Are hyperuricemia and gout different diseases? Comment on the guidelines for the diagnosis and management of hyperuricemia and gout with the healthcare professional perspectives in China.

Abstract

In 2020, the Chinese Society of Endocrinology, Chinese Medical Association, published guidelines for the diagnosis and management of hyperuricemia (HUA) and gout in China (2019). The guideline was completed by following the international general GRADE classification method. The diagnosis, treatment and management of HUA and gout are covered through the description of 3 recommended general rules and 10 clinical questions.1 We are heartened that the guideline has made improvements for HUA and gout, which is largely consistent with global understanding. The guideline standardizes the original serum uric acid (UA, 420 μmol/L) used to assess HUA in men and women, although blood UA varies between genders. Significantly, this guideline recognizes sub-gout (asymptomatic) for the first time. In previous studies, the concept of “subclinical gout” has been derived from the timing of gout onset.2 The understanding of the turning point from HUA to gout has been ambiguous, especially with imaging techniques. Usually, disease-free, asymptomatic, disease episodes and secondary episodes are the manifesting processes. Asymptomatic contains the stage of HUA and urate deposition.3 All the studies in the guidelines are focused on urate as a spotlight. A large body of evidence suggests that HUA is associated with gout; but we found that the genetic and mechanistic basis for the progression from HUA to inflammatory and clinical gout remains uncertain. However, the specific determinants of gout, independent of HUA, are the focus of much needed further research. Inflammation accompanies the full stage of HUA to gout. Inflammation is ubiquitous in metabolic diseases and even becomes a controller of disease progression.4 HUA already has chronic inflammation that progresses to acute with the deposition of urate crystals.5 We note that there is little focus in the guidelines on chronic inflammation in the HUA phase. This may be related to the inconsistency of existing understanding. Although HUA and gout can be distinguished as 2 diseases, the inflammatory status throughout correlates with them, and the possible treatment strategies are different. In addition, traditional Chinese medical (TCM) theory has a unique understanding of the “Bi Pattern” of gout. It considers that the basic cause of gout attacks from HUA to gout lies in damp pathogen. Western medicine focuses on localization while Chinese medicine focuses on a holistic view. Western medicine directly considers lesions of the target organ, including UA and inflammatory factors. This is fundamentally different from the TCM philosophy. In China, TCM is also an option for patients. In the guidelines, many new initiatives for the disease are mentioned. This also completely mirrors the new understanding of the disease process. The treatment of HUA is not consistent worldwide. In fact, guidelines in the European Union and the United States, including the American College of Rheumatology, do not recommend pharmacological treatment for asymptomatic HUA,6 whereas guidelines in Asian countries such as Japan do consider pharmacological treatment for patients who meet certain criteria.7, 8 In China, a positive attitude is also held for the treatment of HUA. The treatment of asymptomatic HUA based on clinical imaging diagnosis is consistent with a cut-off strategy for the imminent onset of gout, which is consistent with intervening in the process. We note the addition of “alkalinization of urine” as a treatment option in the guidelines. Alkalinization of urine is an intermediate step between UA-lowering medication and surgery. Due to individual differences and various comorbidities, urine alkalinization therapy is required with conditions, and the urine pH as the core monitoring indicator. The guideline also suggests the range of limitations that should be present when applying sodium bicarbonate and citrate preparations to alkalinize urine. The benefits and risks are of urgent concern to clinicians when making decisions in the conduct of therapeutic activities. The definition and treatment principles of refractory gout were also given for the first time in the guidelines. Definition of refractory gout and its treatment principles are currently a common focus for clinicians, with a lack of global consensus to date. UA oxidase is mentioned in the guidelines as a potential therapeutic agent. Although it can be an emerging direction for treatment, there are many restrictive conditions for drugs like Precahi. Meanwhile, interleukin (IL)-1β or tumor necrosis factor-α antagonists have been recommended for use in refractory gout. Of course, the risks and benefits of using these drugs need to be carefully balanced. In the guidelines, chemical medicines are mentioned throughout the whole process, but the use of TCM is not focused upon. Due to the practical and empirical use of TCM, it focuses on the overall regulation of the disease progression in the prevention and treatment of gout with the strategy of “integrated treatment”.9 Although we acknowledge the complexity of the components, some TCMs have specific therapeutic effects. The use of herbal medicine is also a sign of a forward-looking treatment strategy. There is an almost worldwide consensus that allopurinol is the drug of choice for lowering UA, as mentioned in the guidelines. However, it is also mentioned that Asian populations carry the human leukocyte antigen-B*5801 gene and that allopurinol has a higher probability of triggering a hypersensitivity reaction.1 We can see that some of the drugs have more restrictive conditions in terms of use due to contraindications. Hence, we believe that the future search for new drugs should focus on the following 4 aspects. (a) Emerging targets are focused upon. The discovery of inhibitors in recent years has focused on xanthine oxidase (XOD), urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), adenosine triphosphate binding cassette subfamily G member 2, and so on. Especially, after XOD, URAT1 is a target for novel drug development. Chinese researchers have identified recently Lesinurad as a series of derivatives by lead compounds as novel human URAT1 inhibitors.10 Nevertheless, there is still a need to develop an XO-specific inhibitor that allows it to affect reactive oxygen species but not xanthine dehydrogenase activity. This would maintain UA levels but reduce the oxidative stress-dependent pathology of chronic inflammation.11 In addition, some new targets could be considered, such as IL-37,12 recently validated to play a role in gout disease.13 (b) High efficiency and low toxicity of natural molecules need to be developed. It is worth focusing on the fact that macromolecules such as proteins, polysaccharides, and so forth, tend to be less toxic and have considerable efficacy in UA lowering. In the future, there is a need to further consider dietary supplements derived from large molecules in food to enhance patient compliance. (c) Two birds with one stone: the development of multifunctional drugs. Recent studies have found that natural product inhibitors of XOD can be effective against cardiovascular disease.14 Such studies will make a case for the treatment of complications. (d) The therapeutic potential of herbal extracts is to be exploited. Herbal medicines tend to play a dominant role, especially in major public health events such as COVID-19. We believe that herbal medicine should be based on the underlying efficacy to find more effective sites (extracts). Meanwhile, extracts with therapeutic potential should be made with clear efficacy, well-defined targets and controlled quality. In conclusion, the guidelines were used to learn about their understanding of HUA and gout, the update of treatments and the diversity of drugs, although some researchers argue that the adequacy of evidence for the evidence-based approach needs further consideration.15 Indeed, clinical evidence-based approaches are often not incorporated into basic research and therefore lack evidence from laboratory studies. It is important to note that the idea of treatment for gout is often to reduce inflammation. However, some studies have reported that inflammation and UA are bidirectional effects and that the reduction of inflammation tends to increase blood UA.16 Know that to know why. Thus, these phenomena are to be further confirmed in future studies to avoid bringing about poor treatment outcomes. In any case, the available guidelines provide the best basis for clinicians and related practitioners to make decisions about the management of HUA and gout. YL drafted the manuscript, JL, YW, HW and BZ revised the manuscript, BZ give final approval of the version to be submitted and any revised version. This work was supported by National Natural Science Foundation of China (U20A20406). The authors declare they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.