血清阴性类风湿关节炎延迟诊断一例并文献复习
Delayed Diagnosis of Serum Negative Rheumatoid: A Case Report and Literature Review
DOI: 10.12677/ACM.2020.108242, PDF, HTML, XML, 下载: 557  浏览: 946 
作者: 薛晓霞, 刘 璐, 胡 松:青岛大学附属医院老年医学科,山东 青岛;冯媛媛, 宫 婷:中国人民解放军海军第九七一医院保健科,山东 青岛
关键词: 类风湿关节炎分类免疫学诊断Rheumatoid Arthritis Classification Immunology Diagnosis
摘要: 目的:探讨血清阴性类风湿关节炎(serum negative rheumatoid arthritis, SNRA)的临床特征及诊断,提高对SNRA的认识,从而早期诊断及治疗。方法:详细回顾分析一例延迟诊断的SNRA患者的病历资料,并复习国内外相关文献。结果:患者为中年女性,因糖尿病足坏疽入院,7年前开始出现大关节囊肿,先后累及双侧踝、肩、肘、膝关节,均考虑为关节退行性变,多次行关节置换术,心理及身体损伤较大。入院后完善全身多关节超声、CT、自身抗体等指标,考虑为SNRA,给予强的松、羟氯喹联合甲氨蝶呤经验性治疗,1周后患者肩、肘关节疼痛明显好转,确诊为SNRA。结论:SNRA缺乏特异性血清指标,诊断时应注意与其他引起关节肿胀、疼痛类疾病相鉴别,避免漏诊误诊,错过进行干预的机会之窗,治疗延迟,带给患者难以挽回的损失。
Abstract: Objective: To explore the clinical characteristics and diagnosis of serum negative rheumatoid arthritis (SNRA), and to improve the understanding of SNRA for early diagnosis and treatment. Methods: A case of delayed diagnosis of SNRA was analyzed in detail, and the related literature at home and abroad were reviewed. Results: The patient was a middle-aged female. She was admitted to the hospital because of diabetic foot gangrene. Seven years ago, large joint cyst began to appear, involving bilateral ankle, shoulder, elbow and knee joints successively. Joint degeneration was considered and joint replacement was performed many times. After admission, the indexes such as systemic multi-joint ultrasound, CT and autoantibody were improved. Considering SNRA, prednisone, hydroxychloroquine and methotrexate were given as empirical treatment. After one week, the pain of shoulder and elbow joint was significantly improved, and SNRA was diagnosed. Conclusion: SNRA is lack of specific serum index, so we should pay attention to distinguish it from other diseases that cause joint swelling and pain, avoid misdiagnosis, miss the window of opportunity for intervention, delay treatment, and bring irreparable loss to patients.
文章引用:薛晓霞, 刘璐, 胡松, 冯媛媛, 宫婷. 血清阴性类风湿关节炎延迟诊断一例并文献复习[J]. 临床医学进展, 2020, 10(8): 1617-1620. https://doi.org/10.12677/ACM.2020.108242

1. 引言

类风湿关节炎(rheumatoid arthritis, RA)是一种以慢性进行性关节炎为主要表现的致畸性自身免疫性疾病,我们将符合RA诊断标准,但血清中类风湿因子(RF)、抗角蛋白抗体(AKA)、抗核周因子(APF)、抗Sa抗体及抗CCP抗体(ACPA)均为阴性者定义为血清阴性类风湿关节炎(SNRA) [1]。CATCH研究表明,SNRA是RA中的一种亚型,约占RA病人中的20% [2] [3],但目前对于SNRA的认识仍不足,早期诊断仍存在一定困难。现将我院1例延迟诊断的SNRA且已获得知情同意的患者病例资料报告如下。

