-
干燥综合征(Sjögren′s syndrome,SS)是一种多系统受累的慢性炎症性自身免疫性疾病,其特点是外分泌腺的淋巴细胞浸润,最常见的表现是口眼干燥。此外,SS的腺体外损伤也普遍存在,其中血液系统是其受累的系统之一,而血小板减少是较为严重的表现[1-2]。对于原发性干燥综合征(pSS)继发免疫性血小板减少症(ITP)的临床研究,国内外文献多见小样本单中心研究以及病例报道[3-4]。本研究旨在了解pSS继发ITP的发生率、临床及免疫学特征,以提高临床医生对该病的认识。
-
498例pSS病人中继发ITP病人89例(17.87%)。2组病人年龄和病程比较差异均无统计学意义(P>0.05),对照组女性构成比(96.5%) 较观察组(86.5%)高(P < 0.01)。观察组血红蛋白含量、凝血酶原活动度(PT比)和纤维蛋白原(Cfib)水平低于对照组,天冬氨酸氨基转移酶(AST)异常升高病人比例高于对照组,差异均有统计学意义(P < 0.05~P < 0.01)。而在白细胞计数、血肌酐及尿素氮、低蛋白血症、凝血酶原时间(PT)、D-二聚体等指标2组差异均无统计学意义(P>0.05)(见表 1)。
分组 n 女 年龄/岁 病程[P50(P25, P75)]/月 白细胞计数/ (×109/L) 血红蛋白含量/(g/L) 丙氨酸氨基转移酶(ALT)增高(>60 U/L) AST增高(>45 U/L) 低蛋白血症 对照组 399 385 52.76±14.20 24.0(6.0, 60.0) 6.16±3.37 117.35±17.29 34 46 65 观察组 89 77 50.47±13.48 21.6(3.9, 60.0) 6.47±4.80 106.73±23.89 7 20 21 t — 12.44* 1.39 9.97△ 1.04 3.97# 0.04* 7.45* 2.68* P — < 0.01 >0.05 >0.05 >0.05 < 0.01 >0.05 < 0.01 >0.05 分组 n 肌酐[P50(P25, P75)]/ (μmol/L) 尿素氮[P50(P25, P75)]/ (mmol/L) PT/s PT比 活化部分凝血酶原时间/s Cfib[P50(P25, P75)]/ (g/L) D-二聚体[P50(P25, P75)]/(mg/L) 对照组 399 57.0(50.0, 66.0) 4.31(3.60, 5.40) 11.59±1.65 105.03±21.41 28.32±6.34 3.00(2.43, 3.90) 0.37(0.22, 0.89) 观察组 89 57.0(48.0, 68.5) 5.20(4.13, 6.51) 12.07±2.20 97.78±26.99 30.21±10.59 2.70(2.26, 3.30) 0.39(0.23, 0.91) t — 0.39△ 4.37△ 1.94 2.37# 1.62# 2.85△ 0.23△ P — >0.05 >0.05 >0.05 < 0.05 >0.05 < 0.01 >0.05 *示χ2值;△示zc值;#示t′值 表 1 2组病人临床危险因素单因素分析(x±s)
-
观察组病人关节累及程度和间质性肺病严重程度低于对照组,ESSDAI评分显著高于对照组,差异均有统计学意义(P < 0.05~P < 0.01);而全身症状、淋巴结累及、腺体累及以及肾脏受累情况2组差异均无统计学意义(P>0.05)(见表 2)。
分组 n 全身症状 淋巴结累及 腺体累及 关节累及 间质性肺病 肾脏受累 ESSDAI评分(x±s)/分 无 轻度 中度 无 有 无 轻度 中重度 无 轻度 中重度 无 有 无 轻度 中重度 对照组 399 380 17 1 394 2 387 11 1 336 61 2 333 76 391 5 3 3.59±3.324 观察组 89 88 1 0 88 0 87 1 1 84 4 1 85 4 86 3 0 6.92±1.860 zc — 1.50 0.45* 0.37 2.47 2.93 0.77 12.92△ P — >0.05 >0.05 >0.05 < 0.05 < 0.01 >0.05 < 0.01 注: 所有病人系统累及的评判标准,均参照2010年ESSDAI[7]按轻中重度分类。*示χ2值;△示t′值 表 2 2组病人系统累及情况比较(n)
-
2组在ESR、CRP、免疫球蛋白、抗SSA抗体、抗SSB抗体及抗着丝点抗体指标方面差异均无统计学意义(P>0.05);但观察组补体C3和C4水平低于对照组,差异均有统计学意义(P < 0.01)(见表 3)。
分组 n CRP[P50(P25, P75)]/(mg/L) ESR[P50(P25, P75)]/(mm/h) 补体C3
[P50(P25, P75)]/(g/L)补体C4
[P50(P25, P75)]/(g/L)IgA升高(>2.80 g/L) IgM升高(>3.00 g/L) 无 有 无 有 对照组 399 5.00(1.05, 18.60) 26.0(14.0, 43.0) 0.768(0.678, 0.981) 0.191(0.138, 0.221) 243 156 373 26 观察组 89 4.90(1.50, 15.20) 20.0(12.0, 40.0) 0.504(0.435, 0.599) 0.146(0.105, 0.175) 55 34 82 7 χ2 — 0.22* 1.09* 10.80* 4.96* 0.03 0.21 P — >0.05 >0.05 < 0.01 < 0.01 >0.05 >0.05 分组 n IgG计数/(g/L) 抗SSA抗体/R060 抗SSA抗体/Ro52 抗SSB抗体 抗着丝点B抗体 < 15 15~20 >20 - + - + - + - + 对照组 399 237 77 69 122 269 271 120 271 120 359 32 观察组 89 42 23 23 20 67 59 28 59 28 78 9 χ2 — 5.88 2.30 0.11 0.07 2.68 P — >0.05 >0.05 >0.05 >0.05 >0.05 *示zc值 表 3 2组病人免疫学指标比较
