CC BY
18
внутренние болезни
internal diseases
DOI: 10.29413/ABS.2021-6.1.2
Behavioral Characteristics of Gout Patients and Their Impact on the Results of Urate Lowering Therapy
Chen J., Zhou P., Tan W., Zheng W., Oshmianska N.
Chengdu Rheumatism Hospital (121 West 2nd Ring Road, Funan str., Qingyang District, Chengdu city,
Sichuan Province, China 610000)
Corresponding author: Oshmianska Nataliia, e-mail: 1283182076@qq.com
Abstract
Background. Gout isfrequently accompanied by hypertension, obesity, and/or impaired glucose tolerance, which are often complicated with heavy smoking and dietary violations, especially in male patients. Objective. To determine the behavioral characteristics of gout patients that could impact the results of urate lowering therapy.
Subjects and methods. The relationship between behavioral characteristics and results of urate lowering therapy were investigated in 74 male gout patients of Chengdu Rheumatism Hospital. The results of treatment were evaluated using serum uric acid contents before and after treatment, VAS pain score before and after treatment. Behavioral characteristics for the last ten years (smoking status, daily volume of drinking water, etc.) were accessed by means of retrospective survey.
Results. In gout patients with poor treatment response, serum uric acid at the beginning of the treatment was already significantly lower (365.76 ± 163.06 цmol/L); this trend was also noted in a "slow progress" group, while patients with higher serum uric acid before treatment had notably better response to urate lowering therapy. During further analysis age negatively correlated with serum uric acid (r = -0.328; p = 0.002) and uric acid clearance ratio (r = -0.299; p = 0.002).
In patients with uric acid clearance ratio above 40 % the prevalence of kidney diseases (stones or dysfunction) was significantly lower compared to other groups. There was no significant influence of hypertension, diabetes mellitus, fatty liver or hyperlipidaemia on uric acid clearance ratio (p > 0.05).
Amount of drinking water also influenced the serum uric acid clearance ratio. Bigger amount of patients in the "fast progress"group (40.0 % compared to 30.44 and 25.0 %) tended to drink more water. Conclusion. In most gout patients, serum uric acid levels before treatment acted as the reliable predictor of good response to urate lowering therapy. Treatment response (serum uric acid clearance ratio) correlated positively with the hyperuricemia and drinking sufficient amounts of water, negatively - with prolonged smoking (more than 10years) and age.
Key words: gout, urate lowering therapy, smoking, uric acid
For citation: Chen J., Zhou P., Tan W., Zheng W., Oshmianska N. Behavioral Characteristics of Gout Patients and Their Impact on the Results of Urate Lowering Therapy. Acta biomedica scientifica. 2021; 6(1): 13-17. doi: 10.29413/ABS.2021-6.1.2.
Поведенческие особенности пациентов с подагрой и их влияние на результаты уратоснижающей терапии
Чэн Д., Жу П., Тан В., Джен У., Ошмянская Н.Ю.
Ревматологический госпиталь г. Чэнду (610000, Вторая кольцевая дорога № 121, ул. Фунань, Циньян, г. Ченду,
провинция Сычуань, Китай)
Автор, ответственный за переписку: Ошмянская Наталья Юрьевна, e-mail: 1283182076@qq.com
резюме
Обоснование. Подагра часто сопровождается гипертонией, ожирением и/или нарушением толерантности к глюкозе, которые нередко осложняют тяжёлое курение и нарушения питания, особенно у пациентов мужского пола.
Цель исследования: оценить поведенческие характеристики пациентов с подагрой, которые могут повлиять на результатыурикозурической терапии.
Материалы иметоды. Связь между поведенческими характеристиками и результатамиуратоснижающей терапии была исследованау 74 пациентов с подагрой в ревматическом госпитале г. Чэнду. Результаты лечения оценивались с использованием содержания мочевой кислоты в сыворотке крови до и после лечения, по шкале болевых ощущений до и после лечения. Поведенческие характеристики за последние десять лет (статус курения, ежедневный объем питьевой воды и т. д.) были оценены с помощью ретроспективного опросника.
