Rheumatoid arthritis
) is an autoimmune disease characterized by multijoint swelling, pain, and destruction of the synovial joints. Treatments are available but new therapies are still required. One source of new therapies is natural products, including herbs used in traditional medicines. In China and neighbouring countries, natural products have been used throughout recorded history and are still in use for RA and its symptoms. This study used text-mining of a database of classical Chinese medical books to identify candidates for future clinical and experimental investigations of therapeutics for RA. Methods. The database Encyclopaedia of Traditional Chinese Medicine (Zhong Hua Yi Dian) includes the full texts of over 1,150 classical books. Eight traditional terms were searched. All citations were assessed for relevance to RA. Results and Conclusions. After removal of duplications, 3,174 citations were considered. After applying the exclusion and inclusion criteria, 548 citations of traditional formulas were included. These derived from 138 books written from 206 CE to 1948. These formulas included 5,018 ingredients (mean, 9 ingredients/formula) comprising 243 different natural products. When these text-mining results were compared to the 18 formulas recommended in a modern Chinese Medicine clinical practice guideline, 44% of the herbal formulas were the same. This suggests considerable continuity in the clinical application of these herbs between classical and modern Chinese medicine practice. Of the 15 herbs most frequently used as ingredients of the classical formulas, all have received research attention, and all have been reported to have anti-inflammatory effects. Two of these 15 herbs have already been developed into new anti-RA therapeutics—sinomenine from Sinomenium acutum (Thunb.) Rehd. & Wils and total glucosides of peony from Paeonia lactiflora Pall. Nevertheless, there remains considerable scope for further research. This text-mining approach was effective in identifying multiple natural product candidates for future research.
1. Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by multijoint swelling and pain and destruction of the synovial joints, leading to severe disability and increased mortality [1–3]. The global prevalence was estimated at 0.24% but it is higher in some populations [4], with 0.5–1% of adults in the United States being affected [5]. Over the last decade, the optimal use of disease modifying antirheumatic drugs (DMARDs) [6, 7] and the increasing availability of new biological agents [8, 9] have enhanced the success of RA management. Traditional treatment methods are widely used in China often in combination with DMARDs and/or biologics [10]. This is likely due to a combination of concerns about the side effects of DMARD combination therapy, the high cost of biological agents in China, the ready availability of traditional treatments in the hospital system [11], and public awareness of the increasing literature on the evidence base for traditional treatments such as herbal formulations and acupuncture [12–16].
Clinical guidelines for prescribing traditional medicines for RA provide criteria for differentiating the Chinese medicine syndromes and selecting appropriate multi-ingredient formulations which are typically administered in the form of decoctions, granules, capsules, and pills [17]. In addition, manufactured medicines based on extracts of plants used traditionally for joint pain have been developed and evaluated in clinical trials [18, 19].
Along with the increasing application of clinical trial methodologies for the evaluation of traditional medicines for RA and other diseases, there has been increasing attention to the systematic assessment of the premodern and classical medical literature using text-mining approaches [20]. Such studies have focused on drug discovery from compounds found in the natural products used in traditional medicines [21–23]; identification of instances of long-term traditional use of natural products for certain diseases or symptoms [24–27]; the logic underlying ancient acupuncture prescriptions [28]; and investigations of continuities and differences between the classical and modern Chinese medicine approaches to certain diseases [29, 30]. It has been proposed that long-term traditional use could be considered as a source of evidence [31], and a “whole-evidence” approach to evidence-based Chinese medicine could concludes systematic searching of the classical literature as one component [32].
This text-mining study identifies traditional formulations and their constituent natural products that have been used for conditions consistent with RA during the classical and premodern period (until 1949), compares these with the approaches recommended in contemporary guidelines for the application of herbal formulations in RA management, and examines the contemporary research into the natural products most frequently used in the traditional formulations. The study aimed to identify prospects for future clinical and experimental studies, which may lead to the development of new treatments for rheumatoid arthritis.
2. Materials and Methods
We searched the Encyclopaedia of Traditional Chinese Medicine (Zhong Hua Yi Dian, 5th edition) an electronic database which contains the full texts of over 1150 medical books spanning more than 2000 years [33]. This source was selected because it was the most comprehensive collection available in electronic format [34, 35].
The procedures for text-mining have been detailed elsewhere [36]. There is no single term in the premodern and classical Chinese literature that directly corresponds to the modern conception of RA; however, descriptions of the clinical features of RA have been included under certain traditional terms. Therefore, multiple search terms were selected based on medical nomenclatures [37, 38], clinical practice guidelines [17, 39], textbooks [40, 41], and specialist books [42–44]. Preliminary searches were conducted to determine terms that located passages of text that were suggestive of RA. After discarding unproductive terms, the following Chinese terms for classical disease names and symptoms were used to search the literature: bi “arthritis” or “painful blockage”, li jie “joint disease”, tong feng “painful wind”, he xi feng “crane’s knee wind”, bai hu bing “white tiger disease”, ji zhua feng “chicken’s claw wind”, gu chui feng “drum stick wind,” and wang “lameness”. Each term was searched in the Zhong Hua Yi Dian (ZHYD) database, and all passages of text identified by these terms were copied to Microsoft Excel spreadsheets (by X.X, B.H.M), together with the identity of the source book and all relevant information on the disorder and intervention. A passage of text that included one or more of the search terms together with an herbal intervention for the disorder was considered a single citation. Duplications were identified and removed. Inclusion and exclusion criteria were used to identify conditions whose signs and symptoms were consistent with the features of rheumatoid arthritis. Each passage was read and allocated codes (by XX, B.H.M).
The inclusion criteria were (1) a specific herbal intervention for oral administration comprising one or more ingredients intended as a treatment for one or more of the search terms and (2) the primary condition had symptoms of joint pain and/or joint swelling, and/or limited joint function. Citations were excluded if the condition (1) had sudden or recent onset (trauma, fever, epidemic or seasonal disorder); (2) was specific to children, teenagers or females; (3) was likely due to a cerebrovascular accident (e.g., zhong feng, stroke, paralysis); or (4) was likely due to other rheumatoid disease (e.g., gout, osteoarthritis).
3. Results and Discussion
After removal of duplications, 3,174 citations were considered, and 548 citations of traditional formulas were included (Figure 1). The most commonly used search term was bi (258 citations) followed li jie (175 citations), tong feng (89 citations), and he xi feng (n = 14) but all terms were productive of citations that could have referred to RA. (TABLE SUPP 1). The citations were derived from 138 different books written from circa (ca.) 206 CE to 1948. Most of the books were written during the Ming (1369–1644) and Qing (1645–1911) dynasties (Table 1). Prescriptions for Universal Relief (Pu Ji Fang c.1406), which is the largest book in ZHYD, provided 56 citations. The next productive book was the Compendium of Medicine (Yi Xue Gang Mu c. 1565) with 28 citations.