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. The characteristic clinical manifestation is a wind cluster of varying size with itching, which may be accompanied by angioedema. Chronic urticaria is defined as at least 2 episodes of urticaria per week lasting ≥ 6 weeks. A small number of patients with chronic urticaria may also exhibit intermittent episodes.
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 and include physical stimuli (friction, pressure, cold, heat, sunlight exposure, etc.), food (animal proteins such as fish, shrimp, crab, shellfish, eggs, etc., plant or fruit 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 mostly persistent and include mast cell hypersensitivity to IgE, chronic occult infections (bacterial, fungal, viral, parasitic, etc., such as 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 infection, 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., is the key to the occurrence, development, prognosis and therapeutic response to 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; there are a few patients with urticaria whose pathogenesis cannot be elucidated yet The mechanism may not even depend on mast cell activation.
4.Clinical manifestations and classification
The clinical manifestations of urticaria are wind clusters with various forms of attacks, mostly accompanied by pruritus, and a few patients may be combined with angioedema. Urticaria can be clinically classified according to the pathogenesis pattern, combined with clinical manifestations [2]. There are some differences in the clinical manifestations of different types of urticaria.
5. Diagnosis and differential diagnosis
5.1 History and physical examination
A thorough history and physical examination should be taken, including possible triggering and relieving factors, duration of disease, frequency of attacks, duration of lesions, diurnal pattern of attacks, size and number of clusters, shape and distribution of clusters, whether angioedema is combined, degree of accompanying itching or pain, whether there is pigmentation after fading, previous personal or family history of allergy, history of infection, history of visceral disease, history of trauma, history of surgery, history of drug use, psychological and psychiatric status. 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.
5.2 Laboratory tests
Usually no additional tests are needed for urticaria. In acute patients, blood tests can be performed to see if the onset 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, stool eggs, liver and kidney function, immunoglobulins, erythrocyte sedimentation rate, C-reactive protein, complement and various autoantibodies can be considered.
The role of IgE-mediated food allergens in the pathogenesis of urticaria is limited, and the results of allergen testing 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.
5.3 Classification and diagnosis
Combining history and physical examination, urticaria is classified as spontaneous or induced. The former was classified as acute versus chronic according to whether the duration of the disease was ≥6 weeks, and the latter was classified as 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. There can be two or more types of urticaria present in the same patient, such as chronic spontaneous urticaria combined with artificial urticaria.
5.4 Differential diagnosis
The main differentiation is with urticarial vasculitis, which is usually characterized by the persistence of a wind cluster for more than 24 h, the recovery of lesions with pigmentation, and pathology suggesting vasculitic changes. It also needs to be differentiated from other diseases that manifest as urticaria or angioedema formation, such as urticaria-type drug}, serum sickness-like reaction, papular urticaria, Staphylococcus aureus infection, adult Still disease, and hereditary angioedema.
6.Treatment
6.1 Patient education
Patients with urticaria, especially those with chronic urticaria, should be educated. 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 vast majority of the benign process.
6.2 Etiological treatment
The elimination of the causative 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 method of detecting possible etiologies or triggers.
In patients with induced urticaria, both physical and non-physical, avoidance of the appropriate 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 in urticaria associated with H. pylori-associated gastritis.
For patients with suspected food-related urticaria, encouraging patients 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 FcεRIa chain or IgE in the body, additional immunosuppressive agents, autologous serum injection therapy or plasma exchange may be considered as appropriate when conventional treatment is ineffective and the condition is severe.
6.3 Control of symptoms
Drug selection should follow the principles of safety, effectiveness and regular use, with the aim of improving patients’ quality of life. It is recommended to develop and adjust the treatment plan according to the patient’s condition and response to treatment.
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.
They can be selected at discretion with attention to contraindications, adverse effects and drug-drug interactions. 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 dose use cannot effectively control symptoms, considering the differences in response to treatment in different individuals or types of urticaria, there are options: change the species or increase the dose by 2~4 times with informed consent from patients; combine with first generation antihistamines, which can be taken at bedtime to reduce adverse effects; combine with second generation antihistamines, and advocate the combination of drugs of similar structure such as loratadine and Desloratadine combination to enhance the anti-inflammatory effect; combination of anti-leukotriene drugs, especially for NSAID-induced urticaria.
Third-line treatment: 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 is used only in severe cases and in 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 advocated 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 shown positive efficacy in refractory chronic urticaria in foreign studies. Phototherapy, for chronic spontaneous urticaria and artificial urticaria patients can try UVA and UVB treatment for 1 to 3 months along with antihistamines.
Treatment of acute urticaria: When the cause is actively clarified and removed and the symptoms cannot be effectively controlled by oral antihistamines, glucocorticoids can be chosen: prednisone 30~40 mg, orally discontinued after 4~5 d, or equivalent doses of dexamethasone intravenously or intramuscularly, especially for severe or urticaria with laryngeal edema; 1:1,000 epinephrine solution 0,2~0,4 ml subcutaneously or intramuscularly injection, 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 administered according to the drug instructions. Similarly, in children who are not responding to treatment, first-generation (nighttime) and second-generation (daytime) antihistamines can be combined, but with concern for the effects of sedating antihistamines on the child’s learning, etc.