-
为了预测pSS继发ITP疾病发生发展的临床危险因素,我们按照前述方法进行了多因素logistic回归分析。其中对AST升高、关节受累和间质性肺病进行赋值。无AST升高赋值为“0”,有AST升高赋值为“1”;无关节受累赋值为“0”,轻度受累赋值为“1”,中重度受累赋值为“2”;无间质性肺病赋值为“0”,有间质性肺病赋值为“1”。其余危险因素均以变量的具体数值纳入回归分析。结果显示: 关节受累、间质性肺病、ESSDAI评分、补体C3为pSS继发ITP病例的独立危险因素(见表 4)。
变量 B SE Waldχ2 OR(95%CI) P 截距 1.397 0.765 3.34 4.044 >0.05 ESSDAI 0.460 0.064 52.00 1.583(1.397~1.794) < 0.01 关节受累 < 0.05 无 1.00 轻度 -1.484 0.609 5.93 0.227(0.069~0.748) < 0.05 中重度 -0.503 1.921 0.07 0.605(0.014~26.905) >0.05 间质性肺病 < 0.01 无 1.00 有 -4.638 0.893 27.01 0.010(0.002~0.056) C3 -7.214 1.136 40.29 0.001(0.000~0.007) < 0.01 表 4 pSS继发ITP相关危险因素分析
原发性干燥综合征继发免疫性血小板减少症的临床特点及危险因素分析
Analysis of clinical characteristics and risk factors in primary Sjögren's syndrome with secondary immune thrombocytopenia
-
摘要:
目的了解原发性干燥综合征(pSS)相关继发免疫性血小板减少症(ITP)的发生率和临床特点。 方法回顾性收集498例pSS病人的临床资料及实验室检查结果,比较pSS继发ITP病人(观察组)和血小板计数正常病人(对照组)间临床表现、实验室检查及免疫学指标特征。 结果498例pSS病人中,有17.86%(89/498)病人继发ITP。与对照组比较,观察组病人表现出更高的疾病活动度、更低的补体C3水平(P < 0.01)。此外,pSS继发ITP病人较少发生关节炎(15.8% vs 5.6%,P < 0.05)及间质性肺病(16.5% vs 4.5%,P < 0.05)。 结论继发性ITP是pSS病人常见并发症。其主要临床特点有更低的补体C3水平及更高的疾病活动度评分,而间质性肺病和关节炎的发生是继发ITP的独立保护因素。 Abstract:ObjectiveTo evaluate the incidence and clinical characteristics in primary Sjögren's syndrome(pSS) with secondary immune thrombocytopenia (ITP). MethodsFour hundred and ninety-eight pSS patients were retrospectively analyzed.Clinical manifestations, laboratory results and immunological index characteristics were compared between pSS patients with or without ITP. ResultsAmong the 498 pSS patients, 17.86%(89/498) had the secondary ITP, and the ITP group showed the higher disease activity and lower C3 levels(P < 0.01) compared with the control group (P < 0.01).In addition, pSS patients with secondary ITP had less arthritis(15.8% vs 5.6%, P < 0.05) and interstitial lung disease(16.5% vs 4.5%, P < 0.05). ConclusionsSecondary ITP is a common complication in patients with pSS.The main clinical characteristics include the decreased complement C3 levels and higher disease activity score.However, the development of interstitial lung diseases and arthritis were independent protective factors for secondary ITP in pSS patients. -
Key words:
- primary Sjögren's syndrome /
- immune thrombocytopenia /
- platelet /
- interstitial lung diseases /
- arthritis
-
表 1 2组病人临床危险因素单因素分析(x±s)
