Abstract
目的
探索类风湿关节炎(rheumatoid arthritis, RA)临床分层及其特征，为RA的发病机制、临床诊治和转归评估提供依据。
方法
选择2018—2021年于北京大学人民医院就诊的RA患者，收集患者一般情况、关节受累部位及数量、关节外表现、合并症及实验室检查结果等信息，采用统计及生物信息分析的方法，以受累关节部位、有无系统受累或合并其他自身免疫性疾病等进行临床分层，并对各亚型患者的特征进行分析。
结果
共纳入411例RA患者，平均年龄(48.84±15.17)岁，其中女性346例(84.2%)。患者被分为小关节型(74，18.0%)、全关节型(154, 37.5%)、系统型(100, 24.3%)、重叠型(83，20.2%)4个亚型。小关节型者无中大关节受累，其中35.1%有系统表现，红细胞沉降率(erythrocyte sedimentation rate, ESR)及C反应蛋白(C-reaction protein, CRP)水平和血小板计数较其他亚型低，而IgA及IgG类风湿因子阳性率较高；全关节型者中大关节和小关节均可受累，关节外表现少见，晨僵发生率和抗核抗体(antinuclear antibodies, ANA)阳性率显著低于其他亚型，而ESR及CRP水平相对较高；系统型者以合并肺间质纤维化和口、眼干燥症状常见, 病情活动指数高；重叠型至少合并另一种风湿病或自身免疫性疾病，以桥本甲状腺炎和原发性干燥综合征最为常见，与其他亚型相比，女性多见，高免疫球蛋白血症、低补体血症和斑点型ANA为其特征。
结论
根据类风湿关节炎的临床特征，可初步将其分为小关节型、全关节型、系统型、重叠型4个亚型，各有其临床和实验室特征，有助于进一步认识RA和为患者进行个体化治疗提供依据。
Keywords: 类风湿关节炎, 临床分层, 聚类分析
Abstract
Objective
To explore the characteristics and clinical phenotypes of rheumatoid arthritis (RA) and provide the basis for further understanding, interventions and outcomes of this disease.
Methods
RA patients attended at Peking University People's Hospital from 2018 to 2021 were enrolled in the study. Data collection included demographic data, the sites and numbers of joints involved, extra-articular manifestations (EAM), comorbidities and laboratory variables. Statistical and bioinformatical analysis was performed to establish clinical subtypes by clustering analysis based on the type of joint involved, EAM involvement and other autoimmune diseases overlapped. The characteristics of each subtype were analyzed.
Results
A total of 411 patients with RA were enrolled. The mean age was (48.84±15.17) years, and 346 (84.2%) were females. The patients were classified into 4 subtypes: small joint subtype (74, 18.0%), total joint subtype (154, 37.5%), systemic subtype (100, 24.3%), and overlapping subtype (83, 20.2%). The small joint subtype had no medium or large joint involvement, and 35.1% had systemic involvement. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and platelet count (PLT) were lower than those in other subtypes, and the rates of positive rheumatoid factors (RF-IgA and RF-IgG) were significantly higher in the small joint subtype. The total joint subtype had both large and small joint involvement but no systemic involvement. The rate of morning stiffness and positive antinuclear antibodies (ANA) in this subtype were lower than those in other subtypes. In the systemic subtype, interstitial lung disease and secondary Sjögren syndrome were the most common systemic involvements, with prominent levels of disease activity score 28-joint count (DAS28-ESR and DAS28-CRP). The overlapping subtype was commonly combined with Hashimoto's thyroiditis or primary Sjögren syndrome. Female in the overlapping subtype was more common than in other subtypes. This subtype was characterized by hyperglobulinemia, hypocomplementemia and high rate of positive ANA, especially spotting type.
Conclusion
Based on the clinical features, RA patients could be classified into 4 subtypes: small joint subtype, total joint subtype, systemic subtype, and overlapping subtype. Each subtype had its own clinical characteristics. They help for further understanding and a more individualized treatment strategy of RA.