2. 病例资料

患者,女,64岁,因发现血糖升高10年,左踝部皮肤破溃1月入院。既往7年前开始出现大关节肿痛、诊断为骨关节炎、关节退行性病变,先后行双侧踝关节关节镜手术、双侧膝关节置换术;5年前开始出现右肩关节、肘关节疼痛肿胀,未予治疗。否认高血压病、心脑血管病病史,无传染病、外伤史,及药物过敏史。入院查体:T:36.5℃;P:89次/分;R:18次/分;BP:153/78 mmHg,患者神清、精神可,双肺呼吸音粗,未闻及干湿性啰音;心脏、腹部查体未见异常;右上肢肿胀,肩关节及肘关节轻压痛,双膝、踝关节外侧中央可见陈旧性瘢痕,右踝关节肿胀,左踝内侧皮肤破溃,范围约2 × 2 cm。完善检查:白细胞计数7.04 × 109/L,中性粒细胞计数4.10 × 109/L (参考值:3.5~9.5 × 109/L),C反应蛋白(CRP) 8.26 mg/L (参考值:0~5 mg/L)。踝关节超声:左踝关节滑膜增厚、左踝关节周围软组织增厚、回声改变,考虑炎性可能,左趾长伸肌肌腱腱鞘滑膜增厚、积液,考虑腱鞘炎。诊断为糖尿病足坏疽,在治疗糖尿病足坏疽过程中,患者反复诉肩肘部疼痛,6天后复查白细胞计数7.64 × 109/L,中性粒细胞计数 4.68 × 109/L,CRP 13.64 mg/L,血沉(ESR) 40.0 mm/1h,降钙素原0.04 ng/mL。患者左足感染控制良好,但CRP、ESR及降钙素原仍高于正常,结合患者既往大关节肿痛、手术病史,进一步完善ANCA、ENA、HLA-B27、RF、抗CCP抗体等无异常,右踝关节DR正侧位:右踝关节退行性变,右踝关节骨质改变;踝关节CT:左足部分趾间关节间隙较窄,边缘可见骨质增生。肩、肘关节CT:关节退行性变,并退变囊肿形成。肘关节、腕关节超声检查:右肘、腕关节滑膜增厚、骨质破坏、骨赘形成、关节腔积液,考虑类风湿关节炎可能。行病例讨论,排除血清阳性RA、强直性脊柱炎、银屑病性关节炎等疾病,考虑为SNRA,给予患者甲强龙40 mg,3天后改为强的松联合羟氯喹、甲氨蝶呤经验性抗风湿治疗,后患者肩、肘部疼痛减轻,水肿消失,复查CRP、ESR恢复正常,明确诊断为SNRA。出院后随访1个月余,患者病情持续稳定,未再出现关节肿痛症状。

3. 讨论

类风湿关节炎(RA)是最常见的风湿病之一,以关节滑膜炎为基本病理特征,致残率高,因此早期准确诊断非常重要,SNRA由于缺乏特异性血清学抗体,早期诊断及治疗往往不能及时,不仅错过了治疗时间窗 [4],还给患者带来了巨大的身体及经济负担。自身抗体对RA的诊断及影响深远,RF (类风湿因子)阳性率约60%~80%,ACPA (抗CCP抗体)阳性率约70%左右,诊断特异性高达90%~95%,临床中主要通过这两种抗体均为阴性进行判断SNRA [5]。本例患者7年间反复关节肿痛,因血清学抗体均为阴性,均未考虑SNRA,从而多次行关节手术治疗,带给患者生理及心理极大损伤,因此早期识别SNRA至关重要。

