Center for Urticaria Research, Chinese Society of Dermatology?

Abstract Urticaria is a common dermatological condition that is characterized by wheals and pruritus.Certain types of urticaria can be resistant to treatment,and recurrence is common.These guidelines supplement and improve upon the previous version (published in 2014) of the Guidelines for the Diagnosis and Treatment of Urticaria in China, and incorporate recent research advances in urticaria. These guidelines are suitable for both Chinese adults and children of Han nationality with urticaria.These guidelines update and broaden the definition,pathogenesis,classification,diagnosis,and treatment of urticaria, and serve as a scientific and authoritative reference for the diagnosis and management of urticaria.

Keywords: urticaria, guidelines, diagnosis, therapy, management

Definition

Urticaria is a localized edematous reaction that occurs secondary to the dilation of small vessels and increased permeability of skin and mucosa. Urticaria manifests clinically as small and large wheals with pruritus, and approximately 20% of patients also have angioedema.1-2Chronic urticaria is defined as the daily or intermittent onset of wheals for longer than six weeks.1

Etiology

The etiology of urticaria is complex and can be caused by exogenous and endogenous factors.3Exogenous causes are usually transient,such as physical factors(friction,pressure,cold, heat, sunlight), food (animal proteins such as fish,shrimp, crab, shellfish, and egg; plants or fruits such as lemon, mango, plum, apricot, strawberry, walnut, cocoa,garlic, and tomato; and alcohol, spoiled food, and food additives), medications (penicillin, sulfonamides, serum preparations,various vaccines,or nonimmunized mast cell release agents such as morphine,codeine,and aspirin),and implants (artificial joints, staples, heart valve membranes,steel plates, steel nails, and contraceptive devices). In contrast, endogenous causes are persistent and include chronic latent bacterial/fungal/viral/parasitic infection, for example,Helicobacter pylori infection may be an important factor in a small number of patients, fatigue, vitamin D deficiency,mental stress,autoimmunity to immunoglobulin E (IgE), or high-affinity IgE receptors, as well as chronic diseases such as rheumatic fever,systemic lupus erythematosus, thyroid disease, lymphoma, leukemia, and inflammatory bowel disease.4-5It is usually easy to identify the cause of acute urticaria;however,it is difficult to specify the etiology of chronic urticaria. Chronic urticaria is rarely caused by type I hypersensitivity.

Pathogenesis

Mast cells are the key effector cells in the pathogenesis of urticaria, and mast cell activation occurs through immune and nonimmune mechanisms.6-8Immune mechanisms include autoimmunity against IgE or high-affinity IgE receptors, IgE-dependent type I hypersensitivity, antigenantibody complexes, and complement system activation.Nonimmune mechanisms include direct mast cell release agents or pseudoallergenic reactions induced by small-and medium-sized food compounds,or changes in arachidonic acid metabolism caused by nonsteroidal anti-inflammatory drugs. Mast cell degranulation leads to the release of histamine and inflammatory factors such as tumor necrosis factor-alpha, interleukin (IL)-2, IL-3, IL-5, and IL-13, and theleukotrienesC4,D4,andE4,whichaffecttheoccurrence,development, prognosis, and treatment of urticaria.8The involvement of basophils, eosinophils, B cells, and T cells increases the complexity of the inflammatory response to urticaria. Furthermore, the presence of the histaminedependent inflammatory reaction is the basis of resistance to antihistamines. Abnormal activation of the coagulation system is also considered to be involved in the pathogenesis of urticaria.7The mechanism of urticaria is unclear, and sometimes may not depend on mast cells.

Clinical manifestation and classification

Urticaria is characterized by the development of wheals(hives) and/or angioedema, which vary in form. Severe acute urticaria can be accompanied by fever, nausea,vomiting, abdominal pain, diarrhea, chest tightness, and laryngeal obstruction.Urticaria is classified in accordance with the disease patterns and clinical manifestations,1,3,8and the clinical manifestations of different types of urticaria vary (Table 1).

Diagnosis and differential diagnoses

Diagnosis

A thorough history and physical examination including inspection and palpation should be performed. This should include questions regarding possible eliciting and eliminating factors, duration and frequency of disease,duration of lesions, whether the lesions occur during the day or at night, size, number, shape, and distribution of wheals, associated angioedema, itching or burning sensation, pigmentation after remission, associated systemic symptoms(e.g., nausea, vomiting, abdominal cramps,diarrhea, chest distress, and throat obstruction), and family and personal history regarding allergy, history of infections, visceral diseases, trauma, surgery, drug use,psychological state, menstrual cycle, habits, work and living environment,and previous response to therapy.This information is required to make a definitive diagnosis,evaluate the disease state, and understand the etiology.

