired angioedema.