Результаты. У пациентов с подагрой, которые демонстрировали неудовлетворительный ответ на лечение, сывороточная мочевая кислота в начале лечения была значительно ниже (365,76 ± 163,06 мкмоль/л); эта тенденция была также была отмечена в группе с «медленным прогрессом», в то время как пациенты с более высоким содержанием мочевой кислоты в сыворотке крови до лечения демонстрировали заметно лучший ответ на терапию. В ходе дальнейшего анализа возраст отрицательно коррелировал с сывороточной мочевой кислотой (r = -0,328; р = 0,002) и коэффициентом клиренса мочевой кислоты (r = -0,299; р = 0,002). У пациентов с коэффициентом клиренса мочевой кислоты выше 40 % распространённость заболеваний почек (камни или дисфункция) была значительно ниже по сравнению с другими группами. Значимого влияния гипертонии, сахарного диабета, ожирения печени или гиперлипидемии на коэффициент клиренса мочевой кислоты отмечено не было (p > 0,05).
Количество питьевой воды также влияло на клиренс мочевой кислоты в сыворотке крови. Большее количество пациентов в группе «быстрого прогресса» (40,0 % по сравнению с 30,44 и 25,0 %) имели тенденцию пить больше воды.
Заключение. У большинства пациентов с подагройуровни мочевой кислоты в сыворотке крови до лечения являлись надёжным предикторомудовлетворительного ответа науратоснижающую терапию. Ответ на лечение (коэффициент клиренса мочевой кислоты в сыворотке крови) положительно коррелировал с ги-перурикемией и употреблением достаточного количества воды, отрицательно - с длительным курением (более 10 лет) и возрастом.
Ключевые слова: подагра,уратоснижающая терапия, курение, мочевая кислота
Для цитирования: Чэн Д., Жу П., Тан В., Джен У, Ошмянская Н.Ю. Поведенческие особенности пациентов с подагрой и их влияние на результаты уратоснижающей терапии. Acta biomedica scientifica. 2021; 6(1): 13-17. doi: 10.29413/ABS.2021-6.1.2.
INTRODUCTION
Gout is one of the most common rheumatic diseases in the world, which affects about 1.14 % of the general population in China, and from 1.4 to 2.5 % in other countries with recent epidemiologic data suggesting that its incidence is increasing [1, 2]. Clinical manifestations of gout include osteoarthritis and associated inflammation as much as system disorders linked to impaired purine metabolism, which often lead to restricted mobility and significantly lower the patients' quality of life.
There is a direct link between the increase of serum uric acid (UA) levels and the deposition of the large number of monosodium urate crystals around the joints [1]. Serum UA levels > 420 ^mol/L for men and > 360 ^mol/L for women are still widely used as main diagnostic criteria.
The treatment of gout includes controlling the disease by urate lowering therapy (xanthine oxidase inhibitor, allo-purinol, etc.) [3, 4]. Additional surgical intervention is needed in cases of gouty arthritis if there is cosmetic deformation or functional disorder of joint.
Multiple studies have assessed the potential effect of smoking on serum UA, either focusing on both serum UA and smoking in the development of gout, or by assessing the effect of smoking and/or serum urate as a secondary variable. There is considerable observational evidence to suggest that cigarette smoking lowers serum UA, however the results have not been consistent, with many reports providing evidence for the opposite effect, or no significant association of smoking and serum UA [12].
In recent years, studies have shown that obesity, oxidative stress, lifestyle and other general factors may also affect the body's uric acid levels, causing resistance to treatment [4]. Recent epidemiologic studies have shed some light on the prognosis of hyperuricemia, but the large scale research is still needed to access the relationship between the urate lowering therapy, behavioral characteristics of gout patients, cardiovascular risk and other comorbidities.
MATERIALS AND METHODS
Medical records of 74 male patients with gout were included to the study. All patients were admitted to Chengdu Rheumatism Hospital in 2019-2020. Patients satisfied the preliminary criteria of gout and were prescribed with urate
lowering therapy. The study was performed in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Committee of Chengdu Rheumatism Hospital. All participants provided written informed consents.
Datacollection. In all patients anthropometrical parameters were measured, including waist circumference, body height and weight, body mass index (BMI). In addition, blood pressure at systolic and diastolic phases, blood levels of triglycerides, fasting serum glucose, and creatinine were measured.
