Angioedema. Interdisciplinary diagnostic and therapeutic recommendations of the Polish Dermatological Society (PTD) and Polish Society of Allergology (PTA)

Idiopathic histaminergic acquired angioedema (AAE-IH)

This is one of the most common types of isolated AE. The mechanism of this type of oedema involves IgE-mediated or non-IgE-mediated mast cell activation with histamine release, and therefore it is termed “histaminergic” oedema. Similarly to urticaria, various factors may trigger this typeof oedema, e.g. drugs, foods, insect venoms and other environmental allergens, as well as physical factors. AAE-IH’s relation to infectious foci and autoimmune diseases is unclear. When the factor that activated mast cells cannot be identified, idiopathic oedema is diagnosed [2, 5]. The condition can occur at any age. Most commonly it is acute, sometimes chronic and recurrent. The symptoms mainly affect the face, predominantly lips and eyelids, less commonly the larynx or the gastrointestinal mucosa. Family history of AE is negative [2].

Diagnostic workup: it is important to try to identify the etiological factors responsible and any co-morbidities, and to rule out other types of AAE and HAE [2, 18].

Treatment: AHs, sometimes at multiplied daily doses, similarly as in urticaria, and in acute forms additionally glucocorticosteroids (GCS) and adrenaline [2].

Idiopathic non-histaminergic acquired angioedema (AAE-InH)

Causes and clinical presentation of this form of oedema are similar to AAE-InH, but the symptoms are not resolved with antihistamines, hence the name “non-histaminergic” oedema. The principal mediator responsible for the symptoms in AAE-InH is bradykinin, but the role of leukotrienes, prostaglandins and platelet activating factor cannot be ruled out [2]. This disease mainly affects middle-aged patients; women are affected slightly more often. Most patients exhibit facial oedema; approximately one third also develop upper respiratory and gastrointestinal symptoms. This type of oedema, as the AAE-IH, is not a familial disease [2, 20].

Diagnostic workup: same as recommended for AAE-IH.

Treatment: a large number of patients respond well to tranexamic acid – a synthetic amino acid with antihemorrhagic activity. In patients with contraindications to this drug, GCS, cyclosporine Aor omalizumab may be considered. The varying responses of AAE-InH patients to different therapies indicate heterogeneity of this type of oedema and participation of various mediators in its pathomechanism[2, 22, 23].

Acquired angioedema with C1 inhibitor deficiency (AAE-C1-INH)

This form of the disorder is diagnosed in patients with C1 inhibitor deficiency without a mutation in the C1-INH gene (SERPING1) and without a family history of oedema [2]. Reduced C1-INH levels in this type of AE may result from increased consumption of this inhibitor or from production of C1-INH-neutralizing antibodies. This is observed in lymphoproliferative diseases, gammopathies as well as autoimmune disorders, e.g. systemic lupus erythematosus [2, 10, 24].

AAE-C1-INH occurs in adults of both sexes, usually over 40 years of age. The oedema usually affectsthe face, tongue, uvula and upper airways, but can also appear at any other location. Gastrointestinalsymptoms are markedly less common than in hereditary angioedema with C1 inhibitor deficiency [2, 24].

Diagnostic workup: the fundamental step is detection of reduced serum C1-INH levels. In the majority of patients this parameter does not exceed 50% of normal value, although in some patients, in particular at an early stage of the disease, C1-INH abnormalities may manifest only during an oedema attack.Reduction of serum C4 and C1q levels is also typical for this form of oedema. If the clinical presentation and test results are inconclusive, identification of the SERPING1 mutation may be necessary to confirm this diagnosis [2].

Testing for co-morbidities, e.g. lymphoreticular proliferations, monoclonal gammopathy of uncertainsignificance (MGUS) or autoimmune diseases is necessary in all patients diagnosed with AAE-C1-INH. Therecommended laboratory tests include complete blood count with differential, C-reactive protein, serumprotein electrophoresis, analysis of light chains in 24-hour urine collection. When complete blood count is abnormal, more detailed haematology tests should be performed [2, 10, 25].

Treatment: involves predominantly therapy of the potential underlying diseases. If such management is impossible or ineffective, and the oedema is severe, anti-oedema therapy should be initiated. Reduction of oedema frequency and intensity can be achieved in some patients with C1-INH supplementation, but not all patients respond to this therapy, which is due to the extremely rapid catabolism of this inhibitor. Use of a type 2 bradykinin receptor antagonist (icatibant) or plasma kallikrein inhibitor (ecallantide) may also be attempted [2, 26]. There are also reports documenting good therapeutic effects of rituximab, a monoclonal anti-CD20 antibody [27, 28]. Attenuated androgens are less effective than in hereditary oedema with C1-INH deficiency. Tranexamic acid is recommended for prophylaxis [2].

