Efficacy and Tolerability of Nintedanib in Idiopathic-Inflammatory-Myopathy-Related Interstitial Lung Disease: A Pilot Study

Junyu Liang, Heng Cao, Yang Yang, Yini Ke, Ye Yu, Chuanyin Sun, Lihuan Yue, Jin Lin, Junyu Liang, Heng Cao, Yang Yang, Yini Ke, Ye Yu, Chuanyin Sun, Lihuan Yue, Jin Lin

Abstract

Objectives: To initially clarify the efficacy and tolerability of nintedanib in patients with idiopathic-inflammatory-myopathy-related interstitial lung disease (IIM-ILD). Methods: A retrospective, real-world analysis was conducted in IIM-ILD patients who regularly received outpatient visit or hospitalization from January 2018 to March 2020 in three centers. And the patients were divided into two groups depending on presence or absence of nintedanib therapy. Comparisons, Kaplan-Meier survival analysis and propensity score matching were made to identify difference in time to death from any cause, incidence of rapidly progressive interstitial lung disease (RP-ILD) and comorbidity of pulmonary infection between the two groups. The following logistic regression analyses and Cox proportional-hazard regression analyses were used to verify the therapeutic value of nintedanib as well as clinical significance of other factors. Adverse events were descriptively recorded. Results: Thirty-six patients receiving nintedanib therapy and 115 patients without use of nintedanib were included. Before and after propensity score matching, the primary comparisons revealed better survival (P = 0.015, P = 0016, respectively) and lower incidence of RP-ILD (P = 0.017, P = 0.014, respectively) in patients with nintedanib therapy. Logistic regression analysis identified that disease activity (P < 0.001), percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%, P = 0.036), nintedanib therapy (P = 0.004, OR value = 0.072) and amyopathic dermatomyositis (ADM, P = 0.012) were significantly correlated with RP-ILD. Cox proportional hazards regression analysis suggested that disease activity (P < 0.001), anti-MDA5 antibody (P < 0.001) and nintedanib therapy (P = 0.013, HR value=0.268) were significantly associated with survival of IIM-ILD patients. Similar results can also be seen in analyses after propensity score matching. In the 36 patients with nintedanib therapy, diarrhea was the most common adverse event (44.4%) and hepatic insufficiency contributed to most dosage reduction (44.4% of nine patients) or therapy discontinuation (60.0% of five patients). Conclusions: Nintedanib was found to reduce incidence of RP-ILD and improve survival in IIM-ILD patients in a real-world setting. Anti-MDA5 antibody could be taken as a risk factor for unfavorable outcome. ADM was significantly correlated with occurrence of RP-ILD. In addition to the most frequent diarrhea, hepatic insufficiency was closely related to dosage reduction or therapy discontinuation.

Keywords: anti-MDA5 antibody; dermatomyositis; interstitial lung disease; nintedanib; polymyositis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Liang, Cao, Yang, Ke, Yu, Sun, Yue and Lin.

Figures

Figure 1
Figure 1
Enrollment and groupings of this study. IIM-ILD, Idiopathic-inflammatory-myopathy-related interstitial lung disease.
Figure 2
Figure 2
The Kaplan-Meier curves between patients receiving nintedanib therapy and patients under conventional medications before and after PSM (A,B). PSM, Propensity score matching.
Figure 3
Figure 3
Adverse events and direct contribution to dosage reduction or therapy discontinuation of nintedanib. (A) Showed distribution of adverse events within 36 patients receiving compassionate nintedanib therapy; (B) revealed distribution of adverse events directly related to dosage reduction of nintedanib in 9 patients; (C) exhibited distribution of adverse events directly related to therapy discontinuation of nintedanib in 5 patients.

