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Scleroderma
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
In the past ten years, there have been significant advancements in the management and treatment of systemic sclerosis. The FDA approval of two medications—nintedanib and tocilizumab—in the treatment of SSc-associated ILD represents major achievements as no approved treatment existed in the past. Nintedanib is to be used in combination with mycophenolate as an antifibrotic to prevent further progression of SSc-associated ILD. Tocilizumab is to be used early in the management of ILD, especially in those patients at high risk of progression whose laboratory values demonstrate elevated inflammatory markers. With multiple randomized clinical trials in the treatment of diffuse cutaneous SSc in the past five years and more such trials on the horizon, prospects for effective drug therapy to treat this complex autoimmune disease are promising, and the future of scleroderma care looks brighter than ever.
Case 20
Published in Andrew Solomon, Julia Anstey, Liora Wittner, Priti Dutta, Clinical Cases, 2021
Andrew Solomon, Julia Anstey, Liora Wittner, Priti Dutta
There are two new agents whose mechanism of action suggests promising potential for efficacy to treat these conditions; nintedanib and pirfenidone. Nintedanib inhibits tyrosine kinase receptors and thus seems to interfere with vascular endothelial growth factor (VEGF) and fibroblast growth factor action thus reducing fibrosis. Pirfenidone appears to have anti-inflammatory and fibrotic-reducing activity.
Pulmonary fibrosis
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Priya Muralidharan, Don Hayes, Heidi M. Mansour
Among the currently available drugs, pirfenidone is an antifibrotic with anti-inflammatory properties, which inhibits the synthesis of growth factors responsible for fibrogenesis. The therapeutic dose given orally is a high dose of 801 mg three times daily. This has been shown to have some gastrointestinal (GI) side effects, including nausea, abdominal pain, dyspepsia, and diarrhea in addition to photosensitivity and rash (14). Nintedanib is a tyrosine kinase receptor inhibitor targeting growth factors that eventually attenuates fibrosis development (15). It is given as 150 mg capsules twice daily orally. Nintedanib is also known to cause GI side effects such as diarrhea, nausea, abdominal pain, and vomiting and liver enzyme elevation. Although nintedanib received a conditional recommendation for its clinical use, the other tyrosine kinase receptor inhibitor imatinib was not recommended for IPF treatment. The committee has strongly recommended against the use of imatinib due to the high cost incurred and the lack of effective benefit from the clinical trial involving 119 patients (16). The use of corticosteroids is also limited due to the reduced clinical benefit. It is recommended only for acute disease exacerbations (15). Anti-GER therapies such as proton pump inhibitors or histamine 2 blocker receptor antagonists are commonly prescribed for IPF patients since GER is commonly seen in IPF patients.
DNA methylation in pulmonary fibrosis and lung cancer
Published in Expert Review of Respiratory Medicine, 2022
Juan Duan, Baiyun Zhong, Zhihua Fan, Hao Zhang, Mengmeng Xu, Xiangyu Zhang, Yan Y Sanders
In addition to these similarities, lung cancer and lung fibrosis share some common pathogenesis mechanisms and treatment methods, such as uncontrolled cell proliferation and aberrant activation of specific signaling pathways, and one anti-cancer agent, nintedanib, has been approved for the treatment of lung fibrosis [10]. Aberrant DNA methylation also contributes to pulmonary fibrosis and lung cancer development and progression [11,12]. For example, hypomethylation of oncogenes and hypermethylation of tumor suppressor genes are established pathogenic mechanisms in most tumors [13]. Similar findings have been reported in IPF, in which hypermethylation-silenced antifibrotic genes have been reported [14]. Genome-wide DNA methylation studies have revealed that differentially methylated cytosine phosphate guanine (CpG) islands overlap in lung cancer and IPF, suggesting common pathogenetic pathways between these two diseases, prompting us to explore DNA methylation as an epigenetic link between lung cancer and fibrosis [15]. In this review, we summarize the role of DNA methylation in lung cancer and fibrosis and its potential clinical applications as epigenetic markers and treatment targets.
Nintedanib: New indication for systemic sclerosis-associated interstitial lung disease
Published in Modern Rheumatology, 2020
Diarrhea is the most common adverse event. In most patients, the event occurs within the first 3 months of treatment. Most of the events are of mild or moderate intensity and were managed by symptomatic treatment, but temporary interruption and/or dose reduction of the nintedanib dose are required in some patients. In the INPULSIS trials in patients with IPF, diarrhea was reported in 62% versus 18% of patients treated with nintedanib and placebo, respectively [4]. Diarrhea led to dose reduction of nintedanib in 11% of the patients and to discontinuation of nintedanib in 4%. In the SENSCIS trial in patients with SSc-ILD, diarrhea was reported in 76% versus 32% of patients treated with nintedanib and placebo, respectively [5]. Diarrhea led to dose reduction of nintedanib in 22% and to discontinuation of nintedanib in 7%. Although there is no clear correlation between pharmacokinetics of nintedanib and diarrhea, dose reduction often improves the symptom. The frequency of diarrhea was higher in patients with SSc-ILD than in those with IPF in both treatment groups, probably because of underlying GI involvement in SSc patients, and concomitant use of mycophenolate in almost half of the patients. Diarrhea should be treated at first signs with adequate hydration and anti-diarrheal medications, e.g. loperamide and pro-biotics. If symptomatic treatment does not relief the symptom, nintedanib should be reduced in the dosage or interrupted. Nintedanib may be resumed, but start at a reduced dose (100 mg twice daily) is preferable. In case of persisting severe diarrhea despite symptomatic treatment, nintedanib should be discontinued.
Effect of nintedanib on airway inflammation in a mouse model of acute asthma
Published in Journal of Asthma, 2020
Jongmin Lee, Chin Kook Rhee, Jong Hyuk Lee, Hyon Jee Yoon, In Kyoung Kim, Jung Hur, Ji Young Kang, Hyoung Kyu Yoon, Sook Young Lee, Young Kyoon Kim
Nintedanib treatment was performed using our previously described protocol [19]. Dry nintedanib powder (Biovision, Inc., Milpitas, CA, USA) was dissolved in 10% ethanol, yielding a solution of 0.01 g nintedanib/mL. The final concentration of the ethanol used in the preparation of nintedanib was 5% EtOH for 50 mg/kg and 10% EtOH for 100 mg/kg. The nintedanib solution was further diluted using PBS. Allergen-sensitized mice were administered 50 or 100 mg nintedanib/kg in 0.2 mL of solution, via oral gavage. Nintedanib was administered once per day via oral gavage on Days 21 through 25. An additional, final nintedanib dose was administered on Day 28. Control mice underwent nearly identical procedures; however, 0.2 mL PBS was used in place of nintedanib solution during oral gavage.