Urticaria usually does not require many laboratory examinations. In general, patients with acute urticaria should undergo routine blood testing to identify any underlying infections.Patients with severe chronic urticaria or a poor response to standard doses of antihistamines should undergo more specific testing such as fecal egg counts, evaluation of hepatic and renal function, and evaluation of immunoglobulin levels,erythrocyte sedimentation rate, C-reactive protein, complement, autoantibodies, and D-dimer concentrations to rule out infections and rheumatic diseases.Certain cases should also undergo allergen screening, autologous serum skin testing, and testing for H.pylori,thyroid autoantibodies,and vitamin D levels to help identify the underlying causes. Additionally,patients with inducible urticaria should undergo elicitable dermatographism and threshold testing, ultraviolet and visible light of different wavelengths and threshold testing,or cold and heat provocation and threshold testing based on different eliciting factors.1,9IgE-mediated allergy to foods suggests sensitivity to specific foods,which helps clarify the potential underlying cause of urticaria,but provides limited help to identify the causes of chronic urticaria.

Classification

Urticaria is classified as spontaneous or inducible based on the history and physical examination findings. Spontaneous urticaria is classified based on its duration as acute(≤6 weeks) or chronic (＞6 weeks). Inducible urticaria is classified as physical or nonphysical based on the urticaria triggers (Table 1). Additionally, two or more different subtypes of urticaria can coexist in one patient, such as chronic spontaneous urticaria with dermographic urticaria.

Differential diagnoses

Urticaria must be differentiated from urticarial vasculitis.In urticarial vasculitis, the wheal lasts ＞24hours andcauses pain followed by pigmentation after resolution,and skin biopsy suggests vasculitic changes.Urticaria must also be differentiated from other medical conditions that manifest with wheals and/or angioedema, for example,urticarial drug eruption, serum sickness-like response,papular urticaria, sepsis, adult-onset Still disease, hereditary angioedema, bullous pemphigoid, mastocytosis,systemic inflammatory response syndrome, and severe anaphylactic reactions. Clinical features, laboratory examinations, and biopsy results may help make a definitive diagnosis.

Table 1Classification of urticaria

Assessing disease activity and control

Urticaria impacts patients’life,work,and psychology.The life quality questionnaire of chronic urticaria and angioedema are often used to define the impact of urticaria on patients. Disease activity is assessed with the urticaria activity score7 and the angioedema activity score.1The urticaria activity score 7 is used to count the number of wheals in one week and assess the pruritus severity. The number of wheals is classified as none (0/24hours), mild(＜20/24hours), moderate (20-50/24hours), and severe(＞50/24hours),and is scored from 0 to 3 points.Pruritus severity is classified as none(no pruritus),mild(no obvious pruritus), moderate (obvious pruritus without effects on routine life or sleep), and severe (severe and intolerable pruritus with serious effects on routine life or sleep),and is scored from 0 to 3 points. Additional daily points are added based on the severity of wheals and pruritus, and range from 0 to 6.The highest possible score for one week is 42.Urticaria is defined as controlled if the weekly score is＜7, and as severe if the score is ＞28. Additionally, the urticaria control test is valuable in determining the level of disease control.1,10

Management of urticaria

Education

Patients with urticaria, especially those with chronic urticaria, should be told that the etiology is unclear, and that the disease can be recurrent and protracted.Urticaria is benign in most patients, except for a small number of patients with concurrent respiratory tract or other systemic symptoms.11The disease is self-limiting, and the goal of treatment is to control symptoms and improve quality of life.

Etiological treatment

Spontaneous remission of urticaria may be achieved by identification and elimination of the underlying causes and avoidance of the eliciting factors.11Treatment should be performed with the following considerations. (1) The medical history is the most important way to determine the possible eliciting factors or causes. 2) For inducible urticaria, avoidance of the stimulating or eliciting factors can improve clinical symptoms, and even lead to spontaneous remission. (3) When drug-induced urticaria is suspected,especially involving nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors, these drugs should be substituted with chemically similar drugs or other drugs. (4) If chronic urticaria is associated with various infections and/or chronic inflammation, and patients are resistant to other treatments or the treatments are ineffective, patients may benefit from treating infections or controlling inflammation. For instance, the treatment of H. pylori infection in patients with H.pylori-related gastritis has effects on urticaria.(5)Patients with suspected food-related urticaria should be encouraged to keep a food diary to uncover possible causes and avoid the causative food, especially natural food ingredients or food additives that can cause nonallergic urticaria. (6) When the results of autologous serum skin testing are positive or confirm the presence of high-affinity IgE receptor chains or IgE autoantibodies, which are serious conditions that are nonresponsive to conventional treatments,it could be considered to add immunosuppressive agents,autologous serum injection therapy,or plasma exchange.