Acquired angioedema related to ACE-I therapy (AAE-ACE-I)

The pathomechanism of this disorder is due to ACE-I affecting bradykinin metabolism. Angiotensin-converting enzyme breaks down bradykinin to inactive metabolites. Inhibition of its activity by administration of ACE-I results in increased bradykinin levels and development of oedema. This disease affectsapproximately 0.5% of patients treated with ACE inhibitors. The development of oedema is favoured by coexistence of other factors that inhibit bradykinin catabolism [2, 29]. Concomitant use of ACE-I and other drugs, e.g.immunosuppressants or calcium channel blockers, increases the risk of angioedema [30]. This type of oedema usually affects patients over the age of 65, more often women. The symptoms usually develop shortly after the initiation of ACE-I therapy, although cases ofonset after many years of good treatment tolerance have also been reported. The symptoms usually affect the face, mainly lips and eyelids, the neck, the tongue and upper airways; they may be mild, but fatal cases of laryngeal oedema have also been observed. Gastrointestinal symptoms are rarely reported [2].

Diagnostic workup: establishment of the relation between the oedema symptoms and intake of ACE-I.

Treatment: discontinue the drug that causes the symptoms as soon as possible. Continuing the therapy may result in marked oedema progression and the patient’s death. There have been cases of persistence of the symptoms, usually in a milder form, despite discontinuation of ACE-I. This may occur in patients with a genetic defect of bradykinin metabolism or those in whom the drug revealed AAE-InH [31]. Off-label use of icatibant, a drug approved for the treatment of hereditary angioedema with C1 inhibitor deficiency, may help in the therapy of persistent, recurrent oedema [32]. Available data indicate that angiotensin receptor blockers (ARBs) are a safe alternative for patients with ACE-I hypersensitivity [33, 34].

Hereditary angioedema with C1-INH deficiency (HAE-C1-INH)

It presents in two forms:

This condition is caused by a mutation in one of the two alleles of the SERPING1 (serpin family G member) gene coding for C1-INH. It is an autosomal dominant condition, thus most patients have a positive family history. De novo mutations have been reported as the cause of the disease in approximately 20–25% of cases; in these cases, family history is negative [1, 10, 35]. Despite the fact that the genedefect has been present since birth, symptoms rarely manifest in the neonatal period or during infancy[36]. The onset usually occurs at a young age, most commonly between 5 and 11 years, but sometimes the first episode occurs in adulthood. This condition usually manifests as the oedema of deeper skin layers and subcutaneous tissue of variable location (face, chest, limbs, genital areas). It may also affect mucosa of the throat, larynx and gastrointestinal tract. The severity of lesions is highly variable, from poorly symptomatic or asymptomatic to very severe cases with numerous life-threatening attacks [2, 6, 10].

Oedema attacks are most commonly triggered by factors such as medical procedures, mechanical injuries, physical exertion, infections or stress. In females, the symptoms are sometimes exacerbated duringpuberty and pregnancy, which is due to increased oestrogen levels. Moreover, some drugs, such as oral contraceptives, hormone replacement agents or ACE-I may increase the frequency and severity of the attacks [6, 37].

Diagnostic workup: an important factor is history of recurrent angioedema episodes without urticaria wheals that do not respond to drugs conventionally used to relieve oedema, such as antihistamines, GCS or adrenaline. Patients with this form of the disease often also report laryngeal oedema and recurrent abdominal pain, often persisting for a few days. A history of ACE-I use should be ruled out and attention should be paid to other drugs and allergens that can trigger the symptoms. Checking for similar symptoms in a family member is very important since it confirms HAE with high degree of probability.Laboratory tests in this type of oedema are focused on measuring complement components – primarily the concentration and activity of C1 inhibitor and C4 component. Most commonly C1-INH activity does not exceed 30% of normal value. These tests should be performed twice with a 1–3 month interval, using different blood samples. If normal values of these parameters are obtained in a patient with a clinical suspicion of HAE-C1-INH, the test should be repeated during an oedema attack. In most patients, C4 component levels are reduced in the asymptomatic period as well, both in HAE-1 and in HAE-2 [2, 6, 10, 38].

Apart from family history, age at first onset and comorbidities, differential diagnostic workup ofhereditary angioedema with C1-INH deficiency (HAE-C1-INH) and acquired angioedema (AAE-C1-INH) shouldinclude the levels of C1q component. This parameter is reduced in approximately 75% of AAE-C1-INH patients, whereas it is usually normal in HAE-C1-INH [2, 6, 38, 39]. Genetic testing (for SERPING1 mutations) is usually required in diagnostically challenging cases, e.g. with a negative family history and late onset of symptoms, and where it is necessary to differentiate from hereditary angioedema with a normal level and activity of C1-INH [6, 10].