Keywords: Rheumatoid arthritis, Clinical phenotypes, Clustering analysis
类风湿关节炎(rheumatoid arthritis, RA)是一种以慢性致残性关节炎为主要表现的自身免疫性疾病，可出现侵蚀性关节炎，以及内脏和多系统损伤[1]，关节受累在不同患者中表现各异，部分患者可合并其他自身免疫性疾病。RA的发生与抗原诱导、遗传因素，以及T、B细胞等免疫异常有关，临床上，RA具有高患病率和高致畸率等特点[2-3]。RA在诊断、治疗和预后判断等方面需要强调规范化和个体化。因此，进行临床分层有利于对RA的发病机制、临床诊断、用药指导及转归评估。基于此，本研究进行了单中心横断面研究，旨在认识RA的临床特征，为病情判断和个体化治疗提供依据。
1. 资料与方法
1.1. 病例资料
本研究为单中心横断面研究，选择2018—2021年在北京大学人民医院就诊的RA患者500例，均符合2010年ACR/EULAR(American College of Rheumatology/European League Against Rheumatism)的RA分类标准[4]，排除了已经临床完全缓解(即不存在关节肿胀或压痛)的患者，筛选资料完善的RA患者共411例。收集患者一般资料(性别、年龄、病程、吸烟史、家族史等)和临床资料(肿胀、压痛关节部位和数量，晨僵时间，关节外表现，合并的其他自身免疫性疾病等)，记录患者实验室检查结果[包括红细胞沉降率(erythrocyte sedimentation rate, ESR)、C反应蛋白(C-reaction protein, CRP)、自身抗体、免疫球蛋白(immunoglobulin，Ig)、补体(complement，C)等]，并计算患者疾病活动性评分(disease activity score 28, DAS28)。本研究开始前已经北京大学人民医院伦理委员会审查批准(2020PHB188-01)。
研究参照2010年ACR/EULAR提出的RA分类标准[4]，小关节的定义包括颞颌关节、胸锁关节、腕关节、掌指关节(metacarpophalangeal joint, MCP)、近端指间关节(proximal interphalangeal joint, PIP)、远端指间关节(distal interphalangeal joint, DIP)、跗骨关节、跖趾关节(metatarsophalangeal joint, MTP)、趾间关节，中大关节包括肩关节、肘关节、髋关节、膝关节和踝关节。系统受累定义为存在与RA相关的关节外系统受累的表现，包括严格定义的肺间质纤维化[5]、皮肤血管炎、胸膜炎、心包炎、眼炎及周围神经炎等。
1.2. 生物信息分析
采用K-means算法进行聚类分析，聚类过程均应用Python软件。初始选择的变量为小关节受累、中大关节受累、系统受累、重叠其他自身免疫性疾病。由于K-means算法本身的初始质心是随机设定的，使得聚类算法有一定的随机性。因此，本研究中采用了半监督的方法，对重叠型RA人群进行了质心固定，以增加结果的稳定性。
1.3. 统计学分析
采用SPSS 24.0统计软件，所有分类变量采用n(%)表示，不同组之间率的比较采用卡方检验；正态分布连续变量采用均数±标准差表示，组间均数的比较采用t检验和方差分析；非正态分布连续变量用M(P25，P75)表示，组间中位数的比较采用秩和检验，采用Kruskal-Wallis单因素方差分析进行多重比较，P＜0.05认为差异有统计学意义。
2. 结果
2.1. RA患者一般情况和临床特征
共纳入411例RA患者，其中女性有346例，占84.2%，发病年龄为(48.84±15.17)岁，平均病程为(141.71±129.14)个月。有RA家族史者占10.9%，有吸烟史者占15.3%，就诊时晨僵时间大于1 h者占15.3%，中位DAS28-ESR为4.86(3.84, 6.05)，中位DAS28-CRP为4.17(3.12, 5.61)。小关节受累者占87.1%，中大关节受累者占76.6%，系统受累者占38.7%，合并其他自身免疫性疾病者占20.0%。
2.2. RA不同亚型及其特征分布
根据患者临床和小关节受累、中大关节受累、系统受累及与其他自身免疫性疾病重叠4个临床特征进行聚类分析，RA患者可分为小关节型(74，18.0%)、全关节型(154, 37.5%)、系统型(100, 24.3%)和重叠型(83，20.2%)4个亚型(图 1)。
图 1.