Controlling symptoms

Drug selection should follow the principles of safe,effective, regular use designed to fully control the symptoms of urticaria to improve quality of life. The treatment should be adjusted in accordance with the patient’s condition and response to treatment.

Treatment of acute urticaria

The underlying etiologies must be addressed. Secondgeneration H1-antihistamines are the first-line treatments for acute urticaria. Commonly used second-generation antihistamines include cetirizine,levocetirizine,loratadine,desloratadine, fexofenadine, acrivastine, ebastine, epinastine, mizolastine, bepotastine besilate, and olopatadine.When the etiology has been identified, but oral antihistamines are not effective in controlling symptoms,glucocorticoids can be used, namely, 30-40mg of oral prednisone daily for four to five days (or equivalent intravenous or intramuscular doses of dexamethasone),especially for severe or chronic urticaria with laryngeal edema.Acute urticaria with shock or severe urticaria with vascular edema can be treated with 0.2-0.4mL of 1:1,000 epinephrine solution injected subcutaneously or intramuscularly.The glucocorticoid dose in children can be reduced in accordance with the child’s weight.

Treatment of chronic urticaria

The treatment flowchart is shown in Figure 1.

First-line therapy: Second-generation nonsedating antihistamines are the first-line symptomatic therapies for chronic urticaria. The antihistamine dosage should be gradually reduced to the lowest dosage that achieves complete control of wheals.The duration of antihistamine treatment should be at least one month, and may be extended to three to six months or longer, if necessary.Although first-generation antihistamines effectively treat chronic urticaria, they are not considered first-line agents because of their anticholinergic effects and sedative actions on the central nervous system.1,12

Second-line therapy:As the curative effect varies among different individuals and urticaria types, antihistamine replacement or combination may enhance the treatment efficacy if the urticaria symptoms do not improve after one to two weeks of treatment with second-generation antihistamines at routine dosages. Taking a combination of second- and first-generation antihistamines at bedtime improves sleep. In addition, certain patients may benefit from a two- to fourfold increase in the dose of secondgeneration antihistamines, with informed consent.

Third-line therapy: The following therapeutic options are available for patients with chronic urticaria who fail to respond to first- or second-line therapies: (1) Oral tripterygium glycosides(1-1.5mg/kg thrice daily);adverse reactions such as myelosuppression, hepatotoxicity, and reproductive toxicity should be closely monitored.13(2)Oral cyclosporine(3-5mg/kg twice or thrice daily)is only recommended for patients with severe disease that is refractory to any dose of antihistamines because of the higher incidence of adverse effects. (3) The biological agent, omalizumab, is very effective in the treatment of chronic spontaneous urticaria. The recommended dose is 150-300mg by hypodermic injection every four weeks14-16; however, rare allergic reactions may occur.(4)Systemic corticosteroids can be used in patients who fail to respond to the first three therapies. The suggested doses 0.3-0.5mg/(kg·day) of prednisone (or corresponding doses of other steroids) should be reduced gradually when symptoms are improved.Oral corticosteroids are not recommended as a routine therapy, and the course of therapy should not be exceeded two weeks. (5)Phototherapy is effective in treating refractory chronic urticaria; especially NB-UVB is more effective.17

Treatment of inducible urticaria

The same principles apply for inducible urticaria as for chronic urticaria.Second-generation nonsedating antihistamines are the recommended first-line treatments,and the dose can be increased by twofold if the curative effect is unsatisfactory.As antihistamines are less effective in some patients with inducible urticaria, other special therapies may be considered18(Table 2).Omalizumab is reportedly effective in cold urticaria,delayed pressure urticaria, heat urticaria, solar urticaria, and urticaria with symptomatic dermographism.19

Treatments for special populations

In general, systemic antihistamines should be avoided during pregnancy.Antihistamines should only be carefully suggested in pregnancy when the disease is recurrent and severe enough to affect the patient’s daily routine and activities.Antihistamine use should be based on individual considerations, as no antihistamines are confirmed to be reliable and safe in pregnancy; cetirizine usage in pregnancy has only been evaluated in small sample-sized studies,while loratadine usage in pregnancy has only been evaluated in one large meta-analysis. However, as there have been no reports of birth defects in pregnant women taking second-generation antihistamines,we suggest using second-generation antihistamines with relatively high reliability and safety (including loratadine, cetirizine, and levocetirizine)in pregnant women after conducting a riskbenefit assessment. All antihistamines can be excreted in breast milk; therefore, the use of second-generation antihistamines is advised,20as nursing infants occasionally develop sedation from first-generation antihistamines transmitted by breastfeeding. Moreover, omalizumab is useful as an add-on treatment in patients unresponsive to high doses of antihistamines in pregnancy, and has been proven safe with no indication of teratogenicity.14,21

Figure 1. Chronic urticaria treatment algorithm.

