1. Definition
Urticaria} is a limited edematous reaction due to the dilation and increased permeability of small blood vessels in the skin and mucous membranes. Clinically, the characteristic manifestation is a wind mass of varying size with pruritus, which may be accompanied by angioedema. Chronic urticaria is defined as at least 2 episodes per week lasting ≥6 weeks. A small number of patients with chronic urticaria may also present with intermittent attacks.
2. Etiology
The cause of acute urticaria can often be found, but the cause of chronic urticaria is more difficult to define. The causes are usually divided into exogenous and endogenous. Exogenous factors are mostly temporary, including physical stimuli (friction, pressure, cold, heat, sunlight exposure, etc.), food (animal proteins such as fish, shrimp, crab, shellfish, eggs, etc., plants or fruits such as lemon, mango, plum, apricot, strawberry, pecan, cocoa, garlic, tomato, etc., spoiled food and food additives), drugs (immune-mediated such as penicillin, sulfonamides, serum preparations, various vaccines, or non-immune-mediated mast cell releasing agents such as morphine, codeine, aspirin, etc.), implants (artificial joints, anastomoses, heart valves, orthopedic plates, steel nails, and gynecological birth control devices, etc.), and exercise.
Endogenous factors are persistent and include mast cell hypersensitivity to IgE, chronic occult infections (bacterial, fungal, viral, parasitic, etc., e.g., Helicobacter pylori infection may be important in a minority of patients), exertion or stress, autoimmunity against IgE or high-affinity IgE receptors, and chronic diseases such as rheumatic fever, systemic lupus erythematosus, thyroid disease, lymphoma, leukemia, inflammatory bowel disease etc. In particular, chronic urticaria} is rarely caused by allergen-mediated causes.
3. Pathogenesis
The pathogenesis of urticaria is still not well understood and may involve infections, allergic reactions, pseudo-allergic reactions and auto-reactivity. Mast cells play a central role in the pathogenesis, and their activation and degranulation, leading to the release of histamine, leukotrienes, prostaglandins, etc., are key to the occurrence, development, prognosis and therapeutic response of urticaria}. Mechanisms that induce mast cell activation and degranulation include immunologic, nonimmunologic, and idiopathic.
Immune mechanisms include autoimmunity against IgE or high-affinity IgE receptors, IgE-dependent, and antigen-antibody complex and complement system-mediated pathways; nonimmune mechanisms include direct induction by mast cell releasing agents, pseudoallergenic responses induced by small molecule compounds in food, or altered arachidonic acid metabolism by nonsteroidal anti-inflammatory drugs; and a minority of urticaria} patients whose pathogenesis cannot be elucidated at present and may even It may not depend on mast cell activation.
4. Clinical manifestations and classification
The clinical manifestation of urticaria is a wind cluster, with various forms of attacks, mostly accompanied by pruritus, and a few patients may be combined with angioedema. According to the pathogenesis pattern, combined with clinical manifestations, urticaria} can be clinically classified. Different types of urticaria} have certain differences in their clinical manifestations.
5. Diagnosis and differential diagnosis
(1) History and physical examination
history of allergy, infection, visceral disease, trauma, surgery, medication, psychological and mental status, menstrual history, lifestyle, work and living environment, and response to previous treatment.
(2) Laboratory tests
Usually no additional tests are needed for urticaria. In acute patients, blood tests can be performed to find out whether the onset of the disease is related to infection or allergy. In chronic patients with severe disease, long duration of disease or poor response to conventional doses of antihistamines, relevant tests such as routine blood tests, eggs, liver and kidney function, immunoglobulins, erythrocyte sedimentation rate, C-reactive protein, complement and various autoantibodies can be considered.
Allergen screening, food diaries, autologous serum skin testing (ASST) and H. pylori infection identification can be performed when necessary to exclude and determine the role of relevant factors in the pathogenesis [5]. IgE-mediated food allergens have a limited role in the pathogenesis of urticaria, and allergen test results should be properly analyzed. Double-blind, placebo-controlled food provocation tests can be performed at the discretion of the unit in which they are available.
(3) Classification and diagnosis
Combining history and physical examination, urticaria} is classified as spontaneous or induced. The former was classified into acute and chronic according to whether the disease duration was ≥6 weeks, and the latter was classified into physical and non-physical urticaria} according to whether the onset was related to physical factors, and further classified according to the definition in Table 1. Two or more types of urticaria may be present in the same patient, such as chronic spontaneous urticaria combined with artificial urticaria.}
(4) Differential diagnosis
The main differentiation is urticarial vasculitis, which is usually characterized by the persistence of the lesions for more than 24 h, with pigmentation after recovery and pathology suggesting vasculitic changes. In addition, it should be differentiated from other diseases that manifest as urticaria or angioedema formation, such as urticaria-type drugs, serum sickness-like reaction, papillary urticaria, Staphylococcus aureus infection, adult Still disease, hereditary angioedema, etc.
6. Treatment
(1) Patient education
Patients with urticaria, especially those with chronic urticaria, should be educated that the etiology of the disease is unknown, the disease is recurrent, the course of the disease is prolonged, except for a very small number of complications of respiratory or other systemic symptoms, the majority of benign.
(2) Etiological treatment
Eliminate the cause or suspected cause is conducive to the natural regression of urticaria. Treatment is mainly considered from the following aspects.
(a) Detailed history taking is the most important way to detect possible causes or triggers.
