CTDILD

,蒋捍东上海交通大学医学院附属仁济医院,结缔组织相关性肺病,讨论内容,结缔组织病肺病的概念CTD的肺部受累情况常见CTD肺病的累积部位CTD对ILD的影响ILD病理类型对疾病的影响AE-CTD-ILDCTD-ILD的治疗,相关概念,肺部优势性肺病Lung-dominant CTD（LD-CTD）自体免疫优势性肺病Autoimmune-Featured ILD（AIF-ILD）结缔组织病相关肺病CTD-associated lung disease(Lung involvement in CTD)胶原血管病相关性肺病CVD-associated ILD（CTD-ILD）未分化结缔组织病相关性肺病（UCTD-ILD）,肺部优势性肺病,“ 肺部优势性肺病LD-CTD”系血清学抗体阳性或病理学提示CTD特征，但不符合明确CTD标准，即缺乏诊断CTD的肺外症状。LD-CTD意味血清学抗体阳性或病理学提示CTD特征单独可以明确CTD-IP.,Aryeh Fischer，Connective Tissue Disease-Associated Interstitial Lung Disease. CHEST / 138 / 2 / AUGUST, 2010,诊断标准,Aryeh Fischer，Connective Tissue Disease-Associated Interstitial Lung Disease. CHEST / 138 / 2 / AUGUST, 2010,自身免疫特征性间质性肺病,We propose a new term to describe a subset of pulmonary ILD patients with features of a connective tissue disease that do not meet ACR criteria: autoimmune-featured ILD (AIF-ILD).间质性肺病伴有结缔组织病特征尚未满足美国风湿病学会诊断标准的一类疾病称为自身免疫特征性间质性肺病-Rekha Vij，et al. Autoimmune-Featured Interstitial Lung Disease: A Distinct Entity. CHEST 2011; 140(5):12921299,自身免疫特征性间质性肺病的诊断标准,Rekha Vij，et al. Autoimmune-Featured Interstitial Lung Disease: A Distinct Entity. CHEST 2011; 140(5):12921299,RF的关节外症状发生,Turesson C. Extra-articular rheumatoid arthritis. Cur Opin Rheumatol 2013;25(5): 3606,CTD-ILD肺部受累及情况,CTD中ILD的发生情况,RF-ILD 15-60%SSC 53%PM/DM 20-80%SjS 25%SLE 9%MCTD 30-50%,Expert Rev. Clin. Pharmacol. 5(2), 219227 (2012),各种类风湿病肺病发病率,Castelino and Varga Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management Arthritis Res Ther. 2010;12(4):213,CTD相关性肺病的类别,胸膜病胸膜炎 积液/增厚气道病变 上气道(a)环杓关节炎(b) 气管病变 下气道(a) 支气管扩张(b) 细支气管炎血管病变,肺实质病变 间质性肺病NSIP, UIP, OP,LIP, DAD, DIP 弥漫性肺泡出血 急性肺炎 类风湿结节感染药物毒性反应,CTD-LD疾病谱,系统硬化最易累及肺间质和血管、皮肌炎最易累及肺间质,Aryeh Fischer, Roland du Bois. Interstitial lung disease in connective tissue disorders Lancet 2012; 380: 68998,CTD-ILD与病理分型,de Lauretis A. Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ? Chronic Respiratory Disease 2011 8(1) 5382,CTD-ILD病理类型分布,Eunice J. Kim,Rheumatoid Arthritis-Associated Interstitial Lung Disease-The Relevance of Histopathologic and Radiographic Pattern. CHEST / 136 / 5 / NOVEMBER, 2009 1397,CTD与ILD关联和影响,IIP与UCTD-ILD病理类型比较,Brent W. Kinder。 Idiopathic Nonspecific Interstitial Pneumonia Lung Manifestation of Undifferentiated Connective Tissue Disease? Am J Respir Crit Care Med Vol 176. pp 691697, 2007,结论：特发性非特异性间质性肺炎很多符合UCTD的诊断标准，iNSIP是否与自身免疫相关,UCTD对ILD的影响,232例IIP（活检病理学诊断）IPF138例NSIP94例14 例(31%) NSIP伴UCTD7例(13%) IPF伴UCTD,T.J. Corte. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J 2012; 39: 661668,UCTD对NSIP的影响,1990-2009期间62 例肺活检诊断iNSIPUCTD 诊断标准为Kinder提出6例出现PM被剔除56例中有47例出现至少4项反应UCTD全身炎症指标这47例中有22例（47%）符合UCTD诊断标准,Takafumi Suda. Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD). Respiratory Medicine (2010) 104, 1527-1534,NSIP与CVD有关联,2000-2006约翰霍普金斯医院ILD诊断：临床+影像+肺功能+病理160例，121例做过自身抗体检测，7例药物反应，余114例结节病与SSc单独34符合明确CVD17 (50%)已有CVD诊断17新近诊断CVDCVD疾病谱：5例特发炎性肌病，5例RA, 3例SLE, 2例重叠综合征, 1 例干燥，1例SSc.ANA+ 29例1:320, 其中18 (62%)有CVD (p= 0.01).RF+与CVD关联小(p=1.0).,Shikha Mittoo Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease Respiratory Medicine (2009) 103, 1152-1158,NSIP与CVD有关联,76例(66%)至少1中血清抗体阳性26例(23%)至少2项以上自身抗体阳性最常见为ANA，其次RF，后anti-Ro anti-Jo-1 anti-Scl 70 anti-La 外科活检最常见病理类型UIP (n=20)27% 其次NSIP (n=18)25% NSIP是与CVD-ILD唯一相关的病理类型NSIP的诊断与新诊断CVD有关联趋势,Shikha Mittoo Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease Respiratory Medicine (2009) 103, 1152-1158,系统性疾病对ILD的影响,CTD对纤维化的影响,998例IPF，其中108例合并CTD，对照组5988例随访898例单纯LCFA（IPF），107例FA-CTD（RF86例80%，SSc15例14%）随访期间386例（44%）LCFA死亡54例（50%）死亡（45例RF，3例PM，5例SSc，1例MCTD）对照组601例（10%）死亡,Rheumatology 2002 41：676,死亡率,LCFA 270/1000.年FA-CTD 280/1000.年普通人群 41/1000.年平均生存期LCFA 2.6yFA-CTD 2.4y结论：CTD不伴有FA生存提高,Rheumatology 2002 41：676,UCTD对ILD的影响,232例IIP（活检病理学诊断）IPF138例NSIP94例14 例(31%) NSIP伴UCTD7例(13%) IPF伴UCTD,T.J. Corte. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J 2012; 39: 661668,UCTD与生存无相关,T.J. Corte. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J 2012; 39: 661668,UIP病理死亡率高UCTD不增加死亡率,UCTD对NSIP的影响,1990-2009期间62 例肺活检诊断iNSIPUCTD 诊断标准为Kinder提出6例出现PM被剔除56例中有47例出现至少4项反应UCTD全身炎症指标这47例中有22例（47%）符合UCTD诊断标准,Takafumi Suda. Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD). Respiratory Medicine (2010) 104, 1527-1534,UCTD对NSIP生存影响,UCTD-NSIP 5年生存率100%非UCTD-NSIP5年生存率58%; p=0.0092).,Takafumi Suda. Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD). Respiratory Medicine (2010) 104, 1527-1534,三种UIP病理特征疾病的转归,UIP118例LD-CTD-28CTD-ILD-29（RF12，mCTD6，SLE5，SSc4，PM2IPF61三组CTD年龄轻，女性多，少吸烟，ANA+RF+多，激素+免疫抑制剂多，其它三组无显著差异,Esam H. Alhamad. Comparison of three groups of patients with usual interstitial pneumonia. Respiratory Medicine (2012) 106, 1575-1585,UIP生存情况,23例死亡，6例LD-CTD，2例CTD-ILD，15例IPF。LD-ILD83%死于呼吸因素CTD-ILD100%呼吸因素UIP-IPF66%死于呼吸因素,p=0.028 CTD-UIP vs IPF,p0.05 LD-UIP vs IPF LD-UIP vs CTD-UIP,Esam H. Alhamad. Comparison of three groups of patients with usual interstitial pneumonia. Respiratory Medicine (2012) 106, 1575-1585,UIP病理类型预后差RF,54例类风湿性肺病，肺部病理活检UlP 15NSIP 16OP 4无法分类肺炎 2DIP 1细支气管病 16,Yutaro Nakamura. Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases. Respiratory Medicine (2012) 106, 1164-1169.,RLD生存曲线,5年生存率93.8%10年生存率平均76.6%, UIP 10年生存率52.5%肺UIP 10年生存率84.3%(p= 0.0452)UIP vs NSIP无显著差异,Yutaro Nakamura. Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases. Respiratory Medicine (2012) 106, 1164-1169.,p=0.0452,SSc-ILD死亡率与肺病理,80例SSc患者，外科手术病理诊断其中NSIP (n = 62, 77.5%),细胞型NSIP (n = 15)，纤维化型NSIP (n = 47) UIP(n = 6)终末期肺病(ESL, n = 6)其它类型(n = 6)25 例死亡，NSIP 16/62, 26%; UIP/ESL 6/12, 50%)5年生存：NSIP (91%)；UIP/ESL (82%)死亡率与DL(CO)和FVC相关(p = 0.004 and p = 0.007),Bouros D, Histopathologic Subsets of Fibrosing Alveolitis in Patients with Systemic Sclerosis and Their Relationship to Outcome. Am J Respir Crit Care Med Vol 165. pp 15811586, 2002,SSC-ILD不同病理类型的生存情况,Bouros D, Histopathologic Subsets of Fibrosing Alveolitis in Patients with Systemic Sclerosis and Their Relationship to Outcome. Am J Respir Crit Care Med Vol 165. pp 15811586, 2002,p0.05,5年生存率NSIP90% UIP82% 10年生存率NSIP69% UIP29%,SSC-NSIP生存与BAL中E,Bouros D, Histopathologic Subsets of Fibrosing Alveolitis in Patients with Systemic Sclerosis and Their Relationship to Outcome. Am J Respir Crit Care Med Vol 165. pp 15811586, 2002,P=0.03,SSC-NSIP的生存与DLCO,Bouros D, Histopathologic Subsets of Fibrosing Alveolitis in Patients with Systemic Sclerosis and Their Relationship to Outcome. Am J Respir Crit Care Med Vol 165. pp 15811586, 2002,SSc-ILD1、肺病理类型与生存无显著关联2、BAL嗜酸性粒细胞增加、DLCO降低生存率低,Bouros D, Histopathologic Subsets of Fibrosing Alveolitis in Patients with Systemic Sclerosis and Their Relationship to Outcome. Am J Respir Crit Care Med Vol 165. pp 15811586, 2002,IIP vs CVD-ILD survival,1990-2006年间韩国亚洲医疗中心362例外科病理诊断UIP类型(269例IIP，93例CVD-IP)UIP类型(203例IPF，36例CVD-UIP) 纤维化型NSIP(66例i-NSIP，57例CVD-NSIP),Demosthenes Bouros Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007 Apr 1;175(7):705-11,CVD-IP vs IIP生存,CVD-IP生存期平均131.0+ 9.1 mo)IIP group平均80.5+ 6.3月P0.001年龄, FVC, DlCO及CVD为预后的独立因素,Demosthenes Bouros Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007 Apr 1;175(7):705-11,CVD-UIP与IPF-UIP比较,年轻、女性、非吸烟者CVD-UIP生存(平均125.5+16.0 月)高于 IPF-UIP ( 66.9+6.5月)3-year生存率分别为(81.6 vs.57.4%)5-year生存率分别为(81.6 vs. 44.8%)CVD-UIP生存高于IPF-UIP(p0.001).,Demosthenes Bouros Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007 Apr 1;175(7):705-11,UIP生存分析,平均生存期CVD-UIP 125.5+ 16.0月IPF-UIP 66.9+ 6.5月 p0.0013年生存率CVD-UIP 81.6IPF-UIP57.4%5年生存率CVD-IPF 81.6IPF-UIP44.8%(p0.001),Demosthenes Bouros Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007 Apr 1;175(7):705-11,CTD-NSIP与iNSIP生存无显著差异CTD-UIP与CVD-NSIP生存无显著差异,3年生存率CVD-NSIP 88.9% iNSIPP 77.6% 5年生存率CVD-NSIP 81.5iNSIP 67.4%多因素分析显示年龄、FVC为NSIP的生存相关，CVD无关,CTD与ILD生存,2533例肺纤维化患者,324例 (13%)并存结缔组织病CTD，如下, RF(8.4%)，SSc (1.6%)最常见2.3随访IPF-CS（特发肺纤维化临床综合征）有1073例(48.6%)死亡CTD-PF有113 (34.9%)死亡IPF-CS死亡率229.8/1000人/年CTD-PF死亡率123.6/1000 人/年 years (95% ConfidenceInterval: 102.8e148.7)平均生存年限IPF-CS 3.1年CTD-PF 6.5年(p=0.043),Navaratnam V, Does the presence of connective tissue disease modify survival in patients with pulmonary fibrosis? Respir