Second-generation nonsedating antihistamines can be used as the first-line treatment in children with urticaria.When the curative effect is unsatisfactory in children, the antihistamine dose should be increased in accordance with the child’s weight after obtaining informed consent from their guardian(s). Sedating antihistamines should be used with caution in children because of the potential impact on learning and performance.

For older patients (over 60s), second-generation antihistamines are better options. First-generation antihistamines are not recommended because of their sedative actions on the central nervous system and anticholinergic effects, which may increase the risk of falling and the incidence of glaucoma,uroschesis,arrhythmias,and other related adverse reactions.

Patients with chronic urticaria with abnormal renal or hepatic function should have their antihistamine category and dosage adjusted in accordance with pharmacological guidelines and the severity of renal or hepatic dysfunction.For example,ebastine and loratadine are mainly metabolized in the liver,while cetirizine is metabolized predominantly in the kidney.Antihistamines should be reduced or avoided in patients with severe hepatic or renal dysfunction.20

Traditional Chinese medicine

Traditional Chinese medicine based on appropriate syndrome differentiation and treatment may also lead to curative effects in patients with urticaria.

Authors list

Shan-Juan Chen, Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology; Xue Chen, Peking University People’s Hospital; Yu-Zhen Li, The 2nd Affiliated Hospital of Harbin Medical University; Yu-Hui Fang, Affiliated Hospital of Yanbian University; Qian Gao, The First Affiliated Hospital, Sun Yat-sen University; Zai-Pei Guo,West China Hospital, Sichuan University;Fei Hao,Third Affiliated Hospital of Chongqing Medical University;Chao Ji, The First Affiliated Hospital of Fujian Medical University; Zhe-Hu Jin, Affiliated Hospital of Yanbian University; Dan Ke, Chongqing Traditional Chinese Medicine Hospital; Cheng-Xin Li, Chinese PLA General Hospital; Hai Long, The Second Xiangya Hospital of Central South University;Jie Li,Xiangya Hospital,Central South University; Jing-Yi Li, West China Hospital,Sichuan University; Lin-Feng Li, Beijing Friendship Hospital; Qian-Jin Lu, The Second Xiangya Hospital of Central South University;Tie-Chi Lei,Renmin Hospital of Wuhan University; Wei Li, Huashan Hospital, Affiliated with Fudan University; Xi-Guang Liu, Heilongjiang People’s Hospital; You-Kun Lin, The First Affiliated Hospital of Guangxi Medical University; Yun-Sheng Liang, Dermatology Hospital of Southern Medical University; Xiang Nong, First Affiliated Hospital of Kunming Medical University; Wei-Min Shi, Shanghai General Hospital; Zhi-Qiang Song, Southwest Hospitalof Military Medical University; Hui Tang, Huashan Hospital, Affiliated with Fudan University; Hui-Ping Wang, General Hospital, Tianjin Medical University;Zai-Xing Wang,First Affiliated Hospital of Anhui Medical University;Jin-Hua Xu,Huashan Hospital,Affiliated with Fudan University;Ting Xiao,The First Hospital of China Medical University; Hui-Lan Yang, Guangzhou General Hospital of Guangzhou Military Region; Wei-Ru Yuan,Ruijin Hospital,affiliated with Shanghai Jiaotong University; Xu Yao, Hospital for Skin Diseases (Institute of Dermatology),Chinese Academy of Medical Sciences;An-Ping Zhang, First Affiliated Hospital of Anhui Medical University; Hui Zhang, Xinhua Hospital, affiliated with Shanghai Jiaotong University School of Medicine; Jian-Zhong Zhang, Peking University People’s Hospital; Min Zheng, The Second Affiliated Hospital of Zhejiang University School of Medicine; Xian-Qi Zhang, The Second Affiliated Hospital of Zhejiang University School of Medicine; Ying Zou, Shanghai Dermatology Hospital;Yue-Ping Zeng,Chinese Academy of Medical Sciences and Peking Union Medical College.

Table 2Special treatments for inducible urticaria