Urticaria and angioedema

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Urticaria and angioedema

Christos Kasparis and Frances Humphreys

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Urticaria is the result of transient leakage of plasma from the dermal vasculature and is characterized by short-lived, itchy, raised wheals due to dermal edema. In angioedema the swelling is deeper, resulting in more diffuse and prolonged edema, particularly affecting the face. These conditions are defined as chronic if symptoms have lasted longer than 6 weeks.

Hereditary angioedema (HAO) and the physical urticarias are dealt with separately in their respective chapters.

Management strategy

Explanation of the nature and prognosis of the disorder is important. Most patients with chronic urticaria (CU) become asymptomatic within 2 years. Patients with a longer history and those with coexisting physical urticarias are less likely to remit. It is important to exclude causative and exacerbating factors, particularly drugs (i.e., aspirin, non-steroidal anti-inflammatories (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors). IgE-mediated allergy is rarely a cause of chronic symptoms and does not need to be tested for routinely. Blood tests and chest radiography should only be performed if history or examination dictates. There is an increased incidence of positive thyroid autoantibodies in CU patients and some evidence of an increased incidence of celiac disease in children. In patients with CU, 30–40% has a positive autologous serum skin test providing evidence of autoimmunity. This test is not performed in routine practice. HAO should be excluded in those with angioedema without urticaria by measuring the C4 and C1 esterase inhibitor levels. Individual urticarial lesions lasting over 24 hours may indicate urticarial vasculitis, necessitating skin biopsy and appropriate investigation if confirmed.

Potent non-sedating antihistamines are the mainstay of treatment and are usually given regularly, but occasionally as required for intermittent symptoms. Many patients show a diurnal variation in symptoms, and timing of once-daily treatment should be adjusted accordingly. In practice acrivastine, cetirizine/levocetirizine, fexofenadine, loratadine/desloratadine, bilastine, mizolastine, and rupatadine are all effective. Individual responses to different antihistamines reportedly vary and tachyphylaxis is reported, so changing H1 antagonists is warranted. Increasing the dose of an individual antihistamine (up to four times the normal dose for levocetirizine and desloratadine), combining two different long-acting ones 12 hours apart, or adding a short-acting antihistamine for breakthrough symptoms, can all be useful maneuvers. Sedative antihistamines can be useful at night, particularly for nocturnal pruritus and sleep disturbance.

There is increasing evidence of some benefit of adding leukotriene antagonists to H1 antihistamines in some patients, although some trials have failed to confirm this. There is some evidence that pseudoallergen-free diets may help in urticaria. It seems logical to try a low-salicylate diet for a 4-week assessment period in patients who report exacerbation of symptoms with aspirin or NSAIDs. Systemic corticosteroids do not help all patients with urticaria and, if introduced and effective in CU, can be very difficult to withdraw. A short course of prednisolone 20–30 mg daily for 3 days can reduce the severity and time course of attacks of angioedema and acute urticaria. Intramuscular epinephrine (adrenaline) is not routinely used, but may be necessary for severe angioedema affecting the upper respiratory tract.

H2 antagonists have been used in combination with H1 antagonists, but their benefit in practice is disappointing. Patients with confirmed Helicobacter pylori infection have a greater chance of remission of urticaria after successful eradication therapy.

Limited evidence exists for other therapies such as doxepin (a tricyclic with H1 antagonist properties), nifedipine, phototherapy (PUVA and narrowband UVB), sulfasalazine, and warfarin. Levamisole (an antihelmintic with immunomodulatory properties) offers an added positive effect when combined with standard H1 antagonists. Non-hereditary angioedema has been treated with stanozolol and tranexamic acid. Dipyridamole has been used in combination with an H1 antagonist. Some authors have used thyroxine, with variable results. The potential benefits of therapies for which evidence is poor must be weighed against possible side effects.

There is now good evidence for an autoimmune etiology in CU. Because most patients have a self-limiting and non-life-threatening condition, immunosuppressive therapy is not indicated for the majority. In those with severe and unremitting problems who are experiencing considerable morbidity associated with the condition, cyclosporine, methotrexate, plasmapheresis, and intravenous immunoglobulin have all now been shown to be effective. The benefit of such treatment may be short-lived. A recent open study has shown that 4 weeks of cyclosporine gives the same degree of benefit as 12 weeks of treatment.

Mycophenolate mofetil and tacrolimus have been used for patients with very severe symptoms in open studies. Omalizumab has been used successfully in refractory CU.

Specific investigations

First-line therapies

imageNon-sedating H1 antagonists A

There are many double-blind studies of non-sedating antihistamines showing efficacy, but few high-quality comparative studies.

