N-acetylcysteine Exposure is Associated with Improved Survival in Anti-nuclear Antibody Seropositive Patients with Usual Interstitial Pneumonia

Overview

Journal BMC Pulm Med

Publisher Biomed Central

Specialty Pulmonary Medicine

Date 2018 Feb 10

PMID 29422061

Citations 5

Authors

Justin M Oldham

Leah J Witt

Ayodeji Adegunsoye

Jonathan H Chung

Cathryn Lee

Scully Hsu

Lena W Chen

Aliya Husain

Steven Montner

Rekha Vij

Mary E Strek

Imre Noth

Affiliations

Soon will be listed here.

Abstract

Background: Mortality is similarly high among individuals with usual interstitial pneumonia (UIP) due to idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF). Circulating anti-nuclear antibodies (ANA) are commonly found in this patient population, suggesting possible aberrant immune activation. Because an environment of oxidative stress can result from immunologic activation, we hypothesized that ANA positive patients with UIP would have improved outcome when exposed to the antioxidant N-acetylcysteine (NAC) compared to ANA negative patients.

Methods: A single center, retrospective cohort analysis was performed. Patients with UIP due to IPF and IPAF were stratified according to ANA status to and NAC exposure. Transplant-free survival (TFS) was assessed using the Kaplan-Meier estimator and multivariable Cox regression adjusted for diagnosis, gender/age/physiology score, immunosuppressant exposure and anti-fibrotic exposure.

Results: Of 293 individuals with UIP due to IPF (74%) or IPAF (26%), NAC exposure was documented in 58 (19.8%). Among NAC exposed individuals, 33 (56.9%) were ANA seropositive and 25 (43.1%) were seronegative. NAC exposure was associated with improved TFS survival among ANA seropositive individuals in unadjusted analysis (p = 0.02) and after multi-variable adjustment (HR 0.51, 95% CI 0.30-0.87; p = 0.01). There was no association between NAC exposure and TFS in ANA seronegative individuals (HR 1.26, 95% CI 0.69-2.32; p = 0.45). Formal interaction testing confirmed NAC*ANA interaction (p = 0.04) and sensitivity analysis demonstrated an increasing effect size associated with NAC therapy as ANA titer increased. Among patients with available genetic data, a marginally higher proportion of ANA positive patients (p = 0.08) carried the rs3750920 (TOLLIP) genotype previously shown to predict favorable outcome in NAC exposed patients.

Conclusion: NAC exposure is associated with improved transplant-free survival ANA positive patients with UIP. These findings support the prospective collection of ANA data in in future NAC clinical trials performed in patients with UIP.

Citing Articles

Associations between genetic variants of Toll-interacting proteins and interstitial lung diseases: a systematic review and meta-analysis.

Li X, Cui B, Jiang L Orphanet J Rare Dis. 2024; 19(1):432.

PMID: 39578840 PMC: 11583435. DOI: 10.1186/s13023-024-03410-8.

Redox Pathogenesis in Rheumatic Diseases.

Laniak O, Winans T, Patel A, Park J, Perl A ACR Open Rheumatol. 2024; 6(6):334-346.

PMID: 38664977 PMC: 11168917. DOI: 10.1002/acr2.11668.

Association of rs3750920 polymorphism in TOLLIP with clinical characteristics of fibrosing interstitial lung diseases in Japanese.

Isshiki T, Koyama K, Homma S, Sakamoto S, Yamasaki A, Shimizu H Sci Rep. 2021; 11(1):16250.

PMID: 34376770 PMC: 8355271. DOI: 10.1038/s41598-021-95869-9.

Air Pollution and Interstitial Lung Diseases: Defining Epigenomic Effects.

Goobie G, Nouraie M, Zhang Y, Kass D, Ryerson C, Carlsten C Am J Respir Crit Care Med. 2020; 202(9):1217-1224.

PMID: 32569479 PMC: 7605178. DOI: 10.1164/rccm.202003-0836PP.

Efficacy of nebulized acetylcysteine for relieving symptoms and reducing usage of expectorants in patients with radiation pneumonitis.

Han D, Ji W, Lee J, Song S, Choi C Thorac Cancer. 2018; 10(2):243-248.

PMID: 30585684 PMC: 6360265. DOI: 10.1111/1759-7714.12938.

