Risk factors associated with non-radiographic bone erosion in patients with gout

Wei LIU; Wen GUO; Zhe GUO; Chunyan LI; Yunlong LI; Siqi LIU; Liang ZHANG; Hui SONG

doi:10.19723/j.issn.1671-167X.2025.04.017

Journal of Peking University(Health Sciences) >

2025 , Vol. 57 >Issue 4: 735 - 739

DOI: https://doi.org/10.19723/j.issn.1671-167X.2025.04.017

Risk factors associated with non-radiographic bone erosion in patients with gout

Wei LIU ¹ ,
Wen GUO ² ,
Zhe GUO ³ ,
Chunyan LI ⁴ ,
Yunlong LI ¹ ,
Siqi LIU ¹ ,
Liang ZHANG ⁵ ,
Hui SONG ^,¹^,*

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1. Department of Rheumatology and Immunology, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China
2. Department of Ultrasound, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China
3. Department of Radiology, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China
4. Department of Laboratory Tests, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China
5. Department of Orthopedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing 100035, China

Received date: 2022-08-12

Online published: 2025-08-02

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Abstract

Objective: To analyze the factors associated with non-radiographic bone erosion in gout patients, to improve the understanding of bone erosion in gout, and to promote the early detection of bone erosion. Methods: A retrospective analysis was conducted on the medical records of gout patients treated at Beijing Jishuitan Hospital from January 2018 to January 2022. Bone erosion was detectable by ultrasound but not detected by X-ray as non-radiographic bone erosion; no bone erosion was detected by both ultrasound and joint X-ray as undetected bone erosion. A case-control study was used, and the two groups were matched 1 ∶ 2 according to age and sex. The differences between the two groups were compared in terms of general information, joint involvement characteristics, laboratory indicators and complications. In the univariate analysis, P < 0.1 was included in the multivariate analysis, and the conditional Logistic regression was used for the multivariate analysis. P < 0.05 was considered to have statistically significant differences. Results: Among the 41 patients with non-radiographic bone erosion, the top three joints with bone erosion before its occurrence were metatarsophalangeal joint (12 cases), ankle (10 cases), and knee (7 cases). There were 82 patients undetected with bone erosion. There were no significant differences in general information between the two groups (P>0.05), including age, gender, body mass index, and alcohol consumption history. The characteristics of affected joints in the non-radio-graphic bone erosion group were compared with those in the no bone erosion detected, and the former had more affected joints (P=0.02), and a higher proportion of patients with at least 3 attacks of gout per year (P < 0.001). There were no significant differences in serum uric acid, fasting blood glucose, cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, creatinine, homocysteine, white blood cell count, and urine pH between the two groups (P>0.05). The results of multivariate analysis showed that at least 3 flares of gout per year was an independent risk factor for radiologically negative bone erosion in patients with gout, with an OR (95%CI) of 5.139 (1.529-17.271). Conclusion: At least 3 flares of gout per year predicts the occurrence of radiologically negative bone erosion, and these patients should be given more attention to achieving treatment targets.

Key words： Gout; Bone erosion; Ultrasound; X-rays; Risk factors

Cite this article

Wei LIU , Wen GUO , Zhe GUO , Chunyan LI , Yunlong LI , Siqi LIU , Liang ZHANG , Hui SONG . Risk factors associated with non-radiographic bone erosion in patients with gout[J]. Journal of Peking University(Health Sciences), 2025 , 57(4) : 735 -739 . DOI: 10.19723/j.issn.1671-167X.2025.04.017