Second-line therapies

imageLeukotriene antagonists A
imageDiet B
imageCorticosteroids A
imageH2 antagonists B
imageEradication of Helicobacter B
imageDoxepin B
imageNifedipine C
imagePUVA C
imageNarrowband UVB B
imageSulfasalazine C
imageWarfarin C
imageStanozolol B
imageTranexamic acid C
imageDipyridamole B
imageThyroid hormone C
imageLevamisole A

Third-line therapies

imageCyclosporine A
imageMethotrexate D
imagePlasmapheresis C
imageIntravenous immunoglobulin C
imageMycophenolate mofetil C
imageTacrolimus C
imageOmalizumab A

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Urticaria and angioedema

Christos Kasparis and Frances Humphreys

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Urticaria is the result of transient leakage of plasma from the dermal vasculature and is characterized by short-lived, itchy, raised wheals due to dermal edema. In angioedema the swelling is deeper, resulting in more diffuse and prolonged edema, particularly affecting the face. These conditions are defined as chronic if symptoms have lasted longer than 6 weeks.

Hereditary angioedema (HAO) and the physical urticarias are dealt with separately in their respective chapters.

Management strategy

Explanation of the nature and prognosis of the disorder is important. Most patients with chronic urticaria (CU) become asymptomatic within 2 years. Patients with a longer history and those with coexisting physical urticarias are less likely to remit. It is important to exclude causative and exacerbating factors, particularly drugs (i.e., aspirin, non-steroidal anti-inflammatories (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors). IgE-mediated allergy is rarely a cause of chronic symptoms and does not need to be tested for routinely. Blood tests and chest radiography should only be performed if history or examination dictates. There is an increased incidence of positive thyroid autoantibodies in CU patients and some evidence of an increased incidence of celiac disease in children. In patients with CU, 30–40% has a positive autologous serum skin test providing evidence of autoimmunity. This test is not performed in routine practice. HAO should be excluded in those with angioedema without urticaria by measuring the C4 and C1 esterase inhibitor levels. Individual urticarial lesions lasting over 24 hours may indicate urticarial vasculitis, necessitating skin biopsy and appropriate investigation if confirmed.

Potent non-sedating antihistamines are the mainstay of treatment and are usually given regularly, but occasionally as required for intermittent symptoms. Many patients show a diurnal variation in symptoms, and timing of once-daily treatment should be adjusted accordingly. In practice acrivastine, cetirizine/levocetirizine, fexofenadine, loratadine/desloratadine, bilastine, mizolastine, and rupatadine are all effective. Individual responses to different antihistamines reportedly vary and tachyphylaxis is reported, so changing H1 antagonists is warranted. Increasing the dose of an individual antihistamine (up to four times the normal dose for levocetirizine and desloratadine), combining two different long-acting ones 12 hours apart, or adding a short-acting antihistamine for breakthrough symptoms, can all be useful maneuvers. Sedative antihistamines can be useful at night, particularly for nocturnal pruritus and sleep disturbance.

There is increasing evidence of some benefit of adding leukotriene antagonists to H1 antihistamines in some patients, although some trials have failed to confirm this. There is some evidence that pseudoallergen-free diets may help in urticaria. It seems logical to try a low-salicylate diet for a 4-week assessment period in patients who report exacerbation of symptoms with aspirin or NSAIDs. Systemic corticosteroids do not help all patients with urticaria and, if introduced and effective in CU, can be very difficult to withdraw. A short course of prednisolone 20–30 mg daily for 3 days can reduce the severity and time course of attacks of angioedema and acute urticaria. Intramuscular epinephrine (adrenaline) is not routinely used, but may be necessary for severe angioedema affecting the upper respiratory tract.

H2 antagonists have been used in combination with H1 antagonists, but their benefit in practice is disappointing. Patients with confirmed Helicobacter pylori infection have a greater chance of remission of urticaria after successful eradication therapy.

Limited evidence exists for other therapies such as doxepin (a tricyclic with H1 antagonist properties), nifedipine, phototherapy (PUVA and narrowband UVB), sulfasalazine, and warfarin. Levamisole (an antihelmintic with immunomodulatory properties) offers an added positive effect when combined with standard H1 antagonists. Non-hereditary angioedema has been treated with stanozolol and tranexamic acid. Dipyridamole has been used in combination with an H1 antagonist. Some authors have used thyroxine, with variable results. The potential benefits of therapies for which evidence is poor must be weighed against possible side effects.

There is now good evidence for an autoimmune etiology in CU. Because most patients have a self-limiting and non-life-threatening condition, immunosuppressive therapy is not indicated for the majority. In those with severe and unremitting problems who are experiencing considerable morbidity associated with the condition, cyclosporine, methotrexate, plasmapheresis, and intravenous immunoglobulin have all now been shown to be effective. The benefit of such treatment may be short-lived. A recent open study has shown that 4 weeks of cyclosporine gives the same degree of benefit as 12 weeks of treatment.

Mycophenolate mofetil and tacrolimus have been used for patients with very severe symptoms in open studies. Omalizumab has been used successfully in refractory CU.

Specific investigations

First-line therapies

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