Treatment of patients differs depending on the disease phase. In the management of HAE-C1-INH patients, it is important to identify and eliminate factors that trigger and exacerbate symptoms, such as ACE-I or oestrogen products [2].

In an acute oedema attack, a complement component C1 inhibitor (C1-INH) should be used. This group includes plasma-derived products: pdC1-INH (Berinert) and recombinant rhC1-INH (Ruconest). These drugs are administered intravenously, at a per kg body weight dose. Berinert is used at a dose of 20 U/kg body weight, and Ruconest at a dose of 50 U/kg body weight. If the symptoms are severe, sometimes the dose needs to be repeated [2, 10, 40].

An alternative for the substitution therapy is type 2 bradykinin receptor antagonist (Firazyr). The drug is administered subcutaneously at a fixed dose of 30 mg as a ready solution in a pre-filled syringe. Occasionally a patient requires another drug dose – it should be administered 6 h after the first injection.

In Poland, therapy with plasma-derived recombinant C1-INH products and bradykinin receptor antagonists is only reimbursed in acute, life-threatening HAE-C1-INH attacks that affect the throat, larynx or the abdominal cavity. In children, only Berinert is fully reimbursed. Ruconest is reimbursed up to the age of 13, and Firazyr is not reimbursed for paediatric patients. All drugs currently used in Poland to stop an attack are approved for self-administration at home.

Patients and/or their caretakers should undergo regular training in the correct and safe use of the drug to be able to initiate the therapy on their own as soon as the first symptoms appear. Early injection of the drug reduces the severity and shortens the duration of symptoms. All patients diagnosed with HAE should be equipped with drugs for self-use, in amounts sufficient to treat 2 attacks; they should always have them at hand.

If the above-mentioned products are not available, fresh frozen plasma can be used to treat an acute attack. Another drug effective in the treatment of acute attacks, a kallikrein blocker (ecallantide), is not available in Poland [10, 40, 41].

Chronic treatment to prevent acute oedema attacks in HAE-C1-INH patients involves long-term, continuous administration of drugs to reduce the number and severity of attacks. A decision to initiate suchtherapy is based mainly on the frequency, severity and location of the oedema, the effectiveness of rescue treatment in stopping the oedema and the socio-occupational situation of the patient.

The first choice in prophylactic treatment is plasma-derived C1-INH, to be administered subcutaneously every 3–4 days, or lanadelumab to be given subcutaneously every 2 weeks [2, 40, 42, 43]. Lanadelumab is a monoclonal antibody, a specific kallikrein inhibitor in the kallikrein-kinin system. Studies revealed its high and lasting efficacy in the inhibition of plasma kallikrein activity, which was associated with a significant reduction of the HAE attack frequency [40, 41].

Androgen derivatives (danazol, stanazolol) are an alternative in this long-term therapy. These products are effective in prevention of acute oedema attacks in most HAE-C1-INH patients, but their use islimited by numerous adverse effects. Moreover, these drugs cannot be used in children and pregnant or lactating women. The dose is selected individually for each patient. Long-term use of danazol at dosesexceeding 200 mg daily is not recommended [2, 44].

Antifibrinolytic drugs (tranexamic acid) are given when other drugs are contraindicated or unavailable. These products can also be used in children. Tranexamic acid is administered orally, usually at adose of 30–50 mg/kg body weight, in 2–3 divided doses. It is usually well tolerated. Thedrug should be avoided in patients with a high risk of thrombosis [2, 6, 40].

Short-term therapy to prevent the attacks should be administered in HAE-C1-INH patients before medical procedures involving mechanical compression or injuries in the oral cavity, throat and larynx, as well as procedures involving disruption of tissue integrity that can induce an attack. Plasma-derived C1-INH is the therapy of choice in these situations. This product should be used at a therapeutic dose at least 6 h before the procedure. If the inhibitor is unavailable, fresh frozen plasma should be used [2, 45].

Hereditary angioedema with normal C1-INH (HAE-nC1-INH)

This variation of isolated angioedema is diagnosed in patients with a positive family history with normal C1 inhibitor levels and activity. Four types with genetic abnormalities have been identified, and one of unknown aetiology:

Clinical presentation, diagnostic workup and therapy of this type of oedema are identical as in HAE-C1-INH. The definite differential diagnosis requires genetic testing. If autoantibodies to C1-INH are present, plasmapheresis and use of cytotoxic drugs, androgens and tranexamic acid may be required.

Table 4 presents typical results of laboratory tests performed as part of the diagnostic workup of each type of isolated angioedema [2, 6, 48].