痛风是由单晶尿酸盐在关节沉积引起的代谢性风湿病，除关节表现外，还容易并发肾损害、高血压、糖尿病及心血管疾病。近年来，痛风疾病负担在全球范围内逐渐增加，据不完全统计我国痛风的发生率为1%~3%^[1]。骨侵蚀是痛风的常见关节损害，骨侵蚀预示着痛风的恶化，与疾病的严重程度相关，特别是晚期严重的骨破坏显著降低关节功能^[2-4]。了解痛风患者骨侵蚀的相关危险因素，有利于骨侵蚀的及时发现、痛风疾病阶段的划分和治疗方案的优化。本研究旨在从一般信息、关节受累特点、实验室指标及并发症等方面，分析痛风患者放射学阴性骨侵蚀的相关危险因素，以期提高对痛风骨侵蚀的认识，促进骨侵蚀的早期发现。

1 资料与方法

1.1 病例选择

选择2018年1月至2022年1月北京积水潭医院诊治的痛风性关节炎患者的病例资料进行回顾性分析，按照如下纳入与排除标准选择病例。纳入标准：(1)符合2015年美国风湿病学会/欧洲抗风湿病联盟(American College of Rheumatology/European League Against Rheumatism，ACR/EULAR)痛风分类标准；(2)完成了痛风受累关节的X线及关节超声检查；(3)年龄>18岁。排除标准：(1)合并其他炎性关节炎(如银屑病关节炎、强直性脊柱炎、类风湿关节炎等)者；(2)骨坏死、骨肿瘤患者。本研究开始前已经北京积水潭医院伦理委员会审查批准(积伦科审字第202008-01号)。

1.2 定义及分组

超声探及的骨侵蚀定义为在两个垂直的平面内可见关节内和/或关节外的骨表面不连续^[5]。

X线探及的骨侵蚀：X线发现骨质破坏，呈偏心性圆形或卵圆形的囊性变，甚或呈虫噬样或穿凿样骨缺损，更为严重者出现关节间隙狭窄、关节半脱位/脱位、关节骨性强直^[1]。

放射学阴性骨侵蚀组定义为超声可探及骨侵蚀但X线检查未发现骨侵蚀^[6-7]，未探及骨侵蚀组超声及关节X线均未发现骨侵蚀。影像结果分别由同一名超声科具有副高职称的专家和同一名影像学具有副高职称的专家各自独立判读。

1.3 观察指标

患者一般临床资料包括年龄、性别、身高、体重、病程、吸烟史、饮酒史及痛风家族史。体重指数(body mass index，BMI)=体重/身高²；饮酒史定义为饮酒时间超过5年，并且换算的乙醇每日摄入量男性大于40 g或女性大于20 g。吸烟史定义为连续或者累计吸烟半年及以上。

患者痛风累及的关节指标：记录痛风急性关节炎每年发作的次数、受累关节的部位、受累关节总数及痛风石。手关节包括腕关节、掌指关节、近端指间关节及远端指间关节。痛风石的判断标准为超声检测到的环形的、不均匀的、高回声和/或低回声的聚集物(伴或不伴后方的声影)，可被小的无回声包围^[5]。

患者实验室指标包括尿酸(uric acid，UA)、葡萄糖(glucose，GLU)、胆固醇(cholesterol, CHOL)、甘油三酯(triglyceride, TG)、低密度脂蛋白(low-density lipoprotein, LDL)、高密度脂蛋白(high-density lipoprotein, HDL)、肌酐(creatinine, Cr)、同型半胱氨酸(homocysteine, HCY)、白细胞计数(white blood counts, WBC)及尿液pH值。

患者合并症包括患者高血压、糖尿病、冠心病及肾结石病史。

1.4 统计学分析

使用R语言4.0.4版中的Matchit包完成病例组与对照组匹配，匹配的方法为按照年龄(±2岁)及性别按1 ∶ 2匹配对照组病例。如匹配过程中对照组多人满足匹配条件则根据就诊时间与匹配病例就诊时间相近的病例优先纳入。采用SPSS 26.0统计软件，符合正态分布的计量资料以${\bar x}$±s表示，组间比较采用配对t检验；不符合正态分布的计量资料以M(P₂₅, P₇₅)表示，组间比较采用Wilcoxon秩和检验。计数资料以n(%)表示，组间比较采用配对四格表资料的McNemar检验，单元格期望频数小于5采用Fisher精确概率检验。单因素分析的因素中P＜0.1者纳入多因素分析，采用条件Logistic回归进行多因素分析，P＜0.05认为差异有统计学意义。