RA临床亚型分布图(n=411)
The distribution of RA subtypes (n=411)
通过对4个亚型临床特征进行分析(表 1和图 2)，小关节型者中35.1%的患者存在系统表现，DAS28-ESR评分为4.30(3.82，5.82)，DAS28-CRP评分为3.63(2.79，5.30)，明显低于其他亚型。最常见的关节肿痛部位为PIP(59.5%)，其次为MCP(56.8%)和腕关节(48.7%)，系统表现以肺间质病变最为常见，其次为口、眼干燥症。
表 1.
RA各亚型间临床特点比较
Comparison of clinical characteristics of various subtypes of RA
| Items | Small joint subtype (n=74) | Total joint subtype (n=154) | Systemic subtye (n=100) | Overlapping subtype (n=83) | F/χ2 | P value |
| RA, rheumatoid arthritis; TJC, tender joint counts; SJC, swollen joint counts; DAS28, disease activity score 28-joint count; ESR, erythrocyte sedimentation rate; CRP, C-reaction protein; AID, autoimmune disease. | ||||||
| Female, n (%) | 60 (81.1) | 125 (81.2) | 85 (85.0) | 76 (91.6) | 5.034 | 0.169 |
| Onset Age/years，x±s | 47.04±18.92 | 47.16±13.89 | 44.80±13.56 | 45.10±17.14 | 0.391 | 0.76 |
| Diseae duration /months, x±s | 140.43±103.01 | 142.03±109.38 | 209.80±143.11 | 116.35±111.78 | 1.757 | 0.155 |
| Family history, n (%) | 8 (10.8) | 19 (12.3) | 11 (11.0) | 7 (8.4) | 0.845 | 0.839 |
| History of smoking, n (%) | 12 (16.2) | 26 (16.9) | 15 (15.0) | 10 (12.0) | 1.028 | 0.794 |
| Morning stiffness time＞1 h，n (%) | 44 (61.1) | 70 (47.0) | 56 (57.1) | 45 (58.4) | 5.415 | 0.144 |
| TJC, M (P25, P75) | 3.00 (0.50，16.00) | 6.00 (2.00，14.00) | 14.00 (4.00，23.00) | 8.50 (2.00，18.75) | 27.983 | ＜0.001 |
| SJC, M (P25, P75) | 4.00 (1.50，12.00) | 4.50 (1.75，13.25) | 6.00 (2.00，16.00) | 4.00 (2.00，12.00) | 4.731 | 0.193 |
| DAS28-ESR， M (P25, P75) | 4.30 (3.82，5.82) | 4.95 (4.02，5.92) | 5.41 (4.51，6.95) | 5.07 (3.86，5.99) | 23.880 | ＜0.001 |
| DAS28-CRP， M (P25, P75) | 3.63 (2.79，5.30) | 4.30 (3.32，5.44) | 4.80 (3.67，6.14) | 4.12 (2.99，5.66) | 26.062 | ＜0.001 |
| Small joint involvement, n (%) | 74 (100.0) | 125 (81.2) | 92 (92.0) | 67 (80.7) | 20.929 | ＜0.001 |
| Medium/large joint involvement, n (%) | 0 (0.0) | 154 (100.0) | 100 (100.0) | 61 (73.5) | 320.682 | ＜0.001 |
| Systemic involvement, n (%) | 26 (35.1) | 0 (0.0) | 100 (100.0) | 33 (39.8) | 256.091 | ＜0.001 |
| Other AID overlapped, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 83 (100.0) | 411.000 | ＜0.001 |
图 2.
亚型临床特征分布
The clinical features distribution of subtypes
The small joint subtype had no medium or large joint involvement. The total joint subtype had both medium/large and small joint involvement but no systemic involvement. In the systemic subtype, interstitial lung disease and secondary Sjögren syndrome were the most common systemic involvements. The overlapping subtype was commonly combined with Hashimoto's thyroiditis or primary Sjögren syndrome. PIP, proximal interphalangeal; MCP, metacarpophalangeal; MTP, metatarsophalangeal joint; DIP, distal interphalangeal joint; ACJ, articulatio temporomandibularis joint; SCJ, sternoclavicular joint; ILD, interstitial lung disease; sSS, secondary Sjögren syndrome; pSS, primary Sjogren syndrome; SLE, systemic lupus erythematosus; AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SSc, systemic sclerosis; PsA, psoriatic arthritis; AS, ankylosing spondylitis; NS, nephrotic syndrome; IM, inflammatory myopathy; AIHA, autoimmune hemolytic anemia; ITP, idiopathic thrombocytopenic purpura; APS, antiphospholipid syndrome.
