The concept of "refractory gout" was first proposed in the study of benzbromarone in 1978, which suggested that benzbromarone was suitable for patients with refractory chronic gouty arthritis who were allergic to probenecid or allopurinol [9]. Since then, "refractory gout" has been frequently referenced; yet, never clearly defined. Refractory gout was described in the 2011 ACR recommendations for the diagnosis and management of gout and hyperuricemia, which proposed pegloticase as a potential treatment option [4]. However, because pegloticase is not suitable for patients with G6PD deficiency, and there are about 400 million patients with G6PD deficiency worldwide, the application of pegloticase is limited [10]. Since 2011, refractory gout has not been mentioned in new guidelines or studies. To the best of our knowledge, this is the first study that investigated refractory gout among specialists in China.
Research on gout has focused on the management of complications. The presence of complications narrows our therapeutic options and increases the difficulty of treatment. Chinese guidelines suggest glucocorticoids as the preferred treatment for the acute phase of gout in patients with moderate to severe renal insufficiency. It also suggests that the dosage of allopurinol in ULT should be tapered so as to lower down urate-lowering effect [8]. Patients with myocardial infarction and cardiac insufficiency should avoid the usage of cyclooxygenase 2 (COX-2) inhibitors during the acute attack of gout, while the febuxostat should be used with caution [11]. Patients with diabetes, hyperlipidemia, and hypertension should take an active approach to simultaneously lower glucose, lipid, and blood pressure, while liver and renal function may affect the use of drugs [6]. The 2016 EULAR recommendations for the diagnosis of gout underline the importance of screening and managing comorbidities frequently associated with gout[12]. According to the 2012 ACR Gout Guidelines, gout patients with more than four tophi palpable on the skin surface, rapid disease progression, and persistent severe arthritis are unanimously considered as having refractory gout [4]. Previous studies have shown that chronic gout patients with tophus had a longer course of the disease, more prominent joint swelling, higher disability index scores, and lower arthritis health index scores. Compared with gout patients without any tophus, physical function, and social function in patients with tophaceous gout were significantly declined, with reduced glomerular filtration rate, which increased the difficulty of treatment [13]. As a sign of refractory gout, the presence of any tophus has become the inclusion criteria for a variety of clinical trials of refractory gout drugs [14]. As confirmed in our study, Chinese specialists agree that comorbidities and complications increase the difficulty of gout treatment, especially renal insufficiency.
According to multiple guidelines, the first-line treatment for gout includes xanthine oxidase inhibitors allopurinol or febuxostat [9, 15], while the second-line treatment may include uricosuric agents such as benzbromarone or probenecid. 2011 ACR guidelines suggest that refractory gout patients should be treated with pegloticase [4]. In the 2016 EULAR guide, allopurinol is recommended as the first-line ULT with dose adjustment according to renal function. If the SU target cannot be achieved with allopurinol, then febuxostat, a uricosuric agent, or combination therapy of a xanthine oxidase inhibitor with a uricosuric agent should be considered. Pegloticase can be considered for patients with refractory gout [12]. In our survey, most physicians preferred xanthine oxidase inhibitor as urate-lowering drugs, specifically febuxostat. Allopurinol can induce adverse reactions such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), while allopurinol-induced SJS/TEN has a strong and significant association between HLA-B*5801[16]. Therefore, HLA-B*5801 allele screening may be considered for patients treated with allopurinol that should be avoided in high-risk groups [4]. Allele screening increases the cost of drugs [17], reduces convenience, while some primary health care institutions do not have the ability to test for this allele. At present, the main form of allopurinol preparation in China is a 0.25 g sustained release tablet. All these factors lead to the limitation of allopurinol in China. However, febuxostat can make up for the above deficiencies, while the dosage of febuxostat in patients with mild to moderate renal insufficiency does not need to be adjusted, which makes it the first choice among Chinese specialists. In addition, 13% of specialists prefer benzbromarone as urate-lowing treatment, probably because more than 90% of hyperuricemia occurs due to decreased renal uric acid excretion [18]. In addition, benzbromarone is recommended by Endocrinology guidelines. The daily dose of allopurinol can be up to 800–900 mg according to the international guidelines [15]; however, the maximum dose of allopurinol in the Chinese guidelines is 600 mg per day. Therefore, we consider a daily dose of 600 mg and above as a sufficient dose of allopurinol. The percentage of specialists whose opinion on the maximum dose of all three drugs was consistent with the official guidelines was significantly lower, and the percentage was higher in the SE, which indicated that the diagnosis and treatment experience, as well as continuing medical education experience, increased the understanding of the disease and urate-lowering drugs. In 2006, our team conducted a questionnaire survey on the diagnosis and treatment of gout among physicians at different levels finding that continuing medical education (CME) was the main factor for improvement of the diagnosis and treatment of gout [19]. Therefore, influenced by the length of continuing medical education, experienced physicians were more confident about the treatment difficulty caused by comorbidities and complications and more aware of the correct use of urate-lowering drugs.
