I. Definition
Urticaria is also known as “rubella”. It 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 and itchy wind masses of different sizes, sometimes accompanied by abdominal pain, diarrhea, shortness of breath and other symptoms. Chronic urticaria is defined as a condition in which the above-mentioned urticaria with pruritus occurs almost daily and lasts for more than 6 weeks. A small number of patients with chronic urticaria may also present with intermittent attacks (at least two attacks per week for at least 6 weeks).
II. Etiology
The cause of most acute urticaria can be found, but the cause of chronic urticaria is difficult to identify, and most patients are unable to find the cause. Common etiologies are as follows.
Food: fish, shrimp, crab, shellfish, eggs, and some animal meat (beef and lamb, etc.); plants or fruits (lemon, mango, plum, apricot, strawberry, pecan, cocoa, garlic, tomato, etc.); dairy products; spoiled food (not fresh food decomposition to produce alkaline peptides can promote the release of histamine), food additives.
Drugs: allergic (penicillin, sulfonamides, furazolidone, serum preparations, various vaccine preparations); direct prohistamine release (morphine, codeine, cocaine, quinine, aspirin, etc.); other drugs.
Infections: Occult infections are an important cause of chronic urticaria, including bacteria (Staphylococcus aureus is the most common), fungi, viruses (respiratory viruses, hepatitis viruses, etc.), parasites, etc. It is debated whether H. pylori causes urticaria.
Inhalants: pollen, animal feathers and dander, dust, smoke, aerosols, volatile chemicals, etc.
Physical factors: friction, pressure, cold, heat, sunlight exposure, exercise, etc.
Systemic diseases: rheumatic fever, systemic lupus erythematosus, thyroid disease, lymphoma, leukemia, infectious mononucleosis, etc.
III. Pathogenesis
The pathogenesis of urticaria is more complex and is still not fully understood. There are two ways of immune and non-immune mediated skin eruptions. Immunity includes IgE-mediated and complement-mediated, while non-immunity can be directly caused by mast cell releasing agents or by impaired arachidonic acid metabolism. In clinical work, most urticaria is idiopathic urticaria of unknown cause.
IV. Classification
Idiopathic urticaria: acute urticaria, chronic urticaria. Physical urticaria: cold urticaria, delayed pressure urticaria, heat urticaria, solar urticaria, artificial urticaria/skin scarring, vibrational urticaria/angiolytic edema, exercise-induced urticaria, autoimmune urticaria. Infection-associated urticaria.
Others: waterborne urticaria, cholinergic urticaria, contact urticaria.
V. Treatment
1.Etiological treatment.
Elimination of irritants or suspicious factors is the most important in the treatment of urticaria. This is because the urticaria may subside naturally after the elimination of the irritant or suspected factor: conversely, the recurrence of urticaria after re-exposure to the relevant factor may provide evidence to determine the causative agent.
(1) Taking a detailed history is the most important way to detect irritants and suspected causes for the patient.
(2) Clinical screening of allergens should be properly recognized and evaluated. Specific IgE testing is only applicable to a small number of patients with IgE-mediated urticaria.
(3) In patients with physical urticaria, clinical symptoms can be improved by alleviating their physical irritants and taking appropriate measures, such as decompression for stress urticaria.
(4) For chronic urticaria associated with infections and/or inflammatory mediators, e.g., antibiotics in combination with anti-H. pylori therapy are more effective for urticaria associated with H. pylori-associated gastritis.
(5) Urticaria caused by parasitic diseases and cancer or food and drug intolerance, de-worming, removal of tumor lesions, and avoidance of suspected foods or drugs are also therapeutic or at least helpful to patients.
(6) Encouraging the patient to keep a diary is a recommended method for finding irritants or suspected causes.
(7) If a suspected drug is found during the diagnosis of urticaria, it should be avoided completely (including drugs with similar chemical structures) or replaced with another drug if necessary.
(8) Treatment of physical urticaria is recommended to avoid exposure to the corresponding physical stimuli, however, for many patients, complete avoidance of attacks is in fact difficult because of the low threshold of stimulation.
(9) Clearance of FceRI autoantibodies.
(10) IgE-mediated food allergy should avoid specific food allergens whenever possible. It should be noted that some natural food components or certain food additives can cause non-allergic urticaria (pseudo-allergic reactions).
2. Antihistamine therapy.
(1) Treatment targeting histamine and H1 receptors.
The first generation of antihistamines for the treatment of urticaria is effective, but because of the central sedative effect, anticholinergic effects and other adverse reactions limit its clinical application. In attention to contraindications, adverse reactions and drug-drug interactions, etc., can still be used as an option for the treatment of urticaria, such as Benadryl, chlorpheniramine maleate (paracetamol), cycloheximide, dechlorperazine, etc..
If the onset is rapid, the rash is widespread, and there is a tendency to respiratory distress, immediate subcutaneous injection of 0.1% epinephrine 0.3-0.5mL, followed by glucocorticoids, such as prednisone, dexamethasone and hydrocortisone, etc., internal or intravenous drip, depending on the patient’s symptoms, the dosage is equivalent to prednisone 0.5-2.0mg-kg/d, which can be applied simultaneously with antihistamines.
For chronic urticaria, the time of administration can be decided according to the time of occurrence of the wind masses. If there are more wind clumps in the morning, give a higher dose before going to bed; if there are more wind clumps at bedtime, give a higher dose after dinner. After the wind mass is controlled, the dose can be continued for more than a month and then gradually reduced.
If an antihistamine treatment is not effective, two kinds of drugs can be given at the same time. H1 receptor antagonists and H2 receptor antagonists can be tried in combination with cimetidine and ranitidine for intractable urticaria. Some studies have shown that high doses (2-4 times the dose) of antihistamines are beneficial for some patients, but further evidence based on evidence-based medicine is needed. Therefore, informed patient consent is required for clinical use of drug doses exceeding the manufacturer’s recommended dose.
(2) Treatments targeting inflammatory mediators and their receptors in the delayed-onset phase.
It has been found that the new generation of non-sedating or less sedating antihistamines (e.g., imipramine, etc.) also have anti-inflammatory effects against late-onset inflammatory mediators and their receptors, such as inhibition of cytokine and leukotriene B4 release from basophils and mast cells, subject to evidence-based medicine in this area.
3. Inhibition of mast cell release mediators.
Mast cell releasing mediators are an important part of the pathogenesis of urticaria, and inhibition of mast cell releasing mediators has an important role in the treatment of urticaria, but there are few effective drugs that can stabilize mast cell membranes and inhibit mast cell releasing mediators. Although adrenocorticotropic hormone has a strong inhibitory effect on mast cell mediators, it must be used in large doses for a long time, and its clinical application is limited by adverse effects.
Ketotifen is a strong mast cell stabilizer, but its clinical application is limited by its sedative effect. In vitro experiments have demonstrated that trinostat, imipramine, loratadine and cetirizine also have some inhibitory effects on mast cell release mediators, but more evidence-based medical evidence is needed for clinical use.
Cyclosporine also has a direct effect on inhibiting the release of mast cell mediators. In a randomized controlled trial, cyclosporine combined with a non-sedating antihistamine was shown to be effective in the treatment of urticaria, but it is not recommended as standard of care because of the high incidence of adverse effects.
PUVA and NB-UVB reduce the number of mast cells in the upper dermis and have been successfully used in the treatment of mast cell hyperplasia, which is useful in the treatment of refractory chronic urticaria. UVA or UVB can also be tried in combination with antihistamines that inhibit the release of mediators from mast cells as described above.