1、结缔组织病肺间质病变诊治进展,北京协和医院风湿免疫科 张 烜,间质性肺病（interstitial lung disease，ILD）,CTD的常见疾病 可以是CTD的首发症状 是预后不良的原因之一 是肺动脉高压(PAH）的原因之一,影响肺功能,呼吸肌受累 反复误吸(食道功能) 血栓栓塞 颈部软骨炎症 支气管扩张,ILD的发生率,15%的CTD合并ILD 70% SSc合并肺部病变，2年内可发展为ILD，组织病理77.5%SSc伴ILD 10%DM/PM合并ILD 胸片显示3.7%RA合并ILD SLE，SS，MCTD,Clin Chest Med 2004;25:549 559 Am J R
2、espir Crit Care Med 2002;165:1581 6 Ann Rheum Dis 2003 ; 62 : 897 900,CTD中的ILD发生率、严重度及病死率的比较1）,CTD中ILD的特点,注：1）指5年之内因呼吸衰竭死亡 2）国外无对比数据 3）均为DM患者,张烜,董怡,张奉春.中华风湿病学杂志, 1999;3:247,分型的目的,自然病程、对激素反应、预后 CTD-UIP是否等同特发UIP?,SSc-ILD-ACR2006报道,美国Denver Fischer A对27例肺活检的SSc患者（14例NSIP，8例UIP）分析表明：尽管都予同样的激素和免疫抑制剂治疗，SS
3、c-NSIP中位生存时间为15.3年，而UIP为3年。,ILD病理和影像学特点,Curr Opin Rheumtol 2004;16:186 191,HRCT - NSIP,SSc DM/PM,HRCT - UIP,SSc RA DM/PM,UIP-HRCT特点,病变不均匀 下肺为主 牵拉性支气管扩张 无明显毛玻璃变,HRCT 慢性LIP,SS RA 药物,HRCT obliterative bronchiolitis,RA SLE Scleroderma PM/DM,HRCT organizing pneumonia,Gold SSZ MTX Sjogrens syndrom RA,HRCT
4、 a patient with RA,33% of with RA associated parenchymal lung disease 31 IPF Radiography: 2-6% 29 HRCT: 10% - 47% 35-8 HRCT: 50% with broncioectases and bronchiolectasis,SLE - Chronic interstitial pneumonia,Radiographic - 624% HRCT 24/34 abnormal 11/34 CIP Fenlon HM, Doran M, Sant SM, et al. Am J Ro
5、entgenol 1996;166:3017. Estes D, Christian CL. Medicine (Baltimore) 1971;50:8595. Raynauds phenomenon, swollen fingers, sclerodactyly, telangiectasia, dyspnoea, nailfold capillary abnormalities May be efficacious: Corticosteroids Immunosuppressive agents,与ILD的相关因素,与病种有关 在RA中与RF的滴度有关 DM/PM与抗Jo-1抗体有关
6、抗RNP抗体,Clin Exp Allergy 2003;33:226 232 Arthritis Rheum 2002;47:614 622,预后,病理分型 CTD,SSc-ILD预后,病理 起病时严重程度 血浆HcY 合并肺高压 BAL细胞？ TGFbeta,MMP,SSc-ILD其它标志物,呼出NO测定：内皮 血清SP-D(A)/KL-6：肺泡II型上皮细胞,治疗,ILD 治疗的中心问题是GC和免疫抑制的指征 GC是最常用药，众多病人无反应 预后取决于分型 GC+CTX疗效好于单用GC,Am J Respir Crit Care Med 1996;154:400 Arthritis Rh
7、eum 1994;37:1290 Semin Arthritis Rheum 2003;32:273,治疗,ILD 治疗的中心问题是GC和免疫抑制的指征 GC是最常用药，众多病人无反应 预后取决于分型 GC+CTX疗效好于单用GC,Am J Respir Crit Care Med 1996;154:400 Arthritis Rheum 1994;37:1290 Semin Arthritis Rheum 2003;32:273,PM/DM-ILD病理类型与治疗,无肌病性皮肌炎者有更高几率发生DAD； 可呈爆发式发展，可在数月内致死。需要积极加用足量环磷酰胺或环孢素以及激素治疗 抗CADM抗
8、体（anti-clinically amyopathic dermatomyositis antibodies）预示快速进展ILD Recent advances in the treatment of interstitial lung disease in patients with polymyositis/dermatomyositis. Endocr Metab Immune Disord Drug Targets. 2006 Dec;6(4):409-15.,足量激素1 mg/kg/day联用大剂量环孢A（需用 200 mg/day ），并在诊断后 15 天内开始使用，可有效降低D
9、M-A/SIP 的死亡率。 足量激素与免疫抑制剂在初始阶段即同时使用要明显优于单用激素控制不佳后再加用环孢A的治疗效果 Early intervention with corticosteroids and cyclosporin A and 2-hour postdose blood concentration monitoring improves the prognosis of acute/subacute interstitial pneumonia in dermatomyositis. J Rheumatol. 2008 Feb;35(2):254-9. Epub 2007 De
10、c 15 Step-up versus primary intensive approach to the treatment of interstitial pneumonia associated with dermatomyositis/ polymyositis: a retrospective study，Mod Rheumatol. 2007;17(2):123-30. Epub 2007 Apr 20.,治疗RA-ILD,CTX,环孢素,AZA,羟基氯喹,the first positive results of a PCT,治疗SSc-ILD-NEJM报道,DBRPCT 美国1
