China Urticaria Treatment Guide
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. It is characterized clinically by itchy, itchy, and 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 etiology is usually divided into exogenous and endogenous [2-3]. 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 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 diseases.
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 response to treatment of urticaria}. Mechanisms that induce mast cell activation and degranulation include immune, non-immune and idiopathic.
Immune mechanisms include autoimmunity against IgE or high-affinity IgE receptors, IgE-dependent as well as antigen-antibody complexes and complement system-mediated pathways; non-immune mechanisms include direct induction by mast cell releasing agents, pseudoallergenic responses induced by small molecular compounds in food, or altered arachidonic acid metabolism by nonsteroidal anti-inflammatory drugs; there are also a few urticaria} patients whose pathogenesis cannot be elucidated yet and may even Not dependent 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 can be combined with angioedema. According to the pathogenesis pattern, combined with clinical manifestations, urticaria} can be clinically classified. The clinical manifestations of different types of urticaria} have some differences, see Table 1.
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 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 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.
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 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 divided into acute and chronic according to whether the duration of the disease was ≥6 weeks, and the latter was divided 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 can be present in the same patient, such as chronic spontaneous urticaria} combined with artificial urticaria}.
5.4 Differential diagnosis
The main differentiation is urticarial vasculitis, which is usually characterized by the persistence of the flocs for more than 24 h, the recovery of the lesions with hyperpigmentation, and pathology suggesting vasculitic changes. It is also necessary to differentiate 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, and hereditary angioedema.
6. Treatment
6.1 Patient education
Patients with urticaria, especially those with chronic urticaria, should be educated, as 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.
6.2 Etiological treatment
Elimination of the causative or suspected cause is conducive to the natural regression of urticaria. Treatment is mainly considered from the following aspects.
Detailed history taking is the most important way to detect possible causes or triggers;
In patients with induced urticaria, including physical and non-physical urticaria, avoiding the corresponding stimulus or trigger may improve clinical symptoms or even lead to self-healing;
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;
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-Helicobacter pylori treatment is effective in urticaria} associated with H. pylori-associated gastritis;
For 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 FcεRIa chain or IgE, add immunosuppressants, autologous serum injection or plasma exchange as appropriate if conventional treatment is ineffective and the condition is severe.
6.3 Symptom control
Drug selection should follow the principles of safety, effectiveness and regular use, with the aim of improving 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 dose cannot effectively control the symptoms, considering the difference in response to treatment of different individuals or types of urticaria, we can choose: 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 advocate the combination of drugs of similar structure such as loratadine and desloratadine combination, to improve 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. Due to its high incidence of adverse reactions, it should only be used 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.} Biological agents, such as omalizumab (anti-IgE monoclonal antibody), have been shown in foreign studies to be effective in refractory chronic urticaria [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 some special treatments are chosen in case of ineffective treatment.
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 option 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.