Abstract
Keywords
Introduction
Urticaria is a common disease in dermatology, manifesting as recurrent itchy wheals and/or angioedema. Among Chinese adolescents, a cross-sectional study reported prevalence for chronic spontaneous urticaria as high as 2.7%, 1 which affected 0.23% of general population in the United States, most of whom were women or adults ≥40 years of age. 2
Chronic urticaria can substantially affect patients’ quality of life (QoL), ability to perform daily tasks, and even mental health. 3 Moreover, according to ASSURE-CSU (ASSessment of the Economic and Humanistic Burden of Chronic Spontaneous/Idiopathic Urticaria patiEnts), average CSU-related out-of-pocket expense for patients reached nearly PPP$500 per year (whereas PPP$1000 in Canada). In addition, CSU considerably affected productivity, such that one in five patients took time off from work and one in four experienced reduced productivity at work. 4 All these findings indicate urgent need to improve urticaria treatment. Unfortunately, there has been little research on prescription from a dermatologist in real-world in China.
Due to unclear pathogenesis, CSU (also known as chronic idiopathic urticaria [CIU]) has been commonly managed with antihistamine therapy in clinical practice.7 The second-generation H1-antihistamines (sgAHs) at licensed doses have been recommended as the first-line treatment for CSU based on International guideline (EAACI/GA2LEN/EDF/WAO). 5 Among multiple types of sgAHs, dermatologists have different opinions upon prescribing in practice. In addition, few studies focused on third-line or fourth-line drugs, such as compound glycyrrhizin and tripterygium wilfordii polyglycoside. Compound glycyrrhizin is composed of monoammonium glycyrrhizinate, glycine L, and half cystine and exerts anti-allergic effects as well as boosts immunity. It is widely used for the treatment of dermato-logical diseases and generally has an acceptable safety profile. 6 Tripterygium wilfordii polyglycoside (TWP, Leigongtengduogan Pian) is one of the functional natural products derived from Tripterygium wilfordii Hook. F. and is approved by National Medical Products Administration (NMPA) to be prescribed to patients with rheumatoid arthritis, nephrotic syndrome, ankylosing spondylitis, psoriasis, and systemic erythematosus lupus. 7 Thus, we aim to assess dermatologists’ preferences for treatment options in China, and compare therapeutic effects on different types of urticaria.
Materials and methods
Study design
This prospective multicenter study was performed from January 1 to December 31 in 2019. 10 tertiary hospitals in mainland China, with geographically dispersed uniformly, were chosen as sampling units, located in six provinces and municipalities including Fujian, Sichuan, Chongqing, Hubei and Liaoning provinces, as well as Beijing. All outpatients diagnosed with urticaria who consented to participate in the current study underwent a questionnaire survey and specific survey. This study had conformed to the STROBE guidelines.
Questionnaire
The questionnaire is validated, 8 which comprised of 33 questions, including demographics (gender, age, ethnicity); disease duration; comorbid conditions (such as allergic, cardiovascular, metabolic, and autoimmune diseases); family history of urticaria; food to be avoided (such as fish-prawn-crab, alcohol consumption, beef, mutton, milk, and egg); laboratory results (such as blood count, plasma allergen, routine urine, thyroid antibody, auto-antibodies and helicobacter pylori); severity of itching and quantity of wheal (at initial visit and follow-up); physician-certified diagnoses (such as CSU, symptomatic dermographism, delayed pressure urticaria, and cold urticaria); current and former therapeutic schedule (dose and type of drugs).
Study objects
Ethical approval no.2019-P2-107-01 for this study was obtained from Institutional Review Board (IRB) committee of Beijing Friendship Hospital, Capital Medical University. Verbal informed consent was obtained from all subjects before the study, and written informed consent was waived by the Institutional Review Board/Ethics Committee.
The inclusion criteria included: diagnosis with urticaria and agreement to participating in this study. Exclusion criteria included outpatients with serious mental illness or organic disease, who could not cooperate with investigators; or who refused to provide informed consent. The doctor diagnosed the disease strictly according to the definition of the disease from International guideline (EAACI/GA2LEN/EDF/WAO) 9 as well as he Chinese guidelines for the diagnosis and treatment of urticaria version (2018). The presence of urticaria was identified by physician-certified diagnoses according to the International Classification of Diseases 10th Revision (ICD-10) codes for various types of urticaria (L500–L509) and angioedema (T783). “Clinical urticaria” was defined as urticaria which caused a patient to visit hospital, subsequently to be diagnosed as a main problem by a clinician. “Symptomatic dermographism” was defined as dermatographism is a transient linear cutaneous wheal pro-duced after applying a force or scratching the skin. Wheals usually appear in about 5–10 min and persist for 15–30 min “Chronic spontaneous urticaria” was defined as the spontaneous development of itchy hives and/or angioedema due to known or unknown causes that last for at least 6 weeks “Angioedema” was defined as these patients had angioedema with or without various types of urticaria. The dermatologists dealt with acute urticaria and chronic urticaria, and multiple diagnoses were allowed. All dermatologists involved in this study had abundant experience in clinical diagnosis and treatment of urticaria; and were trained in a standardized program. After the initial visit, patients were followed-up once per week, for 4 weeks.
