About this Research Topic
Most of the common rheumatic diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and psoriatic arthritis (PsA), are considered as autoimmune disorders. Today, there is no cure for these rheumatic diseases although substantial advances have been made to develop effective drugs for the treatment of these diseases. Thus, the treatment goal of rheumatic diseases is to achieve a low disease activity.
Effective treatment of rheumatic diseases like RA requires the use of disease-modifying anti-rheumatic drugs (DMARDs) that have benefitted a large number of patients but have also brought unwanted side effects, such as myelosuppression as well as liver and kidney injury. Traditional medicines like Chinese medicine, especially herbal medications, has gained attention as alternative remedies as they are believed to be efficacious, safe and have been used for over a thousand years traditionally in treating patients. For example, there was a 24-week, randomized, multicenter, single-blind study comparing Chinese medicine with Western medicine (DMARDs) carried out between June 2002 and December 2004 in nine research centers in China, involving 489 patients, and the result showed that Chinese medicine while effective in treating RA, appears to be less effective than DMARDs in controlling symptoms, but Chinese medicine is associated with fewer side effects.
In 2015 the herbal medication Tripterygium wilfordii Hook f (TwHF) tested in an open-label, randomized clinical trial was found non-inferior to methotrexate (MTX), which is an anchor DMARD in treatment of active RA. Subsequently, a meta-analysis and review published in 2016, in which a total of 22 trials (5255 participants) were identified, has confirmed that TwHF is effective and also safer than MTX in the treatment of rheumatic diseases. These observations received much attention from rheumatologists and pharmacologists. As traditional medicines have a rich resource of bioactive components, there could be potentially many different botanic agents and herbal extracts that are still to be discovered and used for the treatment of rheumatic diseases.
In addition to single active components or herbal extracts, there are many preparations and decoctions of Traditional medicines that have been tested to be effective in the treatment of rheumatic diseases. For example, by analyzing clinical trials conducted in China, we reported last year that several Chinese medicinal formula, mainly Chinese herbal formula or compound Chinese medicine, may provide an efficient treatment option for RA in terms of the bone-protecting efficiency. Thus, Chinese medicine may also function as a type of DMARD, which could be used as an alternative or add-on treatment for patients with rheumatic diseases. However, more high quality studies are urgently needed to apprehend the full potential of traditional medicines for the use in the treatment of rheumatic diseases, especially the studies addressing mechanism of traditional medicinal effects.
In this Research Topic, we intend to publish high-quality evidence-based Research articles as well as Reviews providing an overview of recent advances in the field of the use of traditional medicines in rheumatology. While submissions may inevitably reference concepts unique to Chinese medicine such as qi balancing, the molecular processes underpinning proposed modes of action should be especially emphasized. More specifically, the biological or -omic (microRNA, lncRNA, gut microbiota, etc.) mechanisms of traditional medicinal effects in treating rheumatic diseases are welcomed, but Clinical Trials would not be accepted. In addition, submissions on meta-analysis, the discovery of biologically active compounds, biomarkers for traditional medicinal effects and well-designed experiments testing the potential efficacy of traditional therapies for rheumatic diseases, are welcomed.
All manuscripts must comply with the four pillars of best practice in Ethnopharmacology.
The four pillars of best practice in ethnopharmacology
With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.
a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.
b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.
Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.
c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.
d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.
e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach.
f) Docking studies must be justified with affinity experiments, or other well established experimental methods to support a proposed mechanism of action. Algorithmic docking studies will not be accepted; these indicate if a compound will "fit" into a binding site but do not indicate the binding affinity or the ability to induce a conformational change.
The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.
- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph
- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration
- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.
c) Multiherbal preparations:
Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.
3) Basic requirements and research ethics
Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:
a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.
b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).
c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).
d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.
e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.
4) Other specific requirements
a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.
b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.
c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.
Keywords: Chinese medicinal formula, Bioactive ingredients, Herbal extracts, Rheumatic diseases, mechanism
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.