分组 n 女 年龄/岁 病程[P50(P25, P75)]/月 白细胞计数/ (×109/L) 血红蛋白含量/(g/L) 丙氨酸氨基转移酶(ALT)增高(>60 U/L) AST增高(>45 U/L) 低蛋白血症 对照组 399 385 52.76±14.20 24.0(6.0, 60.0) 6.16±3.37 117.35±17.29 34 46 65 观察组 89 77 50.47±13.48 21.6(3.9, 60.0) 6.47±4.80 106.73±23.89 7 20 21 t — 12.44* 1.39 9.97△ 1.04 3.97# 0.04* 7.45* 2.68* P — < 0.01 >0.05 >0.05 >0.05 < 0.01 >0.05 < 0.01 >0.05 分组 n 肌酐[P50(P25, P75)]/ (μmol/L) 尿素氮[P50(P25, P75)]/ (mmol/L) PT/s PT比 活化部分凝血酶原时间/s Cfib[P50(P25, P75)]/ (g/L) D-二聚体[P50(P25, P75)]/(mg/L) 对照组 399 57.0(50.0, 66.0) 4.31(3.60, 5.40) 11.59±1.65 105.03±21.41 28.32±6.34 3.00(2.43, 3.90) 0.37(0.22, 0.89) 观察组 89 57.0(48.0, 68.5) 5.20(4.13, 6.51) 12.07±2.20 97.78±26.99 30.21±10.59 2.70(2.26, 3.30) 0.39(0.23, 0.91) t — 0.39△ 4.37△ 1.94 2.37# 1.62# 2.85△ 0.23△ P — >0.05 >0.05 >0.05 < 0.05 >0.05 < 0.01 >0.05 *示χ2值;△示zc值;#示t′值 表 2 2组病人系统累及情况比较(n)
分组 n 全身症状 淋巴结累及 腺体累及 关节累及 间质性肺病 肾脏受累 ESSDAI评分(x±s)/分 无 轻度 中度 无 有 无 轻度 中重度 无 轻度 中重度 无 有 无 轻度 中重度 对照组 399 380 17 1 394 2 387 11 1 336 61 2 333 76 391 5 3 3.59±3.324 观察组 89 88 1 0 88 0 87 1 1 84 4 1 85 4 86 3 0 6.92±1.860 zc — 1.50 0.45* 0.37 2.47 2.93 0.77 12.92△ P — >0.05 >0.05 >0.05 < 0.05 < 0.01 >0.05 < 0.01 注: 所有病人系统累及的评判标准,均参照2010年ESSDAI[7]按轻中重度分类。*示χ2值;△示t′值 表 3 2组病人免疫学指标比较
分组 n CRP[P50(P25, P75)]/(mg/L) ESR[P50(P25, P75)]/(mm/h) 补体C3
[P50(P25, P75)]/(g/L)补体C4
[P50(P25, P75)]/(g/L)IgA升高(>2.80 g/L) IgM升高(>3.00 g/L) 无 有 无 有 对照组 399 5.00(1.05, 18.60) 26.0(14.0, 43.0) 0.768(0.678, 0.981) 0.191(0.138, 0.221) 243 156 373 26 观察组 89 4.90(1.50, 15.20) 20.0(12.0, 40.0) 0.504(0.435, 0.599) 0.146(0.105, 0.175) 55 34 82 7 χ2 — 0.22* 1.09* 10.80* 4.96* 0.03 0.21 P — >0.05 >0.05 < 0.01 < 0.01 >0.05 >0.05 分组 n IgG计数/(g/L) 抗SSA抗体/R060 抗SSA抗体/Ro52 抗SSB抗体 抗着丝点B抗体 < 15 15~20 >20 - + - + - + - + 对照组 399 237 77 69 122 269 271 120 271 120 359 32 观察组 89 42 23 23 20 67 59 28 59 28 78 9 χ2 — 5.88 2.30 0.11 0.07 2.68 P — >0.05 >0.05 >0.05 >0.05 >0.05 *示zc值 表 4 pSS继发ITP相关危险因素分析
变量 B SE Waldχ2 OR(95%CI) P 截距 1.397 0.765 3.34 4.044 >0.05 ESSDAI 0.460 0.064 52.00 1.583(1.397~1.794) < 0.01 关节受累 < 0.05 无 1.00 轻度 -1.484 0.609 5.93 0.227(0.069~0.748) < 0.05 中重度 -0.503 1.921 0.07 0.605(0.014~26.905) >0.05 间质性肺病 < 0.01 无 1.00 有 -4.638 0.893 27.01 0.010(0.002~0.056) C3 -7.214 1.136 40.29 0.001(0.000~0.007) < 0.01 -
[1] MARIETTE X, CRISWELL LA. Primary Sjögren's Syndrome[J]. N Engl J Med, 2018, 378(10): 931. doi: 10.1056/NEJMcp1702514 [2] ATAOGLU EH, DEMIR B, TUNA M, et al. Sjögren syndrome presenting with hypopotassemic periodic paralysis due to renal tubular acidosis[J]. Am J Case Rep, 2012, 13(90): 187. [3] CHOUNG BS, YOO WH. Successful treatment with intravenous immunoglobulin of severe thrombocytopenia complicated in primary Sjögren's syndrome[J]. Rheumatol Int, 2012, 32(5), 1353. doi: 10.1007/s00296-010-1395-4 [4] 薛媛, 徐东, 李梦涛, 等. 