Clinical criteria
The treatment effect was determined based on UAS and change in wheal-and-erythema reaction or itching. The efficacy index (%) was calculated as follows: (total score before treatment-total score after treatment)/total score before treatment ×100%. An efficacy index >90% was classified as recovery; whereas 60%∼90% as highly effective; 20%∼60% as effective;
Statistical analysis
All statistical analyses were performed with SPSS software version 20 (IBM, Armonk, NY, USA). Continuous variables were described by mean ± standard deviation (SD) according to distribution. The normality of variables was evaluated by Kolmogorov-Smirnov test. Age was normally distributed, while the distribution of disease duration was skewed. The relationships of follow-up duration with itching degrees or quantities of wheal were analyzed by Spearman Correlation. Each drug combination was assessed by association rule algorithm. Missing data were excluded from data analyses. All tests were two-tailed with a significance level of ≤0.05.
Results
Previous treatment
We approached 1800 outpatients, among whom 1715 agreed to participate in this study (with a response rate of 95.3%), including acute urticaria (198 cases) and chronic urticaria (1517 cases). The leading subtype of chronic urticaria was chronic spontaneous urticaria (1396 cases, 81.4%). 612 outpatients were diagnosed with chronic inducible urticaria. Additionally, 163 patients had angioedema with or without various types of urticaria. The patient was asked about previous treatment options at the first visit. In previous treatment, sgAHs at conventional dose (787 cases, 45.9%) were the most commonly prescribed drugs. Combinations of several antihistamines (649 cases, 37.8%) at conventional dose were far more common than a single drug at escalated dose (59 cases, 3.4%). As a non-antihistamine compound, glycyrrhizin (394 cases, 23%) was the most widely used, followed by traditional Chinese medicine (142 cases, 8.3%), glucocorticoid (87 cases, 5.1%), and tripterygium glycoside (73 cases, 4.3%). By contrast, hydroxychloroquine (8 cases, 0.5%) and cyclosporin (4 cases, 0.2%) were rarely used.
Treatment options
In general, sgAHs were the most commonly prescribed drugs (1632 cases, 95.2%), with ebastine, levocetirizine and olopatadine being the leading ones (41.1%, 36.2%, and 16%, respectively). Comparatively, the proportion of sgAHs, such as loratadine (13.6%) and cetirizine (12.9%), had been reduced. Among the first-generation H1-antihistamines (213 cases, 12.4%), ketotifen (7.2%) was more often applied, followed by chlorphenamine maleate (2%), diphenhydramine (1.9%) and cimetidine (1.9%). As a non-antihistamine compound, glycyrrhizin (34.3%) was the most widely used, followed by traditional Chinese medicine (9.2%) and tripterygium glycoside (8.1%). Moreover, omalizumab (0.6%) had low acceptability (Figure 1). And the study found that there was no correlation between gender and therapeutic options, no matter what type of drug. Proportion of therapeutic options for urticaria patients (N = 1715, %).
Since many patients received more than one treatment, the sum of the proportion was greater than 100%.
Blue gradient: second-generation H1-antihistamines; orange gradient: alternative treatment options; green gradient: H2-antihistamines; yellow gradient: first-generation H1-antihistamines.
Therapeutic options in major types of urticaria outpatients by clinical reality.
A total of 1715 patients were included, a single drug or combination were generally acceptable.
Drug combination
As a whole, combinations of ebastine with levocetirizine were the most common treatment options (18.25%, 313 cases), which almost identical to combinations of ebastine with compound glycyrrhizin (18.2%, 312 cases). Surprisingly, combination of sgAHs and fgAHs is not used frequently, most of which is levocetirizine and ketotifen (2.5%, 43 cases). And similarly, proportion in combination of sgAHs and H2-antihistamines wasn’t high. Compound glycyrrhizin seems to show potential as a versatile collaborator, which was the first choice for drug combinations. The top two drugs most commonly used with compound glycyrrhizin were ebastine (312 cases, 18.2%) and levocetirizine (263, 15.3%), with significantly higher prevalence than that of other drugs (p < .001).