Serum UA was measured on the first day and after the end of treatment by standard ELISA method. The progress of UA clearance was calculated as (serum UA after treatment) / (serum UA before treatment) and mean values was 32-33 % independent of age. In order to look further into the reasons of better or worse UA clearance we divided subjects into 4 groups:
Group 1 - no progress, UA clearance ratio was negative;
Group 2 - very slow progress, UA clearance ratio - below 30 %;
Group 3 - slow progress, UA clearance ratio - 30-40 %;
Group 4 - fast progress, UA clearance ratio - above 40 %.
Presence of fatty liver was detected by B-ultrasonog-raphy, in some cases with additional MRI or liver biopsy. The diagnosis of renal dysfunction was based on serum creatinine and glomerular filtration rate (GFR); kidney stones was detected by X-ray and B-ultrasonography.
Statistical analysis was conducted using IBM IPSS statistics software (version 23, IBM Co., Armonk, NY, USA).
RESULTS
General characteristics of patients. A total of 74 male patients with gout were included in this study. The mean age of patients was 49.55 ± 15.54 years, the mean weight was 72.76 ± 10.87 kg, the mean BMI was 25.97 ± 3.43 kg/m2. BMI data indicated that majority of patients were overweight according to criteria of obesity by the World Health Organization. The mean serum UA level assessed at the first day of treatment was 495.62 ± 127.81 ^mol/L, mean serum UA after treatment was 334.89 ± 112.78. Fatty liver was described in almost half of patients (45.94 %), total of 37.84 % of patients had hypertension and 8.11 % had diabetes mellitus (DM).
TREATMENT CONTROL
All patients were asked to access the level of pain in joints according to VAS pain score before the treatment start and after the last day of treatment. There was a weak link between reported values before treatment and serum UA (r = 0.161; p = 0.05), however, after treatment the majority of patients reported significant improvement in pain which was not linked to serum UA.
Therefore, it has been decided to use UA blood levels on the first day and after the end of the treatment as a control points for this paper. Average blood UA before treatment was 493.09 ± 96,95 |mol/L, and after treatment -334.89 ± 90.93 |mol/L; only in 13.51 % of all patients the levels of serum UA after treatment was higher of equal to the levels before treatment (Fig. 1).
After that, study groups were analyzed according to the clearance ratio of serum UA. In the "no progress" group mean serum UA at the beginning of the treatment was already significantly lower compared to other groups (365.76 ± 163.06 |mol/L); this trend was also noted in a"slow progress"group, while those patients who had higher serum UA before treatment was notably higher UA clearance ratio in response to urate lowering therapy. During further anal-
ysis age negatively correlated with serum UA (r = -0.328, p = 0.002) and UA clearance ratio (r = -0.299, p = 0.002).
In patients with UA clearance ratio above 40 % the prevalence of kidney diseases (stones or dysfunction) was significantly lower compared to other groups. There was no significant influence of hypertension, DM, fatty liver or hyperlipidaemia on UA clearance ratio (p > 0.05). For more details, see Table 1.
Further analysis leads to removing the first group from the statistical analysis, because of the unuinifor-mity of the response due to different outer factors. In the remaining three groups, behavioral characteristics were analyzed. In the "slow progress" group mean serum UA was 485.5 ± 115.87 |mol/L before treatment, and 392.45 ± 92.86 |mol/L after treatment; in the "average progress"group it was equal to 533.36 ± 102.28 |mol/L before treatment, and 341.31 ± 62.06 |mol/L after treatment; and in the "fast progress" group - equal to 532.71 ± 106.61 |mol/L before treatment, and 239.95 ± 72.75 |mol/L after treatment.