2 结果

两组一般信息比较：共有确诊患者471例纳入本研究，符合放射学阴性骨侵蚀组患者共41例，未探及骨侵蚀组患者共338例，根据本文的匹配原则，匹配了82例未探及骨侵蚀患者进行统计分析。

放射学阴性骨侵蚀组41例患者中，发生放射学阴性骨侵蚀前三位的关节分别是跖趾关节(metatarsophalangeal joint，MTP；12例)、踝(10例)、膝(7例)。与未探及骨侵蚀组共82例患者组间比较，放射学阴性骨侵蚀组病程更长(P=0.020)；年龄、性别、BMI及饮酒史等一般信息组间差异均无统计学意义(表 1)。

表1 两组患者一般临床资料比较

Table 1 Comparison of general clinical characteristics between the two groups

Items	Non-radiographic bone erosion (n=41)	No bone erosion detected (n=82)	P
Age/years	48 (33, 54)	49 (33, 53)	0.180
Gender			0.999
Male	40 (97.6)	80 (97.6)
Female	1 (2.4)	2 (2.4)
BMI/ (kg/m²)	27.7 (23.4, 29.4)	27.3 (24.8, 30.1)	0.674
Disease duration/years	6.0 (3.0, 10.0)	3.0 (0.9, 6.0)	0.020
Somking	20 (48.8)	44 (53.7)	0.006
Drinking	19 (46.3)	31 (37.8)	0.272
Family history	8 (19.5)	12 (14.6)	0.002

Data were M(P₂₅, P₇₅) or n (%). BMI, body mass index.

痛风累及关节与未探及骨侵蚀组相比，放射学阴性骨侵蚀组受累关节计数更多(P=0.020)，每年痛风发作≥3次的患者比率更高(P＜0.001，表 2)。

表2 两组患者痛风累及关节比较

Table 2 Comparison of gout-involved joints between the two groups

Items	Non-radiographic bone erosion (n=41)	No bone erosion detected (n=82)	P
Involved joint count	5 (2, 8)	3 (2, 4)	0.020
Flare counts per year≥3	31 (75.6)	39 (47.6)	＜0.001
Foot joint involvement	36 (87.8)	61 (74.4)	＜0.001
Ankle involvement	25 (61.0)	54 (65.9)	＜0.001
Knee involvement	23 (56.1)	45 (54.9)	0.001
Hand joint involvement	17 (41.5)	16 (19.5)	0.268
Elbow involvement	7 (17.1)	7 (8.5)	＜0.227
Tophi	7 (17.1)	7 (8.5)	＜0.227

Data were n (%).

两组实验室指标比较：血尿酸、空腹血糖、胆固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白、肌酐、同型半胱氨酸、白细胞计数及尿pH值等指标组间差异均无统计学意义(P>0.05，表 3)。

表3 两组患者实验室指标比较

Table 3 Comparison of laboratory indicators between the two groups

Items	Non-radiographic bone erosion (n=41)	No bone erosion detected (n=82)	P
UA /(μmol/L)	498.9±146.6	538.4±141.0	0.282
GLU/ (μmol/L)	5.2 (4.9, 5.7)	5.3 (4.9, 5.7)	0.854
CHOL/(mmol/L)	4.8±1.0	4.9±1.1	0.898
TG/(mmol/L)	1.6 (1.3, 2.3)	1.9 (1.2, 2.8)	0.928
LDL/(mmol/L)	3 (2.6, 3.6)	3.3 (2.4, 3.8)	0.604
HDL/(mmol/L)	1.2±0.3	1.2±0.3	0.341
Cr/(μmol/L)	83 (74, 96)	81 (71, 94)	0.995
HCY/(μmol/L)	17.1 (13.2, 22.4)	17.1 (13.3, 24.8)	0.456
WBC/(×10⁹/L)	8.1 (5.9, 10.4)	8.3 (7.0, 10.4)	0.496
pH	5.9 (5.5, 6.5)	5.5 (5.5, 6.0)	0.850

