Efficacy and safety of Tripterygium wilfordii hook F for chronic urticaria: a systematic review and meta-analysis

Urticaria is a recurrent dermatosis, characterized by spontaneous wheals, angioedema, or both. Generally, chronic urticaria is defined as occurrence of urticaria for longer than 6 weeks [1]. It affects 0.5–1% of individuals and reduces the quality of life significantly [2]. Histamine release, driven by mast cells, is regarded as the primary feature in chronic urticaria, resulting in the presence of wheals and flare [3]. Thus, treatment with antihistamines plays a crucial role in chronic urticaria. First-line agents in the routine management of chronic urticaria comprise second-generation antihistamines, such as mizolastine, levocetirizine, and desloratadine [1]. However, high recurrence rate and drug resistance are an ongoing matter of concern. Thus, better therapy is required.

Tripterygium wilfordii Hook F (TwHF) is a vital Chinese herbs belonging to the Celastraceae family. In China, four species of the genus Tripterygium are prevalent, including Tripterygium wilfordii Hook F, Tripterygium hypoglaucum (levl.) Hutch (THH), Tripterygium regelii Sprague and Takeda and Tripterygium forrestii Loes. Molecular analyses have indicated Tripterygium wilfordii and Tripterygium hypoglaucum are not distinct, while Tripterygium regelii is considered as a separate species [4]. Their effects include anti-inflammation, antianaphylaxis, and immunosuppression. In 2007, triptolide and celastrol, the main components of TwHF, along with artemisinin, capsaicin, and curcumin, were listed as the most promising natural traditional medicines [5]. Over the past few decades, several kinds of Tripterygium agents extracted from the root bark of this herb, such as Glucosidorum Tripterygll Totorum tablets (GTT), tripterygium glycosides tablets (TG), and Tripterygium hypoglaucum (levl.) Hutch tablets (THH), have been developed and used for treating autoimmune and inflammatory diseases in China; these diseases include rheumatoid arthritis [6], diabetic nephropathy [7], purpura nephritis [8], and urticaria [9, 10]. Currently, increasing evidence has reported that TwHF combined with antihistamine for chronic urticaria sufferers is satisfactory. Nevertheless, the curative effect and safety of these agents in urticaria is not clear. It is essential to evaluate the trials in this subject in order to effectively conduct the practice of medicine. Hence, we undertook this systematic review of randomized controlled trials (RCTs) to examine the effectiveness of TwHF and Tripterygium agents, in combination with antihistamines, in chronic urticaria.

The review protocol was registered in the PROSPERO database before the start of the review process (CRD42018091595). This study was performed according to the Cochrane Handbook for Systematic Reviews of Interventions [11] and is presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Additional file 1: Table S1) [12].

This systematic review, including 21 trials, evaluated the efficacy and safety of Tripterygium in the treatment of chronic urticaria. Although the quality of these studies were not highly satisfactory, the results showed that, compared to treatment with antihistamines alone, the combination with TwHF or Tripterygium agents improved both, the symptoms and quality of life; even the recurrence rates were lower. However, adverse events could not be ignored. There was marked difference between the two groups in terms of gastrointestinal reactions and menstrual disorders. A total of 47 participants in the drug combination groups experienced gastrointestinal discomfort. Sixteen female patients in these groups experienced menstrual disorders, while those in control groups did not. For men who had not procreated, one trial [22] evaluated sperm motility in the intervention group and found an influence on sperm motility, which suggests that there may be a certain risk to the reproductive system.

In China, Wen et al. [33] performed a systematic evaluation in 2015 of GTT combined with antihistamines for chronic idiopathic urticaria, including 21 trials. Results of their systematic review were consistent with our findings that combined GTT with antihistamines had an obvious effect. However, as increasing evidence emerges every year, systematic reviews should be updated in a timely fashion. In this review, we added literature published in the most recent two years and formulated a set of rigorous inclusion and exclusion criteria. Furthermore, we have included all types of Tripterygium preparations.