Groups were not statistically different in BMI or age. The habit of smoking was reported less often in "fast progress" group but differences were not statistically significant. However, after stratifying patients according to the length
Fig. 1. Serum UA levels in study patients before (blue) and after (red) urate lowering treatment (|mol/L)
Table1
Theprevalenceofaccompanyingdiseasesand conditionsin goutpatientsaccording to UAclearanceratio
Group 1 (no progress), n = 10 Group 2 (< 30 %), n = 23 Group 3 (30-40 %), n =16 Group 4(> 40 %), n = 25
UA baselevelsbefore treatment, ^mol/L 365.76 ± 163.06 485.5 ± 115.87 533.36 ± 102.28 532.71 ± 106.61
BMI 26.47 26.01 25.89 25.79
Hypertension, % 40 52.17 31.25 28.0
Diabetes mellitus, % 0 8.69 6.25 12.0
Fatty liver, % 40 43.49 50 48.0
Hyperlipidaemia, % 10 39.13 25 16.0
Hepatic dysfunction 10 4.35 18.75 8.0
Renaldysfunction 20 34.78 37.5 20.0
Kidneystone 20 17.39 31.25 8.0
of smoking, it was found than smoking more than 10 years was reported significantly less often in "fast progress"group.
Amount of drinking water also influenced the serum UA clearance ratio. Bigger amount of patients in the "fast progress" group (40.0 % compared to 30.44 and 25.0 %) tended to drink more water.
DISCUSSION
Poor response to urate lowering therapy in gout patients became a real concern of many researchers. According to the one of recent studies by Mu et al. [3], which was conducted on 370 patients, patients with poor response to ULT had younger age and higher proportion of obesity, as well as higher baseline UA. Review by Graham et al. [5] dated 2018, also stated tha t h igher pre-treatmentserum UA,younger age ofpatients, higher BMI aedeoreottlcholosSsrolwae associated with a decaeasoS nrobabilitpof atti eoing Oreagmon S success.
However, in those studies poor response was deter-minog onld by serum UA ayooe 0 mg/dL sftar tae ond oftaea0ment,whist ruleh oohhhe eoseswhstey heinitiol serumUA was noCverySid h,otwCen ihwas SSetasd lowereO grodualln i nrespcoratotreatment,but % two aeaoeoo She average values yet.
lunar sfu dy, we used the rate of serum UA clearance to acc eso nee effective nest to ui^aW^c^r^siy/oe^^e^h SFg . up HmdarO^stl iea UA wasa s^i^c^^odo w ith tottea sespante tcoy/aemac ione aigho s Pa cleuaanoo, hutif iuintoauft iog to note that in group 3 and group 4 baseline serum UA WHsalmost °he ^i^me r533.3O ± 1 02.28 pmo^oomfsared to032.S1 ± t 1S6.S1 rtmol/U)we eceastdessrumUAIevel st/ar tteatwentweres¡go¡flcse fly diflArenS (341.31 ± 62.06 pmol/L compoaeO to 23 9/a n 72.Lt omnI/ea
Many patients with gout have additional renal impairment and ot°ers, becams/o1 ^peaton^] y/oonoomtant hitea/euta Sow ore taking loop orth¡ae¡h ef ir^rhe^c^s [SloH^e isflaenc e otaont I Wo atn^^n S ynO did10t ¡psohfho res pwnse to U0T are nhirefore of con/i0eradln c^iiw^al interest.
Renal impairment increases the concentrations of serum UAt)eosusot he re nal cfe atseoegfLra1ie iyreguced [6/, as we N atOho ren^l tletra nceopmxmpu ^^r^ol orothnr med¡oinerWeic h
is cleared by the kidney. However, pharmacokinetic modeling indicates a substantial increase in the dose of allopurinol that is required for an adequate response in patients who are taking concomitant thiazide or loop diuretics [7]. In addition to that, it is important to note that pre-treatment concentration of serum UA as well as the serum urate concentration during treatment is higher in patients taking diuretics [8].
It is advised, that in patients who are prescribed with concomitant diuretics the amount of ULT should be, on average, increased in order to achieve response. But as clinical trials showed, percentage of responders to ULT is not influenced statistically in patients with mild or moderate renal impairment [9].
In tor stadypttirnte w itoUAcle arancerati oalsove4 0% had significantly lower prevalence of renal impairment (stones or dgeSuncfi ontaompsrnO trnotfdr moups, waiee ¡ndifafhs Lhh iodepondent rolesfSidosys in aPhqoato ULTrefeohLe as there was no significant influence of hypertension, DM, fatty ¡°er ar hy°eelipidaenria oo UA cloaaaeoe ratio [p ap .05° However, the larger study needed to fully access the efficacy ot OLTWaHing intoastou nt coaeomitanoe maota theaaay end itsimoaot my r0aumuratecAnceatraC¡sns OuPco tteotment.