关于SNRA临床表现,有文献报道,RA可引起关节骨质破坏、畸形,关节外表现包括网状青斑、感染、溃疡、抑郁、心血管疾病等 [6],而血清阳性RA与SNRA作为RA两种不同机制驱动的疾病亚型 [7],尚无统一的标准,这可能也是SNRA诊断困难的原因。有学者表明血清阳性RA患者疾病活动更重、骨关节破坏进展更严重 [8] [9],Geng等人研究则表明二者免疫学指标与内部免疫紊乱无明显差异 [7],在早期多关节肿胀、红细胞沉降率增快可能是RA的重要危险因素,值得关注 [10]。也有研究表明,SNRA患者X线骨侵蚀的发生率明显高于血清阳性RA,SNRA患者在关节早期影像学进展更快 [11],血液系统损害更重 [12] [13],但由于SNRA诊断往往不能及时,延迟诊断、甚至漏诊、误诊导致SNRA患者的骨关节破坏总是难以挽回。该例患者以大关节起病,关节外及血液系统表现未出现,早期均考虑为关节退行性病变,未考虑SNRA,给予患者手术治疗,不仅漏诊、误诊,也错过了最佳治疗时间窗,因此若能早期诊断SNRA,更多起病症状不典型患者或许可以避免这些损伤,更早获益。

关于SNRA的诊断,有文献表明,IL-10水平降低、IL-18水平升高对于SNRA患者具有一定的早期预测价值和鉴别诊断价值 [14]。其次双侧关节MR扫描发现关节间隙内有血管翳组织增生,也可帮助诊断SNRA [15]。此外,患者关节液抗体检测也有助于诊断SNRA,阳性率高达36.7%,其中抗MCV抗体检出率为20.7%,ACPA检出率为34.5%,两者联合检测的敏感性为48.0%,特异性为82.8% [16]。因此当患者反复出现多关节肿痛患者血清免疫学无明显异常时,应考虑SNRA,并关注IL-10、IL-18水平,及时行关节MR扫描及关节液抗体检测来进一步诊断或者排除SNRA,以带给患者最大的受益。除此之外,有研究表明,遗传变异约占白种人人群RA风险的60% [17],SNRA患者的一级亲属RA患病率是人群患病率的两倍以上 [18],该患者一级亲属否认RA等免疫相关疾病。免疫方面,RA是T细胞介导的免疫失调性疾病 [19],与自身抗体状态无关,SNRA只是RA的一种特定环境、遗传的条件下推动的不同临床表型发展而来血清型之一 [20]。因此,未来是否可以通过基因检测来早期诊断SNRA,为早期诊断SNRA提供理论基础,值得进一步研究。