Data were ${\bar x}$±s or M(P₂₅, P₇₅). UA, uric acid; GLU, glucose; CHOL, cholesterol; TG, triglyceride; LDL, low-density lipoprotein; HDL, high-density lipoprotein; Cr, creatinine; HCY, homocysteine; WBC, white blood counts.

两组合并症比较：两组的高血压和肾结石的合并发症组间差异有统计学意义(P＜0.05)，两组的糖尿病和心血管疾病组间差异无统计学意义(P>0.05，表 4)。

表4 两组患者合并症比较

Table 4 Comparison of comorbidities between the two groups

Items	Non-radiographic bone erosion (n=41)	No bone erosion detected (n=82)	P
Hypertension	21 (51.2)	45 (54.9)	0.003
Diabetes mellitus	3 (7.3)	11 (13.4)	0.382
Cardiovascular disease	1 (2.4)	2 (2.4)	0.999
Renal calculi	5 (12.2)	12 (14.6)	0.001

Data were n (%).

多因素分析发现，每年痛风发作≥3次是痛风放射学阴性骨侵蚀的独立危险因素[OR (95%CI)为5.139(1.529~17.271)，表 5]。

表5 痛风患者放射学阴性骨侵蚀的相关多因素分析

Table 5 Multivariate analysis of factors associated with non-radiographic bone erosion in gout patients

Variable	B	SE	Wald	df	P	OR (95%CI)
Disease duration	0.085	0.054	2.448	1	0.118	1.088 (0.979-1.210)
Somking	0.113	0.472	0.057	1	0.811	1.119 (0.444-2.825)
Family history	0.406	0.597	0.462	1	0.497	1.501 (0.466-4.835)
Involved joint count	0.042	0.101	0.173	1	0.677	1.043 (0.855-1.272)
Flare counts per year≥3	1.637	0.618	7.006	1	0.008	5.139 (1.529-17.271)
Foot joint involvement	0.403	0.692	0.340	1	0.560	1.497 (0.386-5.807)
Ankle involvement	-0.867	0.603	2.066	1	0.151	0.420 (0.129-1.371)
Knee involvement	-0.334	0.557	0.360	1	0.549	0.716 (0.240-2.133)
Hypertension	-0.211	0.481	0.191	1	0.662	0.810 (0.315-2.081)
Renal calculi	-0.670	0.712	0.885	1	0.347	0.512 (0.127-2.066)

