I. Definition of urticaria is a limited edematous reaction due to the dilation and increased permeability of small blood vessels in the skin and mucous membranes. Clinically, it is characterized by itchy, itchy, angioedematous lesions of varying sizes. 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 show intermittent attacks.
Second, the cause of acute urticaria can often be found, but the cause of chronic urticaria is more difficult to specify. The cause is 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., 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.
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., is the 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; there are a few patients with urticaria whose pathogenesis cannot be elucidated yet The pathogenesis of urticaria has not been elucidated yet, and may not even depend on mast cell activation.
The clinical manifestations and classification 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. The clinical manifestations of different types of urticaria have certain differences, see Table 1.
V. Diagnosis and differential diagnosis
1. History and physical examination: A thorough history and physical examination should be taken, including possible triggering and relieving factors, duration of the 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 use of drugs, and history of allergy. History of trauma, surgery, medication history, psychological and mental conditions, menstrual history, lifestyle, work and living environment, and response to previous treatment, etc.
2, laboratory tests: usually urticaria does not require additional tests. Acute patients can be checked for routine blood tests 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 can be considered, such as routine blood, eggs, liver and kidney function, immunoglobulin, erythrocyte sedimentation rate, C-reactive protein, complement and various autoantibodies. 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 conducted at the discretion of the units that are available.
3, classification and diagnosis: Combined with the medical history and physical examination, urticaria is classified as spontaneous or induced. The former is divided into acute and chronic according to whether the disease duration is ≥6 weeks, and the latter is divided into physical and non-physical urticaria according to whether the onset is 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.
4, differential diagnosis: the main difference with urticarial vasculitis, the latter usually lasted more than 24h, lesion recovery with pigmentation, pathology suggests that there are vascular inflammatory changes. In addition, it should be differentiated from other diseases that manifest as urticaria or angioedema formation, such as urticarial drug rash, serum sickness-like reaction, papular urticaria, Staphylococcus aureus infection, adult Still disease, hereditary angioedema, etc.
VI. Treatment
1. Patient education: Patients with urticaria should be educated, especially those with chronic urticaria, because the cause 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: the elimination of causative or suspected causes is conducive to the natural regression of urticaria. Treatment is mainly considered from the following aspects.
① Detailed medical history is the most important method to discover possible causes or triggers.
(ii) In patients with induced urticaria, including physical and non-physical urticaria, avoidance of the corresponding stimulus or triggering factor may improve clinical symptoms or even spontaneous healing.
(iii) When drug-induced urticaria is suspected, especially NSAIDs and angiotensin-converting enzyme inhibitors, avoidance (including drugs with similar chemical structures) or substitution with other drugs may be considered.
(iv) 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.
(v) 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.
(6) 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.
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.
(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 chronic urticaria treatment is generally 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.
(2) Second-line treatment: If the symptoms cannot be effectively controlled after 1 to 2 weeks of conventional dosing, considering the differences in response to treatment in different individuals or types of urticaria, the following options are available: change the species or increase the dose by 2 to 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 advocate the combination of drugs of the same structure such as loratadine Combination of loratadine and desloratadine to improve the anti-inflammatory effect; combination of anti-leukotriene drugs, especially for non-steroidal anti-inflammatory drugs induced urticaria.
(3) Third-line treatment: For patients who are not effective in the above treatment, the following treatment options can be considered: 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), discontinued after 4-5 d of oral administration, are not advocated for routine use in chronic urticaria. Immunoglobulins such as intravenous immunoglobulins at 2g daily for 5d 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 in the antihistamine treatment at the same time can try UVA and UVB treatment for 1 to 3 months.
(4) 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 an equivalent dose of dexamethasone intravenously or intramuscularly, especially for severe urticaria or urticaria with laryngeal edema; 1:1000 epinephrine solution 0.2-0.4 ml subcutaneously or intramuscular injection, can be used for acute urticaria with shock or severe urticaria with angioedema.
(5) Treatment of induced urticaria: Induced urticaria is relatively poorly treated with conventional antihistamines, and some special treatments should be chosen if the treatment is ineffective.
(6) Treatment of pregnant and lactating women and children: In principle, antihistamines should be 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-generation (nighttime use) and second-generation (daytime use) antihistamines can be combined, but with concern for the effects of sedating antihistamines on the child’s learning, etc.
(7) Traditional Chinese medicine: Traditional Chinese medicine has some efficacy in the treatment of urticaria, which requires evidence-based treatment.