Med. 2011 Dec;105(12):1925-30,Navaratnam V, Does the presence of connective tissue disease modify survival in patients with pulmonary fibrosis? Respir Med. 2011 Dec;105(12):1925-30,IIP与CVD-IP的差异,UIP 320例，其中IPF/UIP 272例; CVD-UIP, 48例CVD-UIP生存时间143.8月IPF/UIP生存时间40.1月P 0.001)1年死亡率CVD-UIP 7.9% vs IPF/UIP 17.3%, 3年死亡率CVD-UIP 13.9% vs IPF/UIP 43.2%P 0.001,Jin Woo Song, Pathologic and Radiologic Differences Between Idiopathic and Collagen Vascular Disease-Related Usual Interstitial Pneumonia CHEST 2009; 136:2330),Jin Woo Song, Pathologic and Radiologic Differences Between Idiopathic and Collagen Vascular Disease-Related Usual Interstitial Pneumonia CHEST 2009; 136:2330),Comparison of the survival curves for IPF/UIP(Ab) and IPF/UIP(Ab) patients.,Jin Woo Song, Pathologic and Radiologic Differences Between Idiopathic and Collagen Vascular Disease-Related Usual Interstitial Pneumonia CHEST 2009; 136:2330),RF中，UIP类型有重要意义,2001.1.-2008.11.1加州大学与Mayo Clinic,Kim EJ, Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010 Jun;35(6):1322-8. doi: 10.1183/09031936.00092309. Epub 2009 Dec 8.,RA-UIP与RA-非UIP,Kim EJ, Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010 Jun;35(6):1322-8. doi: 10.1183/09031936.00092309. Epub 2009 Dec 8.,生存分析,RA-ILD 5.0年 RA-UIP 3.2年RA-非UIP 6.6年,RF-非UIP,RF-UIP,IPF-UIP,Kim EJ, Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010 Jun;35(6):1322-8. doi: 10.1183/09031936.00092309. Epub 2009 Dec 8.,生存分析-根据HRCT分型,P=0.02 UIP vs NSIP; 中间类型与其它无差异,NSIP可能,UIP/NSIP,UIP明确,Kim EJ, Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010 Jun;35(6):1322-8. doi: 10.1183/09031936.00092309. Epub 2009 Dec 8.,病理证实类风湿性关节炎肺病预后分析,1989.122009.12期间日本浜松大学医学院30M、24W，平均年龄60.3y组织病理学NSIP16 ，UIP15，OP4，无法分类2，DIP1，细支气管病变16,Yutaro Nakamura, Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases. Respiratory Medicine (2012) 106, 1164-1169,RF-ILD病10年生存比较,10年生存率比较RF-非UIP 84.3%, RF-UIP 52.5%(p = 0.0452)RF-UIP与NSIP比较无显著差异 (p= 0.2648),RF-UIP较其它类型显著差异更大(p= 0.0147),Yutaro Nakamura,Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases. Respiratory Medicine (2012) 106, 1164-1169,RF-ILD病生存分析,10年生存率为76.6%,Yutaro Nakamura,Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases. Respiratory Medicine (2012) 106, 1164-1169,RF-UIP与RF-非UIP-生存曲线,p = 0.0452,Yutaro Nakamura,Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases. Respiratory Medicine (2012) 106, 1164-1169,Yutaro Nakamura,Rheumatoid lung disease: Prognostic analysis of 54 biopsy-proven cases. Respiratory Medicine (2012) 106, 1164-1169,结缔组织相关间质性肺病与急性加重,Ryo Tachikawa，Respiration 2012;83:2027,Ryo Tachikawa，Respiration 2012;83:2027,Ryo Tachikawa，Respiration 2012;83:2027,Ryo Tachikawa，Respiration 2012