全关节型者中大和小关节均有受累，其中小关节、中大关节同时受累占81.2%，18.8%的患者仅有中大关节受累。可伴发热、类风湿结节、肺类风湿结节、肺间质改变、干眼症及雷诺现象等。DAS28-ESR评分为4.95(4.02，5.92)，DAS28-CRP评分为4.30(3.32，5.44)，与其他3个亚型患者相比，晨僵发生率低(47.0%，P=0.144)。最常见的关节肿痛部位为膝关节(66.9%)，其次为腕关节(56.5%)和PIP(55.2%)。患者的年龄在各组间差异无统计学意义。
系统型者以系统表现更常见，小关节和中大关节均可出现，病程比其他亚型相对更长[(209.80±143.11)个月，P=0.155]。系统表现以肺间质纤维化(61.0%)最为常见，其次为继发干燥症状(30.0%)。小关节PIP、MCP、腕关节受累均常见，中大关节病变以膝关节为主(71.0%)。DAS28-ESR评分为5.41(4.51，6.95)，DAS28-CRP评分为4.80(3.67，6.14)，明显高于其他亚型(P＜0.001)。
在重叠型中，所有患者均合并有至少一种其他自身免疫性疾病，小关节、中大关节受累和系统表现均可出现。女性患者比其他亚型多(91.6%，P=0.169)。重叠的其他免疫病以桥本甲状腺炎(37.4%)最为常见，其次为原发干燥综合征(24.1%)。常见小关节受累(80.7%)和膝关节受累(55.4%)，系统表现多为肺间质病变。
患者家族史及吸烟史在4个亚型间差异无统计学意义。
2.3. 实验室检查结果的组间比较
对不同亚型RA患者进行实验室指标分析显示(表 2)，4个亚型在ESR水平、CRP水平及PLT计数上差异有统计学意义。小关节型者ESR、CRP和PLT计数明显低于其他亚型(P＜0.001)，而在全关节型和系统型患者中ESR、CRP和血小板(platelet, PLT)均更高。重叠型ESR和CRP的变化不及系统型和全关节型显著，与小关节型的差异类似。
表 2.
RA各亚型间实验室指标比较
Comparison of laboratory parameters of the four subtypes
| Items | Small joint subtype (n=74) | Total joint subtype (n=154) | Systemic subtye (n=100) | Overlapping subtype (n=83) | χ 2 | P value |
| The variables are denoted by M (P25, P75).ESR, erythrocyte sedimentation rate; CRP, C-reaction protein; WBC, white blood cell; NEU, neutrophil; LYM, lymphocyte; HGB, hemoglobin; PLT, platelet. | ||||||
| ESR/(mm/h) | 37.00 (21.50，55.00) | 42.00 (25.00，74.00) | 60.00 (21.00，88.00) | 41.00 (25.00，66.75) | 21.580 | ＜0.001 |
| CRP/(mg/L) | 10.56 (2.57，30.96) | 19.60 (6.30，58.59) | 21.70 (5.38，53.97) | 12.94 (3.06，37.39) | 25.918 | ＜0.001 |
| WBC/(×109/L) | 5.70 (4.25，7.30) | 6.15 (4.58，8.15) | 5.90 (4.20，7.20) | 5.65 (4.43，6.75) | 4.362 | 0.225 |
| NEU/(×109/L) | 3.60 (2.45，4.60) | 4.15 (2.68，5.40) | 3.80 (2.50，5.20) | 3.35 (2.70，4.78) | 4.652 | 0.199 |
| LYM/(×109/L) | 1.30 (0.80，1.70) | 1.40 (1.00，1.83) | 1.30 (1.00，1.60) | 1.30 (1.00，1.70) | 2.604 | 0.457 |
| HGB/(g/L) | 119.00 (105.50，125.50) | 113.50 (102.50，123.25) | 112.00 (98.00，121.00) | 111.50 (98.00，121.75) | 3.695 | 0.296 |
| PLT/(×109/L) | 207.00 (179.00，276.00) | 259.00 (211.00，315.50) | 249.00 (185.00，295.00) | 223.50 (197.75，266.00) | 25.723 | ＜0.001 |
2.4. RA各亚型免疫学指标的组间比较
对分亚型后的RA患者进行免疫学指标分析显示，4个亚型在IgG、补体3、IgA/IgG型类风湿因子(rheumatoid factors, RF)及抗核抗体(antinuclear antibodies, ANA)阳性率差异有统计学意义。小关节型IgA型RF阳性率41.7%(P=0.037)、IgG型RF阳性率45.1%(P=0.027)，显著高于其他3个亚型。全关节型的ANA阳性率(21.2%)显著低于其他3个亚型(P=0.003)。重叠型者的IgG升高率(25.3%，P=0.035)、C3降低率(25.3%，P=0.018)和ANA阳性率(44.6%，P=0.003)均显著高于其他3个亚型，以斑点型ANA为主(41.0%，P=0.016，表 3)。
表 3.