References

Lee J, Kim E, Lynch K, Elicker B, Ryerson C, Katsumoto T . Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis. Respir Med. 2012; 107(2):249-55. PMC: 3543473. DOI: 10.1016/j.rmed.2012.10.018. View

Ley B, Ryerson C, Vittinghoff E, Ryu J, Tomassetti S, Lee J . A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012; 156(10):684-91. DOI: 10.7326/0003-4819-156-10-201205150-00004. View

Brownell R, Moua T, Henry T, Elicker B, White D, Vittinghoff E . The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia. Thorax. 2017; 72(5):424-429. PMC: 5555580. DOI: 10.1136/thoraxjnl-2016-209671. View

Imai Y, Kuba K, Neely G, Yaghubian-Malhami R, Perkmann T, van Loo G . Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008; 133(2):235-49. PMC: 7112336. DOI: 10.1016/j.cell.2008.02.043. View

Ahmad K, Barba T, Gamondes D, Ginoux M, Khouatra C, Spagnolo P . Interstitial pneumonia with autoimmune features: Clinical, radiologic, and histological characteristics and outcome in a series of 57 patients. Respir Med. 2017; 123:56-62. DOI: 10.1016/j.rmed.2016.10.017. View

Latorre E, Mendoza C, Layunta E, Alcalde A, Mesonero J . TLR2, TLR3, and TLR4 activation specifically alters the oxidative status of intestinal epithelial cells. Cell Stress Chaperones. 2013; 19(2):289-93. PMC: 3933612. DOI: 10.1007/s12192-013-0461-8. View

Oldham J, Ma S, Martinez F, Anstrom K, Raghu G, Schwartz D . TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2015; 192(12):1475-82. PMC: 4731723. DOI: 10.1164/rccm.201505-1010OC. View

Oldham J, Adegunsoye A, Valenzi E, Lee C, Witt L, Chen L . Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 2016; 47(6):1767-75. PMC: 5515625. DOI: 10.1183/13993003.01565-2015. View

King Jr T, Bradford W, Castro-Bernardini S, Fagan E, Glaspole I, Glassberg M . A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22):2083-92. DOI: 10.1056/NEJMoa1402582. View

10.

Chen G, Nunez G . Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010; 10(12):826-37. PMC: 3114424. DOI: 10.1038/nri2873. View

11.

Wahamaa H, Schierbeck H, Hreggvidsdottir H, Palmblad K, Aveberger A, Andersson U . High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts. Arthritis Res Ther. 2011; 13(4):R136. PMC: 3239379. DOI: 10.1186/ar3450. View

12.

Lavieri R, Piccioli P, Carta S, Delfino L, Castellani P, Rubartelli A . TLR costimulation causes oxidative stress with unbalance of proinflammatory and anti-inflammatory cytokine production. J Immunol. 2014; 192(11):5373-81. DOI: 10.4049/jimmunol.1303480. View

13.

Lau C, Broughton C, Tabor A, Akira S, Flavell R, Mamula M . RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med. 2005; 202(9):1171-7. PMC: 2213226. DOI: 10.1084/jem.20050630. View

14.

Koarai A, Sugiura H, Yanagisawa S, Ichikawa T, Minakata Y, Matsunaga K . Oxidative stress enhances toll-like receptor 3 response to double-stranded RNA in airway epithelial cells. Am J Respir Cell Mol Biol. 2009; 42(6):651-60. PMC: 2891495. DOI: 10.1165/rcmb.2008-0345OC. View

15.

Chartrand S, Swigris J, Stanchev L, Lee J, Brown K, Fischer A . Clinical features and natural history of interstitial pneumonia with autoimmune features: A single center experience. Respir Med. 2016; 119:150-154. DOI: 10.1016/j.rmed.2016.09.002. View

16.

Kovach M, Standiford T . Toll like receptors in diseases of the lung. Int Immunopharmacol. 2011; 11(10):1399-406. PMC: 3575025. DOI: 10.1016/j.intimp.2011.05.013. View

17.

Asehnoune K, Strassheim D, Mitra S, Kim J, Abraham E . Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. J Immunol. 2004; 172(4):2522-9. DOI: 10.4049/jimmunol.172.4.2522. View

18.

Bhattacharyya S, Kelley K, Melichian D, Tamaki Z, Fang F, Su Y . Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2012; 182(1):192-205. PMC: 3538029. DOI: 10.1016/j.ajpath.2012.09.007. View

19.

Noble P, Albera C, Bradford W, Costabel U, Glassberg M, Kardatzke D . Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011; 377(9779):1760-9. DOI: 10.1016/S0140-6736(11)60405-4. View

20.

Richeldi L, du Bois R, Raghu G, Azuma A, Brown K, Costabel U . Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22):2071-82. DOI: 10.1056/NEJMoa1402584. View