In 2016, 88 rheumatologists with interest in gout from multiple countries established the preliminary remission criteria for Gout through Delphi. SUA level was identified as an important measurement to define the treatment target. The timeframe to achieve the SUA target was not established after 3 Delphi rounds, with 58% choosing 6 months, 36% choosing 1 year, and 6% choosing 3 months [20], which was consistent with our survey results. When asked how long it should take to achieve the target for refractory gout, 52% of the specialists thought 3–6 months and 28% thought 6–12 months. However, compared with the international panel of experts, our physicians expected a shorter timeframe to reach the target, so the "refractory gout" encountered by Chinese physicians might be attributable to that.
Fels E proposed that refractory gout describes patients with gout who suffer from persistent symptoms and inability to maintain the target serum uric acid levels (< 6 mg/dl), which are usually associated with delayed or inadequate drug administration [21]. The inclusion criteria of clinical trials in pegloticase for refractory patients, required a baseline serum uric acid of 8.0 mg / dL or more and at least one of the following: 1) 3 or more self-reported gout flares during the previous 18 months; 2) 1 or more tophi; 3) gouty arthropathy, defined clinically or radiographically as joint damage due to gout. Patients also had contraindications to treatment with allopurinol or history of failure to normalize SUA despite at least three months of optimal allopurinol treatment (determined by the treating physician) [22]. Our findings are in line with the 2011 ACR guidelines:1) after the initiation of ULT, acute episodes occur despite the use of prophylactic drugs, or the titration of urate-lowering drugs from a small dose. Or maximal NSAIDs cannot control the symptoms effectively; 2) the serum uric acid cannot reach the standard with monotherapy; 3) tophus or tophi cannot shrink after more than one year of standard ULT. These guidelines are accepted by most physicians. Interestingly, many physicians believe that failure to improve lifestyle and compliance is also an important aspect of refractory gout. A British study that compared the nurse-led gout care and the usual care led by general practitioners (GPs) in the long-term treatment of gout patients over a period of two years found better compliance in gout patients, better treatment outcomes and lower costs under the nurse-led gout care [23]. Therefore, the compliance of patients has a vital role in the treatment outcomes. Our team pointed out that currently, gout patients in our country are mainly treated in tertiary medical institutions. As the largest developing country, our primary health care system is not fully developed, and patient compliance directly leads to the changes in treatment outcome.
In the analysis of individual and social factors that lead to the difficulty of gout treatment, patients' compliance, self-discipline, and understanding of the disease were identified as important factors by all physicians. A survey on the medication compliance among gout patients found that up to 40%-50% of gout patients took medication irregularly [24], while 69.9% of gout patients in our country had poor compliance, which was often associated with poor prognosis [25]. Therefore, combined with our research results, we believe that patients' poor lifestyle and compliance were also important factors impacting the difficulty of gout treatment. In the previous randomized controlled trials, flare prophylaxis for up to 6 months during the initiation of ULT appeared to provide greater benefit than flare prophylaxis for 8 weeks, with no increase in adverse effects (AEs) [26]. The flare prophylaxis treatment determines whether the process of titration of urate-lowing treatment will go as planned and whether the patient can be regularly treated. Compared with the SE, a lower percentage of physicians in the GE consider recurrence of symptoms after initiation of ULT and preventive medications as being indicative of refractory gout. The difference between the two groups reveals that the higher experience was beneficial to the understanding of refractory gout.
Among the factors affecting the recovery of joint function in patients with refractory gout, joint destruction was the most recognized factor. The frequent onset of gout can cause joint damage, loss of function, and, eventually, disability [27] that has been widely recognized by physicians. Gout often needs to be differentiated from other crystal arthritis, especially pseudogout–calcium pyrophosphate arthritis [28]. However, in China, there are not so many tertiary medical institutions with the ability to perform arthrocentesis, thus making it so difficult to treat. Also, joint rehabilitation is a common concern among physicians. Previous studies have confirmed that long-term rehabilitation treatment in gout patients can significantly reduce the frequency of gout attacks [29]. Our team advocates rehabilitation exercises for gout patients and has begun comprehensive management of health education, joint rehabilitation, and drug therapy for patients.
Besides, there is a small population of gout patients who are challenging to treat due to genetic susceptibilities or some other predispositions [30]. This population usually requires a higher dose or a combined therapy along with a protracted treatment course, which may potentially pose even more difficulties; however, this entity is not within the scope of this study. The present study has some limitations. All the specialists included in the study had experience in gout diagnosis and treatment. They were all constantly continuing medical education, which is why knowledge level tests were not conducted on the study subjects.