Clinical manifestations during follow-up
USA7 for various drugs during follow-up.
Patients enrolled had completed 4 week’s follow-up, a single drug or combination were generally acceptable.
Discussion
Our study provides epidemiological evidence on drugs for urticaria. This finding was based on functional mechanism of health care system in China, which was completely different from Western countries. In this study, almost all patients sought help from dermatologists in the first place, because of lack of general practitioners and family doctors. Even acute urticaria patients were treated by dermatologists, rather than emergency departments. Globally, antihistamine therapy is the most commonly applied in clinical practice at present. In our survey, with popularization and wide utilization of the sgAHs, the fgAHs displayed obvious signs of decline. A similar drug administration pattern was reported by Rimoldi M et al. who found that the second-generation H1-antihistamines at the registered dose were the most common treatment in Italy. 10 By contrast, in Poland, more than one-third of physicians chose the first-generation sedative H1-antihistamines and systemic steroids either alone or in combination as the initial therapy. 11 Approximately 20% of German specialists (mainly dermatologists and allergists) applied the first-generation H1-antihistamines or steroids as the first-line treatment for CU. 12 Treatment choice was closely associated with the specialist’s knowledge of current guidelines. Both EAACI/GA2LEN/EDF/WAO and Chinese guidelines suggested the 2nd-generation H1-antihistamines over the 1st-generation H1-antihistamines for chronic urticaria (evidence-based and consensus-based). 13 However, these guidelines differ with regards to the second-line treatment, where the international guideline recommended escalated dosing sgAHs up to 4-fold after a maximum for 2 weeks, although the study had found that increase in antihistamine was performed without improvement and with a high prevalence of adverse events. 14 And the Chinese guideline recommended to change the current type of sgAH, multi-sgAH combination, along with the first-generation H1-antihistamine, or mono-sgAH up dosing regimens with informed consent. 13 Except for ebastine, no other sgAHs definitely doubled the dose in medicine instruction, which explained why it had been extensively applied.
The lifetime prevalence of angioedema in the United States is approximately 25%. It presents as unpredictable frequent edematous episodes of cutaneous and mucosal tissues such as lips, eyes, oral cavity, larynx, and gastrointestinal system (GIS). 15 In this study, we noticed that tripterygium glycoside, hydroxychloroquine as well as systemic steroids were prescribed more often in angioedema than in others, which might reflect physician’s conviction that angioedema was more difficult to control by standard regimen. Non-hereditary angioedema (AE) with normal C1 esterase inhibitor (C1INH) can be presumably bradykinin- or mast cell-mediated, or of unknown cause. 16 Differentiating histamine-mediated versus bradykinin mediated angioedema is essential, as therapy or response to therapy is quite different. 17 In Chinese guidelines for urticaria (2018 version), tripterygium glycoside, system application glucocorticoids, and/or omalizumab were added as the third-line treatment. Tripterygium wilfordii Hook F (TwHF) is a vital Chinese herb belonging to Celastraceae family, with anti-inflammation, anti-anaphylaxis, and immunosuppression effects. 18 It has been reported by Liu et al. 19 and Yao et al. 20 that tripterine, a primary component in TwHF, inhibited degranulation of mast cells and histamine release. Active ingredients in TwHF are toxic components that may be harmful to liver, kidneys, reproductive tissues, and immune system. Because of side effects, TwHF is often used clinically for treating complicated autoimmune and inflammatory diseases in China, such as rheumatoid arthritis, 21 diabetic nephropathy, 22 purpura nephritis, 23 and urticaria.24,25 Except for omalizumab and ciclosporin A, which both have restrictions due to high cost, alternative protocols, such as combinations of sgAHs with tripterygium glycoside, are based on clinical trials lack of supporting evidence. In this study, efficacy index of tripterygium glycoside (36.3% in 1 week) was lower than other drugs (Table 2), indicating that tripterygium glycoside was not outstanding and dominant. A large sample-size, multi-center, high-quality clinical study is required to verify efficacy and safety of tripterygium glycoside in angioedema and urticaria.