References

    1. Mariampillai K, Granger B, Amelin D, Guiguet M, Hachulla E, Maurier F, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. (2018) 75:1528–37. 10.1001/jamaneurol.2018.2598
    1. Mammen AL. Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis. Nat Rev Neurol. (2011) 7:343–54. 10.1038/nrneurol.2011.63
    1. Jiang T, Huang Y, Liu H, Xu Q, Gong Y, Chen Y, et al. Reduced miR-146a promotes REG3A expression and macrophage migration in polymyositis and dermatomyositis. Front Immunol. (2020) 11:37 10.3389/fimmu.2020.00037
    1. Li L, D'Silva KM, Lu N, Huang K, Esdaile JM, Choi HK, et al. . Mortality trends in polymyositis and dermatomyositis: a general population-based study. Semin Arthritis Rheum. (2020) 50:834–9. 10.1016/j.semarthrit.2020.08.009
    1. Fathi M, Vikgren J, Boijsen M, Tylen U, Jorfeldt L, Tornling G, et al. . Interstitial lung disease in polymyositis and dermatomyositis: longitudinal evaluation by pulmonary function and radiology. Arthritis Rheum. (2008) 59:677–85. 10.1002/art.23571
    1. Fathi M, Dastmalchi M, Rasmussen E, Lundberg IE, Tornling G. Interstitial lung disease, a common manifestation of newly diagnosed polymyositis and dermatomyositis. Ann Rheum Dis. (2004) 63:297–301. 10.1136/ard.2003.006122
    1. Saketkoo LA, Ascherman DP, Cottin V, Christopher-Stine L, Danoff SK, Oddis CV. Interstitial lung disease in idiopathic inflammatory myopathy. Curr Rheumatol Rev. (2010) 6:108–19. 10.2174/157339710791330740
    1. Schiffenbauer A, Garg M, Castro C, Pokrovnichka A, Joe G, Shrader J, et al. . A randomized, double-blind, placebo-controlled trial of infliximab in refractory polymyositis and dermatomyositis. Semin Arthritis Rheum. (2018) 47:858–64. 10.1016/j.semarthrit.2017.10.010
    1. Jablonski R, Bhorade S, Strek ME, Dematte J. Recognition and management of myositis-associated rapidly progressive interstitial lung disease. Chest. (2020) 158:252–63. 10.1016/j.chest.2020.01.033
    1. Karino K, Kono M, Kono M, Sakamoto K, Fujieda Y, Kato M, et al. . Myofascia-dominant involvement on whole-body MRI as a risk factor for rapidly progressive interstitial lung disease in dermatomyositis. Rheumatology (Oxford). (2020) 59:1734–42. 10.1093/rheumatology/kez642
    1. Li Y, Gao X, Li Y, Jia X, Zhang X, Xu Y, et al. . Predictors and mortality of rapidly progressive interstitial lung disease in patients with idiopathic inflammatory myopathy: a series of 474 patients. Front Med (Lausanne). (2020) 7:363. 10.3389/fmed.2020.00363
    1. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. . Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. (2016) 194:265–75. 10.1164/rccm.201604-0801CI
    1. Tomiyama F, Watanabe R, Ishii T, Kamogawa Y, Fujita Y, Shirota Y, et al. . High prevalence of acute exacerbation of interstitial lung disease in japanese patients with systemic sclerosis. Tohoku J Exp Med. (2016) 239:297–305. 10.1620/tjem.239.297
    1. Solimani F, Meier K, Ghoreschi K. Emerging topical and systemic JAK inhibitors in dermatology. Front Immunol. (2019) 10:2847. 10.3389/fimmu.2019.02847
    1. Lian X, Zou J, Guo Q, Chen S, Lu L, Wang R, et al. . Mortality risk prediction in amyopathic dermatomyositis associated with interstitial lung disease: the FLAIR model. Chest. (2020) 158:1535–45. 10.1016/j.chest.2020.04.057
    1. Barba T, Mainbourg S, Nasser M, Lega JC, Cottin V. Lung diseases in inflammatory myopathies. Semin Respir Crit Care Med. (2019) 40:255–70. 10.1055/s-0039-1685187
    1. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, et al. . BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. (2008) 68:4774–82. 10.1158/0008-5472.CAN-07-6307
    1. Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. (2014) 349:209–20. 10.1124/jpet.113.208223
    1. Bendstrup E, Wuyts W, Alfaro T, Chaudhuri N, Cornelissen R, Kreuter M, et al. . Nintedanib in idiopathic pulmonary fibrosis: practical management recommendations for potential adverse events. Respiration. (2019) 97:173–84. 10.1159/000495046
    1. Wollin L, Distler JHW, Redente EF, Riches DWH, Stowasser S, Schlenker-Herceg R, et al. . Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases. Eur Respir J. (2019) 54:1900161. 10.1183/13993003.00161-2019