原发性干燥综合征合并严重血小板减少症患者的治疗反应预测[J]. 中华内科杂志, 2019, 58(4): 282. [5] VITALI C, BOMBARDIERI S, JONSSON R, et al. Classification criteria for Sjögren's syndrome: a revisedversion of the European criteria proposed by the American-European Consensus Group[J]. Ann Rheum Dis, 2002, 61(6): 554. doi: 10.1136/ard.61.6.554 [6] NEUNERT C, LIM W, CROWTHER M, et al. The American society of hematology 2011 evidence-based practice guideline for immune thrombocytopenia[J]. Blood, 2011, 117(16): 4190. doi: 10.1182/blood-2010-08-302984 [7] SEROR R, RAVAUD P, BOWMAN SJ, et al. EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome[J]. Ann Rheum Dis, 2009, 69(6): 1103. [8] PROVAN D, ARNOLD DM, BUSSEL JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia[J]. Blood, 2019, 3(22): 3780. [9] CINES DB, BUSSEL JB, LIEBMAN HA, et al. The ITP syndrome: pathogenic and clinical diversity[J]. Blood, 2009, 113(26): 6511 doi: 10.1182/blood-2009-01-129155 [10] MOULIS G, PALMARO A, MONTASTRUC JL, et al. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France[J]. Blood, 2014, 124(22): 3308. doi: 10.1182/blood-2014-05-578336 [11] AOKI A, OHNO S, UEDA A, et al. Hematological abnormalities of primary Sjogren's syndrome[J]. Nihon Rinsho Meneki Gakkai Kaishi, 2000, 23(2): 124. doi: 10.2177/jsci.23.124 [12] DAI F, YANG G, RAO P, et al. Clinical characteristics of secondary immune thrombocytopenia associated with primary Sjögren's syndrome[J]. Front Med, 2020, 138(7): 462. [13] HABETS KL, HUIZINGA TW, TOES RE, et al. Platelets and autoimmunity[J]. Eur J Clin Invest, 2013, 43(7): 746. doi: 10.1111/eci.12101 [14] KOUPENOVA M, CLANCY L, CORKREY HA, et al. Circulating platelets as mediators of immunity, inflammation, and thrombosis[J]. Circ Res, 2018, 122(2): 337. doi: 10.1161/CIRCRESAHA.117.310795 [15] SEMPLE JW, ITALIANO JE JR, FREEDMAN J. Platelets and the immune continuum[J]. Nat Rev Immunol, 2011, 11(4): 264. doi: 10.1038/nri2956 [16] VIEIRA-DE-ABREU A, CAMPBELL RA, WEYRICH AS, et al. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum[J]. Semin Immunopathol, 2012, 34(1): 5. doi: 10.1007/s00281-011-0286-4 [17] BOILARD E, BLANCO P, NIGROVIC PA. Platelets: active players in the pathogenesis of arthritis SLE[J]. Nat Rev Rheumatol, 2012, 8(9): 534. doi: 10.1038/nrrheum.2012.118 [18] BOILARD E, NIGROVIC PA, LARABEE K, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production[J]. Science, 2010, 327(5969): 580. [19] LINDEMANN S, TOLLEY ND, DIXON DA, et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis[J]. Cell Biol, 2001, 154(3): 