参考文献

[1] 耿研, 张卓莉. 血清学阴性与血清学阳性类风湿关节炎患者临床及免疫学特征的差异[J]. 中华临床免疫和变态反应杂志, 2011, 5(2): 143-147.
[2] 周惠浩. 血清类风温因子阴性的多关节炎[J]. 国外医学(内科学分册), 1982(7): 360.
[3] Sun, J., Zhang, Y., Liu, L., et al. (2014) Diagnostic Accuracy of Combined Tests of Anti Cyclic Citrullinated Peptide Antibody and Rheumatoid Factor for Rheumatoid Arthritis: A Meta-Analysis. Clinical and Experimental Rheumatology, 32, 11-21.
[4] Coffey, C.M., Crowson, C.S., Myasoedova, E., et al. (2019) Evidence of Diagnostic and Treatment Delay in Seronegative Rheumatoid Arthritis: Missing the Window of Opportunity. Mayo Clinic Proceedings, 94, 2241-2248.
https://doi.org/10.1016/j.mayocp.2019.05.023
[5] 张国栋, 林辉, 刘毅. 血清学阴性类风湿关节炎诊治进展[J]. 西部医学, 2015, 27(11): 1754-1758.
[6] Dale, J., Paterson, C., Tierney, A., et al. (2016) The Scottish Early Rheumatoid Arthritis (SERA) Study: An Inception Cohort and Biobank. BMC Musculoskeletal Disorders, 17, 461.
https://doi.org/10.1186/s12891-016-1318-y
[7] Geng, Y., Zhou, W. and Zhang, Z.L. (2012) A Comparative Study on the Diversity of Clinical Features between the Sero-Negative and Sero-Positive Rheumatoid Arthritis Patients. Rheumatology International, 32, 3897-3901.
https://doi.org/10.1007/s00296-011-2329-5
[8] Aletaha, D., Alasti, F. and Smolen, J.S. (2013) Rheumatoid Factor Determines Structural Progression of Rheumatoid Arthritis Dependent and Independent of Disease Activity. Annals of the Rheumatic Diseases, 72, 875-880.
https://doi.org/10.1136/annrheumdis-2012-201517
[9] Van Oosterhout, M., Bajema, I., Levarht, E.W., et al. (2008) Differences in Synovial Tissue Infiltrates between Anti-Cyclic Citrullinated Peptide-Positive Rheumatoid Arthritis and Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis. Arthritis & Rheumatology, 58, 53-60.
https://doi.org/10.1002/art.23148
[10] Barnabe, C., Xiong, J., Pope, J.E., et al. (2014) Factors Associated with Time to Diagnosis in Early Rheumatoid Arthritis. Rheumatology International, 34, 85-92.
https://doi.org/10.1007/s00296-013-2846-5
[11] 张明珠, 郭东更, 季晨, 等. 早期血清学阴性类风湿关节炎患者临床特点分析[J]. 宁夏医学杂志, 2019(8): 1-4.
[12] 罗静, 王妍华, 俱博苗, 等. 西部地区血清阴性类风湿关节炎临床特点及传统抗风湿药治疗1年的转归分析[J]. 西安交通大学学报(医学版), 2017, 38(1): 88-91.
[13] 张丽中, 王瑞雪, 周永年, 等. 血清学阴性类风湿关节炎的临床及实验室特点[J]. 中国药物与临床, 2018, 18(6): 935-936.
[14] 周厚清, 吴瑾滨, 董敏. 类风湿因子阴性类风湿关节炎患者血清抗瓜氨酸肽或蛋白抗体、IL-10及IL-18检测分析[J]. 国际检验医学杂志, 2011, 32(13): 1441-1442.
[15] 马强, 王峻, 马大庆, 等. 腕关节MRI对关节炎诊断的临床价值[J]. 中华放射学杂志, 2006(1): 92-96.
[16] 曲世晶, 叶华, 贾汝琳, 等. 血清学阴性类风湿关节炎关节液中抗环瓜氨酸肽抗体、抗突变型瓜氨酸波形蛋白抗体的测定及临床意义[J]. 北京大学学报(医学版), 2016, 48(6): 933-936.
[17] MacGregor, A.J., Snieder, H., Rigby, A.S., et al. (2000) Characterizing the Quantitative Genetic Contribution to Rheumatoid Arthritis Using Data from Twins. Arthritis & Rheumatology, 43, 30-37.
https://doi.org/10.1002/1529-0131(200001)43:1<30::AID-ANR5>3.0.CO;2-B
[18] Pratt, A.G. and Isaacs, J.D. (2014) Seronegative Rheumatoid Arthritis: Pathogenetic and Therapeutic Aspects. Best Practice & Research Clinical Rheumatology, 28, 651-659.
https://doi.org/10.1016/j.berh.2014.10.016
[19] Pratt, A.G., Swan, D.C., Richardson, S., et al. (2012) A CD4 T Cell Gene Signature for Early Rheumatoid Arthritis Implicates Interleukin 6-Mediated STAT3 Signalling, Particularly in Anti-Citrullinated Peptide Antibody-Negative Disease. Annals of the Rheumatic Diseases, 71, 1374-1381.
https://doi.org/10.1136/annrheumdis-2011-200968
[20] Tobon, G.J., Youinou, P. and Saraux, A. (2010) The Environment, Geo-Epidemiology, and Autoimmune Disease: Rheumatoid Arthritis. Journal of Autoimmunity, 35, 10-14.
https://doi.org/10.1016/j.jaut.2009.12.009