RA各亚型间免疫学指标比较
Comparison of immunologic parameters of the four subtypes
| Items | Small joint subtype (n=74) | Total joint subtype (n=154) | Systemic subtype (n=100) | Overlapping subtype (n=83) | χ 2 | P value |
| The variables are denoted by n(%).γG, γ globulin; TP, total protein; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; C3, complement 3; RF, rheumatoid factors; CCP, cyclic citrullinated polypeptide; APF, antiperinuclear factor; MCV, mutant citrullinated vimentin antibody; GPI, glucose 6-phosphate isomerase antibody; ANA, antinuclear antibodies. | ||||||
| γG/TP elevation/%, M (P25, P75) | 17.40 (14.90，20.80) | 20.50 (16.45，23.13) | 19.90 (17.10，23.20) | 22.25 (17.85，25.38) | 12.892 | 0.005 |
| IgA elevation | 8 (11.1) | 25 (16.9) | 21 (22.1) | 13 (15.7) | 3.651 | 0.302 |
| IgG elevation | 6 (8.3) | 35 (23.6) | 20 (21.1) | 21 (25.3) | 8.597 | 0.035 |
| IgM elevation | 1 (1.4) | 4 (2.7) | 4 (4.2) | 6 (7.2) | 4.379 | 0.223 |
| C3 reduction | 17 (23.6) | 16 (10.9) | 15 (15.8) | 21 (25.3) | 10.060 | 0.018 |
| RF-IgM | 62 (83.8) | 108 (70.6) | 74 (75.5) | 64 (77.1) | 4.855 | 0.183 |
| RF-IgA | 15 (41.7) | 17 (22.4) | 9 (16.1) | 9 (20.9) | 8.486 | 0.037 |
| RF-IgG | 32 (45.1) | 36 (24.8) | 33 (33.3) | 28 (34.6) | 9.182 | 0.027 |
| anti-CCP | 66 (90.4) | 125 (82.8) | 87 (87.9) | 72 (87.8) | 3.008 | 0.39 |
| APF | 50 (70.4) | 89 (61.4) | 69 (69.7) | 50 (61.7) | 3.097 | 0.377 |
| anti-MCV | 28 (75.7) | 47 (64.4) | 33 (78.6) | 27 (67.5) | 3.263 | 0.353 |
| GPI | 25 (35.2) | 56 (38.6) | 46 (46.5) | 29 (35.8) | 3.067 | 0.381 |
| ANA | 24 (33.8) | 31 (21.2) | 34 (34.7) | 37 (44.6) | 14.306 | 0.003 |
| Homogeneous type ANA | 23 (32.4) | 57 (39.0) | 36 (36.7) | 26 (31.3) | 1.786 | 0.618 |
| Spotting type ANA | 20 (28.2) | 31 (21.2) | 26 (26.5) | 34 (41.0) | 10.364 | 0.016 |