3 讨论

关节是痛风患者尿酸盐形成和沉积的主要部位，单晶尿酸盐在关节部位的沉积可以导致多种病变，如双轨征、聚集体、痛风石和骨侵蚀等^[8]。骨侵蚀是痛风的常见关节病变之一，痛风骨侵蚀的发病机制不但涉及到破骨与成骨的失衡，还涉及到固有免疫和适应性免疫。研究显示，单晶尿酸钠不但对成骨细胞和骨基质细胞有溶解作用，还可以改变核因子κB配体激活剂与骨保护素的比例，从而促进破骨细胞活化，而且IL-1和TNF-α等细胞因子参与了骨侵蚀的发生^{[4, 9-10]}。骨侵蚀的出现预示着痛风的恶化，持续进展的骨侵蚀会造成关节残毁，有学者报道约44%的痛风患者出现骨侵蚀^[2]。依据X线探及的放射学阳性骨侵蚀通常已经出现显著的骨质破坏，由超声或MRI探及的放射学阴性的骨侵蚀通常早于放射学阳性的骨侵蚀出现^[11-12]。因此，了解痛风患者放射学阴性骨侵蚀的相关因素，有利于病变的及时发现、痛风疾病阶段的划分和治疗方案的优化。肌骨超声在探查放射学阴性骨侵蚀方面具有独到优势，肌骨超声检测方法较为方便、价格较低且无创，检测骨侵蚀的效能也与MRI相当^[13]。本研究重点分析了超声探及的放射学阴性骨侵蚀的相关因素。一项采用双能CT判断痛风骨侵蚀的研究发现，病程(OR=1.11, 95%CI: 1.00~1.24)与骨侵蚀独立相关^[3]。本研究结果同样显示放射学阴性骨侵蚀痛风患者的病程更长，与上述报道相符，提示骨侵蚀是痛风的自然病程进展导致的后果之一。虽然有研究指出，有效的降尿酸可以修复痛风石患者糜烂的骨质^[14-15]，但血液中尿酸水平与骨侵蚀独立相关性如何有不同的报道。Liu等^[3]发现血尿酸水平与骨侵蚀独立相关(OR=1.01, 95%CI: 1.00~1.02)，而Wu等^[2]认为血尿酸不是骨侵蚀的独立危险因素。本研究结果显示血尿酸水平与痛风骨侵蚀的无独立相关性。尿酸在痛风恶化过程中扮演的角色复杂，如痛风急性关节炎发作时血尿酸水平反而较间歇期降低，尿酸盐沉积、软组织炎症和骨侵蚀之间的复杂联系目前并不明确，具体体现到血液中尿酸水平与骨侵蚀的关系也是一个复杂的问题，尚待进一步深入研究以明确两者之间的关系。

本研究发现，每年痛风发作≥3次是痛风患者放射学阴性骨侵蚀的独立危险因素，痛风发作越频发越容易出现骨侵蚀，这符合痛风的自然病程。有研究指出上肢关节的受累与痛风石的出现独立相关(OR=2.084, 95%CI: 1.663~2.613)，而痛风石标志着痛风进入慢性期，也是痛风恶化的标志之一^[16]。本研究结果提示放射学阴性骨侵蚀的痛风患者手关节受累有升高趋势，可能因为样本量的限制未得到有统计学意义的结果。结合相关文献^[16]，出现手关节受累的痛风患者仍需注意骨侵蚀的出现。另外，有学者发现痛风石与骨侵蚀的发生有显著联系，组织学研究显示，在痛风石骨界面处，成骨细胞减少，破骨细胞样细胞增多^[9-17]。本研究结果也显示放射学阴性骨侵蚀的痛风患者痛风石发生率为17.1%，未探及骨侵蚀的痛风患者痛风石发生率为8.5%，虽然，本研究结果显示出了放射学阴性骨侵蚀患者痛风石发生率更高，但差异无统计学意义，这可能与本研究纳入病例数仍偏少有关。

在一定程度上，本研究结果为痛风放射学阴性骨侵蚀的研究提供了参考和方向，但仍存在一定局限性，如双能CT与核磁共振在发现骨侵蚀上也有独到优势，本研究未纳入这两种影像学数据，期待未来更多的系统性研究揭示痛风放射学阴性骨侵蚀的发病规律和发病机制，从而提高痛风的诊疗水平。

综上所述，采用病例对照研究的方法，本研究分析了痛风患者放射学阴性骨侵蚀的相关危险因素，发现独立相关因素为每年痛风发作次数≥3，提示每年痛风发作≥3次预示着放射学阴性骨侵蚀的出现，临床上需要更加关注这类痛风患者的达标治疗。

利益冲突 所有作者均声明不存在利益冲突。

作者贡献声明 刘伟：实验设计，统计分析，撰写文章；郭稳：超声结果判读；过哲：X线结果判读；李春艳：实验室指标收集；李云龙、刘思奇、张亮：病例收集；宋慧：实验设计，总体把关和审定论文。所有作者均参与论文修改。

References

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