In China, regulatory approval for the use of omalizumab has recently obtained on April 15, 2022. This study was conducted from January 2019 to November 2019, when omalizumab was still an off-label drug for CU in China. This goes a long way to explaining why omalizumab was so rarely prescribed in this survey. The use of omalizumab, a recombinant humanized anti-IgE antibody, has been recommended for antihistamine-resistant patients. The mechanisms of action of omalizumab in CU include its effects on IgE, lowering free IgE levels, and on the high affinity IgE receptor, FceRI, lowering its expression on mast cells and basophils. 26 Omalizumab is approved for the treatment of CSU treatment in Europe and shows remarkable efficacy and safety.27,28 Similarly, a clinical study from China found that omalizumab is highly effective in patients with difficult-to-treat CSU, CIndU, or both. 29 It is worth mentioning that the status of omalizumab continues to rise, and in the latest version of Chinese guidelines (2022), 30 it becomes not the only one, but listed as the preferred option for third-line treatment. The application of non-conventional drugs not included in the international guidelines (glycyrrhizin, tripterygium glycoside, etc.) reflects that there is still a larger room for improving present treatment condition. There is reason to believe that with regulatory approval and the updating of guidelines, more dermatologists will apply omalizumab in their routine clinical management of CU. Here, the present study provides information on application background of omalizumab.
Interestingly, this study provides preliminary evidence that compound glycyrrhizin holds potential as a versatile collaborator, which has been widely used in combination with a variety of drugs. The oral compound glycyrrhizin is a preparation composed of glycyrrhizin, cysteine hydro-chloride, and glycine. Primary active component is glycyrrhizic acid, an active substance found in licorice. 31 Glycyrrhiza glabra (Fabaceae) commonly known as liquorice is considered to possess carminative, antimicrobial, hypolipidemic, anti-atherosclerotic, antiviral, antiulcerogenic, hepatoprotective, cardio-protective, immunomodulatory, antimutagenic, anti-pyretic, and anti‐inflammatory activities. 32 Broad anti-inflammatory activity of glycyrrhizin is mediated by interaction with lipid bilayer, thereby attenuating receptor-mediated signaling. In China, although not recommended in guidelines, compound glycyrrhizin has been widely used to treat urticaria with high clinical efficacy as an anti-allergic and anti-inflammatory agent. Compound glycyrrhizin has minor adverse effects, including hypertension, hypokalemia, and pseudo-aldosteronism. In particular, glycyrrhizin in conjunction with conventional therapy has been used in clinical practice, especially for severe clinical symptoms, however, supporting evidence for such practice has not been evaluated systematically. In our survey, combination has achieved better therapeutic effect (efficacy index of 54.2% in 1 week, whereas 90.7% in 4 weeks). To our knowledge, few high-quality studies have been published on efficacy evaluation of compound glycyrrhizin in urticaria. Further research is required to determine acceptable long-term efficacy and safety of compound glycyrrhizin in urticaria patients.
In general, urticaria patients obtained good clinical outcome in response to single or in combination regimen. After 4-week followed up, 71.8% of patients recovered from urticaria, 11% was highly effective, and 14.2% was effective. Patients with more severe symptoms were often treated with a combination regimen, such as an antihistamine drug in combination with compound glycyrrhizin or traditional Chinese medicine. In the current study, patients on olopatadine, who had the highest starting USA7 scores (33.7), showed a high first-week efficacy indicator (55.2%) with an efficacy index of >90% at the end of follow-up. Previous studies on olopatadine and levocetirizine have shown that urticaria activity score (UAS) and urticaria total severity score (TSS) values declined significantly over the treatment period, however, the reduction was greater with olopatadine. 33 Mild to moderate urticaria could be controlled by standard application, while severe urticaria could be managed by a standard application of olopatadine, however, levocetirizine might need an additional dose to control severe urticaria. The booklets of medicine instruction indicate that olopatadine is more suitable for poor first-line treatment, attributed to the highest starting USA7 scores. Compared with other sgAHs, olopatadine has fast-acting and curative effect, especially during the first week. Several limitations should be considered when interpreting our results: Ⅰ. Due to limited conditions, the power analysis for sample size calculation was not done. Ⅱ.As a hospital-based study, a selective bias was inevitable due to a nonhomogeneous population and differential spatial distribution. All these factors may lead to an unavoidable bias.
Conclusions
In conclusion, this study provides a profile of therapeutics of urticaria in Chinese outpatients, which demonstrates curative effects. The sgAHs at conventional dose, especially ebastine, have been the most commonly prescribed drugs. Olopatadine has fast-acting and curative effect. Compound glycyrrhizin holds potential as a versatile collaborator.
Footnotes
Acknowledgments
We thank all the dermatologists in Beijing Friendship Hospital affiliated with Capital Medical University. We also thank the associate editor and the reviewers for their useful feedback that improved this paper.
Author’s note
A preprint has previously been published [Xin Wang, Lin-Feng Li, Xiao-Dong Shi, Yi-Wei Shen. 2022 years]. 33
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Statement
Data Availability Statement
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.