The Effect of Chronic Disease Management on the Treat-to-Target of Gout: A Cross-Sectional Study

Background: The treat-to-target (T2T) strategy is essential for patients with gout. However, the rate of T2T is low. This study aimed to explore doctor-led chronic disease management on the T2T of gout, survey the rate of T2T and assess the predictors associated with poor control of serum urate levels (SUA) in a large population of patients with gout receiving urate-lowering treatment (ULT). Methods: A multi-center, cross-sectional study was conducted. We surveyed the relevant information of outpatients who received ULT for more than six months using electronic questionnaires, including demographics, disease-related conditions, comorbid conditions, and management. The patients with gout were divided into the SUA > 360 µmol/L and ≤ 360 µmol/L, and the patient characteristics between the two groups were compared. We analyzed the predictors of SUA > 360 µmol/L and poor disease control. Results: We collected 425 (90.8% of the patients) valid questionnaires. There were signicant differences in the gender, education level, regular visits, medication adherence, diabetes, economic burden and community doctor's help between the SUA > 360 µmol/L (n=311, 73.18%) and ≤ 360 µmol/L (n=114, 26.82%) groups. The predictors of SUA >360 µmol/L were general medication adherence (OR=2.35; 95% CI 1.17–4.77; p=0.016), poor medication adherence (OR=4.63; 95% CI 2.28–9.51; p<0.001) and community doctor’s help (OR=0.60; 95% CI 0.37–0.97; p=0.036 for full model, OR=0.58; 95% CI 0.36–0.93; p=0.023 for simplied model). There were signicant differences in the gender, regular visits, medication adherence, gout popular science, established health les, and community doctor’s help between the not well controlled (n=361, 84.94%) and well controlled (n=61, 14.35%) groups. The predictors of not well controlled were Tophi (OR=2.48; 95% CI 1.17–5.61; p=0.023), general medication adherence (OR=2.78; 95% CI 1.28–6.05; p=0.009), poor medication adherence (OR=6.23; 95% CI 2.68–14.77; p<0.001) and no gout popular science (OR=4.07; 95% CI 1.41–13.91; p=0.015). Conclusion: The T2T and well controlled rates were very low. The medication adherence, the community doctor’s help and gout popular science which was the doctor-led chronic gout management should be further improved to increase the T2T and well controlled rate.


Introduction
Gout is a common arthritic condition that results from monosodium urate (MSU) crystal deposition. The prevalence of gout is 3-4% among adults in the USA [1], and the prevalence of gout increases with age [2]. Obesity, cardiovascular disease (CVD) [3], and chronic kidney disease (CKD) [4][5][6] are associated with gout. Gout is an independent risk factor for all-cause and cardiovascular mortality [7].
Urate-lowering treatment (ULT) is essential for patients with gout. It can reduce the frequency of gout attacks, reduce the number of joints involved, reduce urate deposition, and protect articular cartilage and kidneys [8]. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines recommended the treat-to-target (T2T) strategy for gout in 2016 [9]. However, the rate of T2T was unsatisfactory. A prevalence survey in France found that 22.3% patients had reached the target of 6 mg/dL SUA, and the rate was only 11% for the ULT in more than 12 months.
The EULAR guidelines recommend that the optimum long-term management of gout should include patient education and lifestyle modi cations [10]. However, similar to other chronic diseases, the treatment of chronic gout appears to be inadequate, and long-term adherence to ULTs is suboptimal [11][12][13]. Despite the availability of ULT, under-recognition of gout and its societal burden contribute to inadequately controlled SUA levels and its management failure as a chronic disease [14,15]. Inadequately controlled SUA leads to substantially negative disease burden of chronic gout, both socially and nancially. Hence, patients need to realize the importance of adherence to ULT and maintain the SUA target level for long-term [16]. Although nurse [17] and pharmacist [18,19] led interventions to improve T2T have been reported, the panel recognized the necessity for the treating physician to educate the patient and implement a T2T protocol [20], but there is no relevant study. Hence, this study aimed to explore doctor-led chronic disease management on the T2T of gout, survey the rate of T2T and assess the predictors associated with poor control of SUA in a large population of patients with gout who received ULT for more than six months.

Participants
This cross-sectional study was conducted in seven centers between July 2020 and May 2021 (chictr.org.cn ChiCTR2000034700). This study was approved by the Institutional Medical Ethics Committee of the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine. Informed written consent was obtained from all study participants. Male and female outpatients aged 18-80 years were enrolled. The patients met the 1977 American College of Rheumatology (ACR) criteria for acute arthritis of gout [21] or the 2015 ACR/European League Against Rheumatism gout classi cation criteria [22]. The patients received ULT for more than six months, and could complete the questionnaire independently. Patient exclusion criteria were as follows: secondary gout (chronic kidney disease, blood disorders, etc.), refusal to provide information. The state of well-controlled disease was de ned as treatment target reached and no are or use of anti-in ammatory medication for one month [23]. A total of 468 gout patients were successively invited to participate in this study and complete the questionnaire under the researchers' supervision in a clinical setting, and 425 (90.8% of the patients) valid questionnaires were collected for statistical analysis.