11、3个中心，158例患者 口服CTX或安慰剂年，随访年 PEP-FVC,治疗SSc-ILD-NEJM报道,Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC% predicted between the CTX and placebo groups was 2.53% (95%CI 0.28 to 4.79%), favoring CTX (P0
12、.03).,治疗SSc-ILD-NEJM报道,There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the CTX group, but the difference not significant.,治疗SSc-ILD-NEJM报道,在治疗年时，HRCT纤维化严重病人在
13、安慰剂组FVC下降明显，而在CTX组纤维化对FVC影响不明显 (P = 0.009),对SSc中已有纤维化说明存在相对早期活动性肺泡炎，如不治疗，病情容易进展。,治疗SSc-ILD-NEJM结论,One year of oral CTX in symptomatic SSc-ILD had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung
14、function were maintained through the 24 ms of the study.,治疗SSc-ILD-NEJM问题,DLco差别无显著意义,治疗ILD排除感染,PCP感染 SLE, myositis,WG长期激素，MTX, TNFa抑制剂,治疗ILD排除感染,CMV感染,左下肺T结节影，TB,05-11-23 双下肺渗出影,05-12-7 经静脉大扶康治疗2周后，渗出明显吸收,06-3-1右肺渗出影,06-4-3予口服伊曲康唑1月后,右肺渗出影吸收,治疗ILDMTX?,急性超敏性肺泡炎及慢性肺纤维化 诱发PCP感染 ILD尽量不用MTX 小剂量MTX？,治疗IP
15、F启示,治疗IPF启示,The synthesis of glutathione can be accelerated by the administration of NAC, which crosses cell membranes easily and can be converted to l-cysteine. Uptake of l-cysteine is an important rate-limiting step for the synthesis of glutathione. NAC increases the pool of other antioxidant thio
16、ls that also protect cells from injury.,182 例 (92 NAC， 90安慰剂). 155例 (80 NAC and 75 安慰剂)UIP HRCT和病理诊断,57/80 NAC (71%) and 51/75 taking placebo (68%) completed one year of treatment. NAC slowed the deterioration of VCand Dlco at 12 months, absolute differences in the change from baseline between patie
17、nts taking NAC and those taking placebo were 0.18 liter (95%CI, 0.03 to 0.32), relative difference of 9% , for VC(P=0.02), and 0.75 mmol per minute per kilopascal (95%CI, 0.27 to 1.23), or 24%, for Dlco(P=0.003).,Mortality during the study was 9 %NAC and 11 %placebo(P=0.69). There were no significan
18、t differences in the type or severity of adverse events between patients taking NAC and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking NAC (P=0.03).,生物靶向治疗效果尚不明确,-TNF靶向治疗,荟萃分析表明：有233例RA、SLE等疾病的患者使用-TNF靶向治疗后继发了皮肤血管炎、ILD等，其中24例发生了ILD，即使停药后预后仍较差，部分
19、可能与MTX联用有关。 Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore). 2007 Jul;86(4):242-51. 有病例报道etanercept 的治疗使原有ILD 的RA患者的肺部病变急性加重 Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis. J R
20、heumatol. 2007 May;34(5):1151-4. Epub 2007 Apr 15. 但也有报道称未发现Infliximab、etanercept 、AZA的使用导致肺间质病变的发生增加 Rheumatoid arthritis treatment and the risk of severe interstitial lung disease，Scand J Rheumatol. 2007 May-Jun;36(3):172-8,Imatinib,有研究表明SSc中PDGFR自身抗体导致PDGFR酪氨酸激酶活性增高 Stimulatory Autoantibodies to
21、the PDGF Receptor in Systemic Sclerosis，N Engl J Med 354:2667, June 22, 2006 Imatinib为酪氨酸激酶抑制剂，抑制 Bcr-Abl, c-Kit ， PDGFR tyrosine kinases。已被证明有抑制纤维母细胞合成胶原以及细胞增殖的作用 联合使用CTX（抑制B细胞功能）与Imatinib（PDGFR抑制剂），其体内安全性已初步证实，有效性待进一步研究 Rheumatology (Oxford). 2009 Jan;48(1):49-52. Epub 2008 Sep 24,CTD/ILD治疗,罗格列酮，吡格列酮：PPAR 减少博来霉素诱导皮肤硬化和炎症 减少TGF-B诱导胶原基因转录 负调正常fibroblast移行和 myofibroblast转化 他克莫司 DM/ILD Bosentan 无效,谢谢！,