485. doi: 10.1083/jcb.200105058 [20] ROLFES V, RIBEIRO LS, HAWWARI I, et al. Platelets fuel the inflammasome activation of innate immune cells[J]. Cell Rep, 2020, 31(6): 107615. doi: 10.1016/j.celrep.2020.107615 [21] GUO T, LONG Y, SHEN Q, et al. Clinical profiles of SS-ILD compared with SS-NILD in a Chinese population: a retrospective analysis of 735 patients[J]. Ann Med, 2021, 53(1): 1340. doi: 10.1080/07853890.2021.1965205 [22] CHRISTMANN RB, SAMPAIO-BARROS P, STIFANO G, et al. Association of interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis[J]. Arthritis Rheumatol, 2014, 66(3): 714. doi: 10.1002/art.38288 [23] LAFYATIS R. Transforming growth factor β--at the centre of systemic sclerosis[J]. Nat Rev Rheumatol, 2014, 10(12): 706. doi: 10.1038/nrrheum.2014.137 [24] ASSOIAN RK, KOMORIYA A, MEYERS CA, et al. Transforming growth factor-b in human platelets. Identification of major storage site, purification and characterization[J]. J Biol Chem, 1983, 258(11): 7155. doi: 10.1016/S0021-9258(18)32345-7 [25] MEYER A, WANG W, QU J, et al. Ahamed. Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload[J]. Blood, 2012, 119(4): 1064. doi: 10.1182/blood-2011-09-377648 [26] GHAFOORY S, VARSHNEY R, ROBISON T, et al. Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury[J]. Blood Adv, 2018, 2(5): 470. doi: 10.1182/bloodadvances.2017010868 [27] TANIGUCHI Y, YOSHIOKA T, SUGAYA H. Growth factor levels in leukocyte-poor platelet-rich plasma and correlations with donor age, gender, and platelets in the Japanese population[J]. J Exp Orthop, 2019, 6(1): 4. doi: 10.1186/s40634-019-0175-7 [28] JIN T, ALMEHED K, CARLSTEN H, et al. Decreased serum levels of TGF-β1 are associated with renal damage in female patients with systemic lupus erythematosus[J]. Lupus, 2012, 21(3): 310. doi: 10.1177/0961203311425528 [29] LU RB, LEE SY, WANG TY, et al. Long-term heroin use was associated with the downregulation of systemic platelets, BDNF, and TGF-β1, and it contributed to the disruption of executive function in Taiwanese Han Chinese[J]. Drug Alcohol Depend, 2017, 179: 139. doi: 10.1016/j.drugalcdep.2017.06.035 [30] GUO Y, CUI W, PEI Y, et al. Platelets promote invasion and induce epithelial to mesenchymal transition in ovarian cancer cells by TGF-β signalling pathway[J]. Gynecol Oncol, 2019, 153(3): 639. doi: 10.1016/j.ygyno.2019.02.026 [31] ZHANG S, QU J, WANG L, et al. Activation of toll-like receptor 7 signaling pathway in primary Sjögren's syndrome-associated thrombocytopenia[J]. Front Immunol, 2021, 12: 637659. doi: 10.3389/fimmu.2021.637659