Assessments
For representativeness, each participating physician could not include more than ve consecutive patients. We used electronic questionnaires to conduct surveys. Patients with gout were asked to complete a set of standardized self-report questionnaires as follows: Demographic variables such as age, gender, body mass index (BMI), education, mental work, and family history. Disease-related conditions such as disease duration, highest creatinine level in a month, Tophi, acute ares in preceding 1-year, medicine used, attitude to gout and eight-item Morisky Medication Adherence Scale (MMAS-8) [24].
Comorbid conditions such as hypertension, diabetes, hyperlipidemia, kidney stones and coronary atherosclerotic heart disease. Management including information provided by the doctor, diet management, exercise, gout popular science, patient communication, own expense, economic burden, established health les and community doctor's help.

Sample size
The sample size was estimated using the nQuery Advisor software. According to the 2016 Chinese Rheumatism Data Center (CRDC), the rate of target SUA achieved for six-month was 38.20%, assuming the rate was 0.4, the allowable error was 0.05, and the estimated sample size was 369.

Statistical analysis
Demographic variables were described as mean ± standard deviation (SD) for continuous variables or as frequency and percentage for categorical variables. The characteristics of the subjects in the achieved target SUA group and the none achieved target SUA group were compared using independent t-tests or Mann-Whitney U tests for normal and non-normal data, respectively. Univariate analysis was performed to identify variables associated with SUA > 360 µmol/L and well controlled. Multivariable logistic regression was used to develop the risk model. We selected predictors using both statistical signi cance (p< 0.05) and clinical importance criteria. The predictive accuracy of the model was assessed using calibration slope. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC) and R Package Regression Modeling Strategies.

Discussion
There is no relevant research on the effect of chronic gout management to T2T in China. It is easy to reach the target SUA level in the short-term. However, long-term control of the target SUA level remains a challenge. This study found that the rate of T2T was low. Patients with SUA ≤ 360 µmol/L were compared with those > 360 µmol/L to determine factors associated with achieving target SUA level. Our ndings substantiate the importance of medicine adherence. Signi cant differences were found in medicine adherence, regular visits and community doctor's help between the SUA ≤ 360 µmol/L and SUA > 360 µmol/L groups as well as between the well-controlled and not well-controlled groups in this study. Consistent with known epidemiology, we observed susceptibility to gout among males in our study, especially those over 40 years of age [25]. Notably, patients with lower education were more likely to achieve SUA target in this study. As the use of ULT most directly in uences SUA, it is important to emphasize the signi cance of maintaining SUA target when educating patients about the disease[26].
Our study suggested that patients with community doctor's help tend to have stronger belief about the necessity of ULT. Education and disease management information provided by doctors may improve the patient's medicine adherence and regular visits.
Low awareness of the disease, lack of appropriate knowledge about gout and poor understanding of the need for long-term treatment reduced the patients' compliance of treatment. Some doctors did not have su cient time to offer appropriate education about gout and ULT to their patients, which led to acute ares of gout, and patients did not adhere to the ULT for long-term effective control of SUA levels [14]. Furthermore, few patients receive clear education to reduce risk factors and co-morbidities or personalized lifestyle advice about chronic gout [11,13]. Consequently, only a minority of patients are relieved of gout, which leads to an increasing disease burden [27]. Recently, there were management measures led by nurses and pharmacists, but the 2020 ACR guidelines recommended that treating physicians should provide education and management [20]. Hence, doctors are very important for the chronic gout management in patients. Since gout is a chronic disease that is susceptible to relapse, the daily self-management and treatment of patients are equally important. Clinically, the education about gout and management principles underpin successful treatment. A healthy lifestyle is always recommended and patient education is critical to support self-management and long-term adherence. Therefore, health education should be strengthened for gout patients with recurrent and long-term ULT to eliminate the root cause of gout pain and disease progression[28].
The present study had some limitations. First, the universality of the sample population and the research centers involved in the trial were limited. Although this was a multi-center study, the discrepancies due to developed and underdeveloped regions, different regions in East and West China, and different eating habits, may require a larger sample size to con rm. Second, we only studied the compliance rate for more than six months, so our study highlights the need for ≥1 year compliance research to provide support for future clinical treatment. Lastly, this was a cross-sectional study, and our results con rmed the importance of doctor-led chronic disease management.

Conclusions
In summary, the T2T and well controlled rate were very low. The medication adherence, the community doctor's help and gout popular science which was the doctor-led chronic gout management should be further improved to increase the T2T and well controlled rate.

Con ict of Interest:
The authors declare they have no con icts of interest.

Availability of data and materials
Data are available upon reasonable request. For inquiries about data sharing, please send request at sailing1980@126.com. Tables Table 1 Characteristics of the patients with gout between the SUA > 360 umol/L and ≤ 360 umol/L.       Figure 1 Calibration plot (left) and receiving operating characteristic curve (right) for the high uric acid risk model.

Ethics approval and consent to participate
In calibration plot, dashed line indicates ideal reference line where predicted probabilities would match the observed proportions, and the points with error bars represent the nomogram-predicted probabilities and 95% con dence interval grouped for each of the four quartile groups.