    1. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, et al. . Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. (2011) 365:1079–87. 10.1056/NEJMoa1103690
    1. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. . Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. (2014) 370:2071–82. 10.1056/NEJMoa1402584
    1. Rivera-Ortega P, Hayton C, Blaikley J, Leonard C, Chaudhuri N. Nintedanib in the management of idiopathic pulmonary fibrosis: clinical trial evidence and real-world experience. Ther Adv Respir Dis. (2018) 12:1753466618800618. 10.1177/1753466618800618
    1. Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. . Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. (2019) 380:2518–28. 10.1056/NEJMoa1903076
    1. Kuwana M, Azuma A. Nintedanib: new indication for systemic sclerosis-associated interstitial lung disease. Mod Rheumatol. (2020) 30:225–31. 10.1080/14397595.2019.1696505
    1. Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. . Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. (2020) 8:453–60. 10.1016/S2213-2600(20)30036-9
    1. Lundberg IE, Tjarnlund A, Bottai M, Werth VP, Pilkington C, Visser M, et al. . European league against rheumatism/American college of rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. (2017) 76:1955–64. 10.1136/annrheumdis-2017-212786
    1. Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE, et al. . International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford). (2004) 43:49–54. 10.1093/rheumatology/keg427
    1. Sato T, Teramukai S, Kondo H, Watanabe A, Ebina M, Kishi K, et al. . Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg. (2014) 147:1604–11.e3. 10.1016/j.jtcvs.2013.09.050
    1. Hozumi H, Fujisawa T, Nakashima R, Johkoh T, Sumikawa H, Murakami A, et al. . Comprehensive assessment of myositis-specific autoantibodies in polymyositis/dermatomyositis-associated interstitial lung disease. Respir Med. (2016) 121:91–9. 10.1016/j.rmed.2016.10.019
    1. Horiike Y, Suzuki Y, Fujisawa T, Yasui H, Karayama M, Hozumi H, et al. . Successful classification of macrophage-mannose receptor CD206 in severity of anti-MDA5 antibody positive dermatomyositis associated ILD. Rheumatology (Oxford). (2019) 58:2143–52. 10.1093/rheumatology/kez185
    1. Sato S, Hirakata M, Kuwana M, Suwa A, Inada S, Mimori T, et al. . Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum. (2005) 52:1571–6. 10.1002/art.21023
    1. Abe Y, Matsushita M, Tada K, Yamaji K, Takasaki Y, Tamura N. Clinical characteristics and change in the antibody titres of patients with anti-MDA5 antibody-positive inflammatory myositis. Rheumatology (Oxford). (2017) 56:1492–7. 10.1093/rheumatology/kex188
    1. Mahler M, Betteridge Z, Bentow C, Richards M, Seaman A, Chinoy H, et al. . Comparison of three immunoassays for the detection of myositis specific antibodies. Front Immunol. (2019) 10:848. 10.3389/fimmu.2019.00848
    1. Costabel U, Inoue Y, Richeldi L, Collard HR, Tschoepe I, Stowasser S, et al. . Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified subgroups in INPULSIS. Am J Respir Crit Care Med. (2016) 193:178–85. 10.1164/rccm.201503-0562OC
    1. Kolb M, Richeldi L, Behr J, Maher TM, Tang W, Stowasser S, et al. . Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. (2017) 72:340–6. 10.1136/thoraxjnl-2016-208710
    1. Rodriguez-Portal JA. Efficacy and safety of nintedanib for the treatment of idiopathic pulmonary fibrosis: an update. Drugs R D. (2018) 18:19–25. 10.1007/s40268-017-0221-9
    1. Bonella F, Kreuter M, Hagmeyer L, Neurohr C, Keller C, Kohlhaeufl MJ, et al. . Insights from the German compassionate use program of nintedanib for the treatment of idiopathic pulmonary fibrosis. Respiration. (2016) 92:98–106. 10.1159/000448288
    1. Toellner H, Hughes G, Beswick W, Crooks MG, Donaldson C, Forrest I, et al. . Early clinical experiences with nintedanib in three UK tertiary interstitial lung disease centres. Clin Transl Med. (2017) 6:41. 10.1186/s40169-017-0172-3