Urticaria is known as a mast cell-driven disease, the key aspect of which is degranulation of mast cells with release of histamines and synthesis of inflammatory cytokines, causing an increase in capillary permeability and leading to edema of the dermis. Although antihistamines are effective, there are reports of drug resistance, high recurrence rates, and several side effects in RCTs. TwHF, as a significant traditional Chinese herbal medicine, has effects on numerous symptoms, according to basic theory of Chinese medicine. Pharmacological studies demonstrated that TwHF plays a significant role in antitumor, anti-inflammatory, and immune suppression mechanisms [34]. Chronic urticaria is classically thought to have a basis in autoimmunity and mast cells are vital to it. It has been reported by Liu et al. [35] and Yao et al. [36] that tripterine, a primary component in TwHF, has the ability to inhibit the degranulation of mast cells and histamine release. Although the role of TwHF in chronic urticaria remains unclear, multiple studies have reported stronger effects when treated with TwHF and its agents.

Nevertheless, adverse events are always a focus of concern. It is generally known that the active ingredients in TwHF are also toxic components that may be harmful to the liver, kidneys, reproductive tissues, and immune tissues. Although Tripterygium agents are developed with attenuation measures, toxic effects are inevitable. In this meta-analysis, we found that patients in drug combination groups were more likely to experience gastrointestinal disorders and altered menstruation. Gastrointestinal disorder is a serious adverse event in trials involving TwHF and Tripterygium agents, the incidence rate of which is 25.2% [37]. Even within the normal dose range, the main manifestations are nausea, vomiting, and bloating. Yang et al. [38] treated NIH mice and Sprague-Dawley rats with different doses and found that they all exhibited pathological changes in the gastrointestinal tract in a dose-dependent manner. Over time, gastrointestinal reactions are gradually adapted to. These may be ascribed to spasms of smooth muscle caused by Tripterygium agent-based irritation of the gastrointestinal mucosa [39]. However, this kind of adverse event was tolerable; after continuing medication or drug withdrawal, it disappeared spontaneously. It has been reported that impairment of the reproductive system is the second most common adverse event, with an incidence rate of 16.7% [37]. During treatment, 16 female patients suffered menstrual disorder, which may result from dysfunction of hypothalamic-hypophyseal-ovarian axis [40]. TwHF and Tripterygium agents have abilities to inhibit formation of the corpus luteum and follicles, suppress luteal function and ovulation, and to decrease the levels of estrogen and progesterone; consequently, they may reduce ovarian function [41]. For males, lowered sperm motility is the most common side effect. After discontinuation of the drug, damage to the reproductive system can be restored.

In addition, some included trials reported abnormal liver function after administration of TwHF or Tripterygium agents. Although these results were not statistically significant, damage to liver function cannot be ignored. Three trials reported two patients with elevated transaminases, whereas three patients showed slightly abnormal liver function. Lipid production and peroxidation in the liver, induced by TwHF, may be related to this type of adverse event [42].

Currently, numerous methods of alleviating toxic effects have been suggested, such as compatibility with medicines, use of low-dose medication over the long term, and stronger prevention measures [43, 44]. Once adverse events appear, patients should discontinue medication immediately, and clinicians should perform measures to manage adverse events when necessary.

There are also some limitations of this systematic review: (1) the quality of the included trials was not very high. Of the 21 trials, five were RCTs and another five were quasi-randomized controls; the remaining trials simply mentioned “random.” As for allocation concealment and blinding method, only one study described these aspects in detail. Thus, there appeared to be a high risk of selection and detection bias; (2) the sample size was insufficient to reach a robust conclusion; (3) the very low number of events (several subgroup analysis was included in only one study in Figs. 4, 5 and 6) on which the results were based was another limitation that can affect the interpretation of results; (4) the funnel plot was asymmetrical, suggesting a risk of publication bias.