In patients with induced urticaria}, both physical and non-physical, avoidance of the corresponding stimulus or triggering factor may improve clinical symptoms or even lead to spontaneous resolution.
when drug-induced urticaria} is suspected, particularly NSAIDs and angiotensin-converting enzyme inhibitors, avoidance (including drugs with similar chemical structures) or substitution with other drugs may be considered
Chronic urticaria} clinically suspected to be associated with various infections and/or chronic inflammation may benefit some patients by considering treatment such as anti-infection or inflammation control when other treatments are resistant or ineffective, as appropriate. For example, anti-H. pylori therapy has been shown to be effective for urticaria} associated with H. pylori-associated gastritis.
In patients with suspected food-related urticaria}, patients are encouraged to keep a food diary to look for possible foods and avoid them, especially since some natural food components or certain food additives can cause non-allergic urticaria}.
For patients with positive ASST or confirmed presence of autoantibodies against the FcεRIa chain or IgE in the body, the addition of immunosuppressants, autologous serum injection therapy or plasma exchange may be considered as appropriate when conventional treatment is ineffective and the condition is severe.
(3) Control of symptoms
Drug selection should follow the principles of safety, effectiveness and regular use to improve the quality of life of patients. It is recommended to develop and adjust the treatment plan according to the patient’s condition and response to treatment. See Figure 1.
First-line treatment: second-generation non-sedating or hypo-sedating antihistamines are preferred, and the dose is gradually reduced after effective treatment to achieve effective control of the onset of the wind cluster as the standard. To improve the patient’s quality of life, the course of treatment for chronic urticaria is usually not less than 1 month, and can be extended to 3-6 months or longer if necessary. The efficacy of first-generation antihistamines in the treatment of urticaria} is definite, but their clinical application is limited by adverse effects such as central sedation and anticholinergic effects.
With attention to contraindications, adverse effects, and drug-drug interactions, they can be selected as appropriate. Commonly used first-generation antihistamines include chlorpheniramine, diphenhydramine, doxepin, ipratropium, ketotifen, etc. Second-generation antihistamines include cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, avastin, epinastine, epinastine, imipramine, olopatadine, etc.
Second-line treatment: after 1~2 weeks of conventional dosing, if the symptoms cannot be effectively controlled, considering the differences in response to treatment between individuals or types of urticaria, the following options are available: change the species or increase the dose by 2~4 times with informed consent of the patient; combine with first-generation antihistamines, which can be taken at bedtime to reduce adverse effects; combine with second-generation antihistamines, and promote the combination of drugs of the same structure such as loratadine and desloratadine combination to improve anti-inflammatory effects; combination of anti-leukotriene drugs, especially for NSAID-induced urticaria}.
Third-line therapy: for patients who fail to respond to the above treatments, the following treatment options can be considered [6-9]: cyclosporine, 3-5 mg/kg daily in 2-3 oral doses. Because of its high incidence of adverse reactions, it should only be used in severe patients who have failed to respond to any dose of antihistamines. Glucocorticoids, for acute, severe, or urticaria with laryngeal edema}, prednisone 30-40 mg (or equivalent dose) orally for 4-5 d and then discontinued, are not recommended for routine use in chronic urticaria}.
Immunoglobulins, such as intravenous immunoglobulins at 2 g daily for 5 d, are suitable for severe autoimmune urticaria.} Biologic agents, such as omalizumab (anti-IgE monoclonal antibody), have been shown to be effective in refractory chronic urticaria in foreign studies [10]. Phototherapy, for chronic spontaneous urticaria} and artificial urticaria} patients can be tried for 1 to 3 months with UVA and UVB treatment in parallel with antihistamines.
Treatment of acute urticaria: when the etiology is actively defined and eliminated and the symptoms cannot be effectively controlled by oral antihistamines, glucocorticoids can be chosen: prednisone 30-40 mg orally for 4-5 d and then discontinued, or an equivalent dose of dexamethasone intravenously or intramuscularly, especially for severe urticaria or urticaria with laryngeal edema; 1:1,000 epinephrine solution 0,2-0,4 ml subcutaneously or intramuscularly, which can be used for acute urticaria with shock or severe urticaria} with angioedema.
Treatment of induced urticaria}: Induced urticaria} is relatively poorly treated with conventional antihistamines, and in cases where treatment is ineffective, some special treatments are chosen.
Treatment of pregnant and lactating women and children: In principle, antihistamines are avoided during pregnancy as much as possible. However, if symptoms recur and seriously affect the patient’s life and work, and antihistamines must be used for treatment, the patient should be informed that there are no absolutely safe and reliable drugs available, and relatively safe and reliable drugs such as loratadine should be chosen on the balance of pros and cons. Most antihistamines can be secreted into breast milk.
In comparison, cetirizine and loratadine are secreted at lower levels in breast milk and may be recommended at the discretion of lactating women, using lower doses if possible. Chlorpheniramine can be secreted through breast milk, reduce the infant’s appetite and cause drowsiness, etc., and should be avoided.
Non-sedating antihistamines are also a first-line choice for the treatment of urticaria in children. The minimum age limits and doses vary significantly among drugs and should be used according to the drug instructions. Similarly, in children who have failed to respond to treatment, first (nighttime) and second (daytime) generation antihistamines can be combined, with concern for the effects of sedating antihistamines on the child’s learning, etc.