TNF 靶向治疗引起或加重的间质性肺疾病：122 例分析。

Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases.

机构信息

Department of Internal Medicine, Hospital do Meixoeiro, Vigo, Spain.

出版信息

Semin Arthritis Rheum. 2011 Oct;41(2):256-64. doi: 10.1016/j.semarthrit.2010.11.002. Epub 2011 Feb 1.

DOI:10.1016/j.semarthrit.2010.11.002

PMID:21277618

Abstract

OBJECTIVES

To analyze the clinical characteristics, outcomes, and patterns of association with the different biologic agents used in all reported cases of adult patients developing interstitial lung disease (ILD) after biologic therapy.

METHODS

In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project. One objective was to collect data on autoimmune diseases secondary to the use of biologic agents by quarterly Medline search surveillance of reported cases. For this study, the baseline included articles published between January 1990 and March 2010, including the MeSH term "lung diseases, interstitial" as the key research term. In addition, we report an unpublished case of ILD secondary to biologic therapy.

RESULTS

There are 122 reported cases of new-onset or exacerbation of ILD secondary to administration of biologic therapies. Biologic agents associated with ILD were overwhelmingly anti-tumor necrosis factor agents (etanercept in 58 cases and infliximab in 56) and were administered for rheumatoid arthritis in 108 (89%) patients. ILD appeared a mean of 26 weeks after initiation of biologic agents. ILD was confirmed by pulmonary biopsy in 26 cases, although a specific histopathologic description was detailed in only 20: 7 patients were classified as usual interstitial pneumonia, 6 as nonspecific interstitial pneumonia, 5 as organizing pneumonia, 1 as diffuse alveolar damage, and 1 as lymphoid interstitial pneumonia. Treatment of ILD included withdrawal of biologic agents in all cases but 1. The outcome of ILD was detailed in 52 cases. Complete resolution was reported in 21 (40%) cases, improvement or partial resolution in 13 (25%), and no resolution in 18 (35%). Fifteen (29%) patients died during the follow-up, the majority (70%) during the first 5 weeks after initiating biologic therapy. In comparison with survivors, patients who died were aged >65 years (67% vs 33%, P = 0.036), with later onset of ILD (46 weeks vs 15 weeks, P = 0.006), received immunosuppressive drugs more frequently (33% vs 8%, P = 0.036), and more often had a previous diagnosis of ILD (67% vs 29%, P = 0.025).

CONCLUSIONS

We found that 97% of cases of ILD associated with biologic agents were associated with agents blocking tumor necrosis factor-α, a cytokine that has been implicated in the pathophysiology of pulmonary fibrosis. Strikingly, drug-induced ILD had a poor prognosis, with an overall mortality rate of around one third, rising to two thirds in patients with preexisting ILD.

摘要

目的

分析所有报告的生物治疗后成人患者发生间质性肺病（ILD）的临床特征、结局和与不同生物制剂关联的模式。

方法

2006 年，西班牙内科学会自身免疫疾病研究组创建了 BIOGEAS 项目。该项目的目标之一是通过每季度对报告病例的 Medline 搜索监测，收集生物制剂使用继发自身免疫疾病的数据。为此，本研究的基线包括 1990 年 1 月至 2010 年 3 月期间发表的文章，并将“肺部疾病，间质性”作为关键研究术语纳入 MeSH 项。此外，我们还报告了 1 例生物治疗继发 ILD 的未发表病例。

结果

共报告了 122 例生物治疗继发新发或加重的 ILD 病例。与 ILD 相关的生物制剂主要为抗肿瘤坏死因子制剂（依那西普 58 例，英夫利昔单抗 56 例），用于治疗 108 例（89%）类风湿关节炎患者。ILD 于生物制剂治疗开始后平均 26 周出现。26 例通过肺活检证实了 ILD，但仅详细描述了 20 例的特定组织病理学描述：7 例为普通间质性肺炎，6 例为非特异性间质性肺炎，5 例为机化性肺炎，1 例为弥漫性肺泡损伤，1 例为淋巴样间质性肺炎。所有病例均停用生物制剂治疗 ILD，但有 1 例例外。52 例报告了 ILD 的结局。完全缓解 21 例（40%），改善或部分缓解 13 例（25%），无缓解 18 例（35%）。在随访期间，15 例（29%）患者死亡，其中大多数（70%）在开始生物治疗后 5 周内死亡。与幸存者相比，死亡患者年龄>65 岁（67% vs 33%，P = 0.036），ILD 发病时间较晚（46 周 vs 15 周，P = 0.006），更常接受免疫抑制药物治疗（33% vs 8%，P = 0.036），且更常患有先前诊断的 ILD（67% vs 29%，P = 0.025）。