3. 讨论
本研究对类风湿关节炎患者进行了临床分层，并通过半监督聚类分析的方法, 根据关节受累类型及是否合并系统受累或其他自身免疫性疾病，将RA患者分成小关节型、全关节型、系统型和重叠型4个亚型，这4个亚型在DAS28-ESR/CRP、炎性指标ESR/CRP水平、血小板计数、免疫球蛋白IgG、补体C3、IgA/IgG型RF阳性率及ANA阳性率等方面差异均有统计学意义。
小关节型为最经典的RA类型，表现为以PIP、MCP为主的小关节的肿痛，部分合并肺间质病变为主的关节外表现，ESR及CRP较其他3个亚组稍低，可能是治疗效果相对好的类型。
全关节型是较为不典型的RA，累及中大关节，以膝关节最为常见，大部分患者有小关节受累，系统表现少见，晨僵不明显，ESR及CRP水平及PLT计数较高，患者的起病年龄与其他亚组相当。既往研究显示，中大关节的受累多指示早期小关节骨破坏及活动受限[6-7]，表明中大关节受累在RA病情评估中的重要性。本研究发现小关节型与全关节型之间存在显著的晨僵程度、炎性程度和抗体阳性率的差异，提示临床上应重视不同关节受累患者的临床异质性。
系统型的临床表现范围较为广泛，不仅有全关节受累，且存在系统受累的表现，最常见为肺间质纤维化，其次为继发干燥表现，炎性程度最高，由于全身症状和较高的ANA抗体阳性率，使其容易被误诊为其他系统性风湿病[1]，因此临床上需要作出仔细的甄别。本研究发现系统型RA在疾病活动度和炎性因子水平上与全关节型RA相当，但系统型因病变范围更广，在治疗上不应以仅仅控制关节肿痛和炎性因子为目标，更应关注其全身表现，并采取个体化的治疗措施。
重叠型以高免疫球蛋白血症、低补体血症和较高的斑点型ANA阳性率为主要表现，女性更多见。虽然在炎性指标上，ESR、DAS28-ESR较小关节型更高，但CRP水平和DAS28-CRP水平较小关节型差异无统计学意义，可能原因为ESR升高与高球蛋白血症相关，而CRP水平和DAS28-CRP在该型中可能更能反映真实的炎性状态。既往研究提示，合并多种自身免疫性疾病的患者与单纯免疫病患者不同[8]，合并其他免疫性疾病的RA患者以女性更多见，与本研究结果相似。因此，单纯RA与重叠RA之间可能存在机制上的差异。
本研究RA亚型的分型结果符合临床上对RA异质性特点的认知，目前有越来越多的研究应用聚类分析方法来探索自身免疫性疾病的临床异质性[9-10]，针对于RA分型的既往研究发现，所关注的侧重点不同(如关节畸形、疼痛程度等)，得到的分型结果不同[11-14]。也有研究将所有关联指标均设置为分型变量[15]，但得到的分型结果明显受变量的数量、性质和质量影响。本研究利用临床相关指标作为分型依据，再结合聚类分析，判断更为准确，可能具有更好的临床应用价值。
本研究不足之处在于单中心研究分型所应用的数据样本量较小，且均为住院患者，病情整体偏重，疾病活动度更高，而全关节型中部分患者合并继发性骨关节炎，难以完全除外，对患者的临床表现特征可能有影响。因此，本研究的结果可能存在一定选择偏倚。
利用上述临床分层，本课题组将进一步分析患者的细胞亚群和细胞因子的差异，以及治疗方案差异等，探索不同亚型的机制以及影响预后的因素，为RA患者的个体化诊疗提供依据。
综上所述，根据类风湿关节炎的临床特征，可初步将其分为小关节型、全关节型、系统型和重叠型4个亚型，各有其临床和实验室特征，这些结果有助于进一步认识RA和对患者进行临床分层和更准确的个体化治疗。
Funding Statement
国家自然科学基金(32141004)
Supported by the National Natural Science Foundation of China (32141004)
Contributor Information
邓 立宗 (Li-zong DENG), Email: denglz@ism.pumc.edu.cn.
李 茹 (Ru LI), Email: doctorliru123@163.com.
栗 占国 (Zhan-guo LI), Email: zgli99@aliyun.com.
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