Smoking is associated with some of the known risk factors for gout, especially obesity and alcohol intake, but consensus hatyot to barnacOeO os sotO e eafent oS s my king so serum Ure 8tgo ut)isd / smdaets. Stn0yУgWpng tn<0 Kaithoosnt] puOioeed iaea1У thowydtaafaf1¡ht 0<^justore ntto/ twooe d BMI, cigarette smoking was associated not with higher, but w rth ¡owor a°dof guut Laaer,Aengo1iol. [[1] ^na ^os peHtiue cohoaS t^i^t^y Th 2Pd daWoi pan!/) od Snioddfhefame resalts.
In our study, we did not find any association between smoking ^^i^sr^n dao snoete to ULH. Howeaoa, aSOer analyzt ing the duration of smoking, we found that in patients who re p/atei1 smo° :hg more thHn 1 (¡^sra, UAdo i/awc/ ratio was sign¡fiaonSlo lowea.
SdgsePndindf mi ghtb eysrtiaiia ogplam ea bteh^feca teoo prota/gad smokieg serom O/^ isУe^so^nW
ly to treatment [12]. Indeed, we found that serum UA levels Itefote tteol: mea^ete sightfkant ^^toa ]u patimnte who regarted pmeUiag moae/een 10 yerart.
900 800 700 600 500 400 300 200 100 0
Mean BT
Min BT
Max BT
Mean AT
Min AT
Max AT
Fig. 2. Mean,minimumandmaximum valuesof serumUAingoutpatientsbefore treatment (BT) andafter treatment (AT),|mol/L,distributed according to UA clearance ratio; group 1 - no progress (n = 10); group 2 - UA clearance ratio < 30 % (n = 23); group 3 - UA clearance ratio30-40% (n =16);group4-UAclearanceratio > 40 %(n = 25)
As mentioned above, the initial levels of UA before treatment may be a predictor of the response to ULT. Therefore, prolonged smoking, gradually reducing the level of serum UA, can thus affect the effectiveness of treatment.
Drinking sufficient amounts of water also may influence the effectiveness of treatment [13]. In our study, drinking habit also influenced the serum UA clearance ratio. Bigger amount of patients in the "fast progress" group (40.0 % compared to 30.44 and 25.0 %) tended to drink more water.
It is important to note that this link is explained not only by the serum UA increase due to dehydration, but via more complex mechanisms as well, such as oxidative stress and endothelial dysfunction.
Regardless the efficacy of ULT, previous observations identify gout patients with comorbidities as likely to be prescribed with the greater volume of pharmacological treatment. Based on the notion that hiperuricemia alone is insufficient to account for the impact of gout on the development of metabolic syndrome, liver diseases and other comorbidities, studying the behavioral characteristics of patients before treatment could make the prescription of drugs more precise, abiding recent inclination toward the individual-based personalized medicine practices.
Conflict of interest
None of the authors have any conflict of interest regarding this manuscript.