    1. Brunnemer E, Walscher J, Tenenbaum S, Hausmanns J, Schulze K, Seiter M, et al. . Real-world experience with nintedanib in patients with idiopathic pulmonary fibrosis. Respiration. (2018) 95:301–9. 10.1159/000485933
    1. Varone F, Sgalla G, Iovene B, Bruni T, Richeldi L. Nintedanib for the treatment of idiopathic pulmonary fibrosis. Expert Opin Pharmacother. (2018) 19:167–75. 10.1080/14656566.2018.1425681
    1. Harari S, Caminati A, Poletti V, Confalonieri M, Gasparini S, Lacedonia D, et al. A real-life multicenter national study on nintedanib in severe idiopathic pulmonary fibrosis. Respiration. (2018) 95:433–40. 10.1159/000487711
    1. Huang J, Beyer C, Palumbo-Zerr K, Zhang Y, Ramming A, Distler A, et al. . Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis. (2016) 75:883–90. 10.1136/annrheumdis-2014-207109
    1. Paniagua RT, Fiorentino DF, Chung L, Robinson WH. Tyrosine kinases in inflammatory dermatologic disease. J Am Acad Dermatol. (2011) 65:389–403. 10.1016/j.jaad.2010.04.026
    1. Liu F, Bayliss G, Zhuang S. Application of nintedanib and other potential anti-fibrotic agents in fibrotic diseases. Clin Sci (Lond). (2019) 133:1309–20. 10.1042/CS20190249
    1. Tzouvelekis A, Karampitsakos T, Kontou M, Granitsas A, Malliou I, Anagnostopoulos A, et al. . Safety and efficacy of nintedanib in idiopathic pulmonary fibrosis: a real-life observational study in Greece. Pulm Pharmacol Ther. (2018) 49:61–6. 10.1016/j.pupt.2018.01.006
    1. Mecoli CA, Christopher-Stine L. Management of interstitial lung disease in patients with myositis specific autoantibodies. Curr Rheumatol Rep. (2018) 20:27. 10.1007/s11926-018-0731-7
    1. Moghadam-Kia S, Oddis CV, Sato S, Kuwana M, Aggarwal R. Antimelanoma differentiation-associated gene 5 antibody: expanding the clinical spectrum in North American patients with dermatomyositis. J Rheumatol. (2017) 44:319–25. 10.3899/jrheum.160682
    1. Kang EH, Go DJ, Mimori T, Lee SJ, Kwon HM, Park JW, et al. . Novel susceptibility alleles in HLA region for myositis and myositis specific autoantibodies in Korean patients. Semin Arthritis Rheum. (2019) 49:283–7. 10.1016/j.semarthrit.2019.03.005
    1. Barratt SL, Blythe T, Ourradi K, Jarrett C, Welsh GI, Bates DO, et al. . Effects of hypoxia and hyperoxia on the differential expression of VEGF-A isoforms and receptors in idiopathic pulmonary fibrosis (IPF). Respir Res. (2018) 19:9. 10.1186/s12931-017-0711-x
    1. Braun RK, Broytman O, Braun FM, Brinkman JA, Clithero A, Modi D, et al. . Chronic intermittent hypoxia worsens bleomycin-induced lung fibrosis in rats. Respir Physiol Neurobiol. (2018) 256:97–108. 10.1016/j.resp.2017.04.010
    1. Suda T, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Naito T, et al. . Interstitial lung diseases associated with amyopathic dermatomyositis. Eur Respir J. (2006) 28:1005–12. 10.1183/09031936.06.00038806
    1. Ito M, Kaise S, Suzuki S, Kazuta Y, Sato Y, Miyata M, et al. . Clinico-laboratory characteristics of patients with dermatomyositis accompanied by rapidly progressive interstitial lung disease. Clin Rheumatol. (1999) 18:462–7. 10.1007/s100670050139
    1. Mukae H, Ishimoto H, Sakamoto N, Hara S, Kakugawa T, Nakayama S, et al. . Clinical differences between interstitial lung disease associated with clinically amyopathic dermatomyositis and classic dermatomyositis. Chest. (2009) 136:1341–7. 10.1378/chest.08-2740
    1. Plestilova L, Mann H, Andres Cerezo L, Pecha O, Vencovsky J, Senolt L. The metastasis promoting protein S100A4 levels associate with disease activity rather than cancer development in patients with idiopathic inflammatory myopathies. Arthritis Res Ther. (2014) 16:468. 10.1186/s13075-014-0468-2
    1. Rider LG, Aggarwal R, Machado PM, Hogrel JY, Reed AM, Christopher-Stine L, et al. . Update on outcome assessment in myositis. Nat Rev Rheumatol. (2018) 14:303–18. 10.1038/nrrheum.2018.33
    1. Kotani T, Takeuchi T, Ishida T, Masutani R, Isoda K, Hata K, et al. . Increased serum LIGHT levels correlate with disease progression and severity of interstitial pneumonia in patients with dermatomyositis: a case control study. PLoS ONE. (2015) 10:e0140117. 10.1371/journal.pone.0140117

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