REFERENCES
1. Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: Prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020; 16(7): 380-390. doi: 10.1038/s41584-020-0441-1
2. Mattiuzzi C, Lippi G. Recent updates on worldwide gout epidemiology. Clin Rheumatol. 2020; 39(4): 1061-1063. doi: 10.1007/ s10067-019-04868-9
3. Mu Z, Wang W, Wang J, Lv W, Chen Y, Wang F, et al. Predictors of poor response to urate-lowering therapy in patients with gout and hyperuricemia: A post-hoc analysis of a multicenter randomized trial. Clin Rheumatol. 2019; 38(12): 3511-3519. doi: 10.1007/s10067-019-04737-5
4. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006; 8(Suppl 1): S2. doi: 10.1186/ar1907
5. Graham GG, Stocker SL, Kannangara DR, Day RO. Predicting response or non-response to urate-lowering therapy in patients with gout. Curr Rheumatol Rep. 2018; 20(8): 47. doi: 10.1007/ s11926-018-0760-2
6. Sánchez-Lozada LG. The pathophysiology of uric acid on renal diseases. Contrib Nephrol. 2018; 192: 17-24. doi: 10.1159/000484274
7. Wright DF, Duffull SB, Merriman TR, Dalbeth N, Barclay ML, Stamp LK. Predicting allopurinol response in patients with gout. Br J Clin Pharmacol. 2016; 81(2): 277-289. doi: 10.1111/bcp.12799
8. Goldfarb DS. Review: Thiazide, citrate, or allopurinol reduces recurrence after > 2 kidney stone episodes. Ann Intern Med. 2013; 159(2): JC12. doi: 10.7326/0003-4819-159-2-201307160-02012
9. Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febux-ostat in the treatment of the hyperuricemia of gout: The CONFIRMS trial. Arthritis Res Ther. 2010; 12(2): R63. doi: 10.1186/ar2978
10. Wang W, Krishnan E. Cigarette smoking is associated with a reduction in the risk of incident gout: Results from the Fram-ingham Heart Study original cohort. Rheumatology. 2015; 54(1): 91-95. doi: 10.1093/rheumatology/keu304
11. Teng GG, Pan A, Yuan JM, Koh WP. Cigarette smoking and the risk of incident gout in a prospective cohort study. Arthritis Care Res. 2016; 68(8): 1135-1142. doi: 10.1002/acr.22821
12. Fanning N, Merriman TR, Dalbeth N, Stamp LK. An association of smoking with serum urate and gout: A health paradox. Semin Arthritis Rheum. 2018; 47(6): 825-842. doi: 10.1016/j.semar-thrit.2017.11.004
13. Hisatome I, Ohtahara A, Hamada T, Ogino K. Development of Guideline for the management of hyperuricemia and gout in Japan 3rd edition. Gout and Nucleic Acid Metabolism. 2018; 42(2): 147-156. doi: 10.6032/gnam.42.147
Information about the authors
Chen Jianchun - Doctor at the Rheumatology Department, Chengdu Rheumatism Hospital, e-mail: cjc18030541834@163.com, https://orcid.org/0000-0003-2538-2132
Zhou Pan - Doctor at the Rheumatology Department, Chengdu Rheumatism Hospital, e-mail: 464834845@qq.com, https://orcid.org/0000-0001-8904-8876
Tan Wei - Doctor at the Surgical Department, Chengdu Rheumatism Hospital, e-mail: tw18181420391@163.com, https://orcid.org/0000-0002-8560-1870
Zheng Wuyan - Cand. Sc. (Med.), Head of the Scientific Research Department, Chengdu Rheumatism Hospital, e-mail: 1642637460@qq.com, https://orcid.org/0000-0002-5133-9472
Nataliia Y. Oshmianska - Research Officer at the Scientific Research Department, Chengdu Rheumatism Hospital, e-mail: 1283182076@qq.com, https://orcid.org/0000-0001-8027-5693
Сведения об авторах
Чэн Дзянчун - врач отделения ревматологии, Ревматологический госпиталь г. Чэнду, e-mail: cjc18030541834@163.com, https://orcid.org/0000-0003-2538-2132
Жу Пан - врач отделения ревматологии, Ревматологический госпиталь г. Чэнду, e-mail: 464834845@qq.com, https://orcid.org/0000-0001-8904-8876
Тан Вэй - врач отделения хирургии, Ревматологический госпиталь г. Чэнду, e-mail: tw18181420391@163.com, https://orcid.org/0000-0002-8560-1870
Джен Уянь - кандидат медицинских наук, заведующая отделом научных разработок и инноваций, Ревматологический госпиталь г. Чэнду, e-mail: 1642637460@qq.com,
https://orcid.org/0000-0002-5133-9472
Ошмянская Наталья Юрьевна - кандидат медицинских наук, научный сотрудник отдела научных разработок и инноваций, Ревматологический госпиталь г. Чэнду, e-mail: 1283182076@qq.com, https://orcid.org/0000-0001-8027-5693
Received: 07.08.2020. Accepted: 27.10.2020. Published: 26.02.2021. Статья получена: 07.08.2020. Статья принята: 27.10.2020. Статья опубликована: 26.02.2021.
