Management of Connective Tissue Disease–related Interstitial Lung Disease

Current Pulmonology Reports https://doi.org/10.1007/s13665-022-00290-w INTERSTITIAL LUNG DISEASE (S DHOORIA, SECTION EDITOR) Management of Connective Tissue Disease–related Interstitial Lung Disease Sakir Ahmed1 · Rohini Handa2 Accepted: 5 April 2022 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022 Abstract Purpose of Review This review aims to collate current evidence on the screening, diagnosis, and treatment of various connective tissue disease (CTD)–associated interstitial lung diseases (CTD-ILD) and present a contemporary framework for the management of such patients. It also seeks to summarize treatment outcomes including efficacy and safety of immunosuppressants, anti-fibrotics, and stem cell transplantation in CTD-ILD. Recent Findings Screening for ILD has been augmented by the use of artificial intelligence, ultra-low dose computerized tomography (CT) of the chest, and the use of chest ultrasound. Serum biomarkers have not found their way into clinical practice as yet. Identifying patients who need treatment and choosing the appropriate therapy is important to minimize the risk of therapy-related toxicity. The first-line drugs for systemic sclerosis (SSc) ILD include mycophenolate and cyclophosphamide. Nintedanib, an anti-fibrotic tyrosine kinase inhibitor, is approved for use in SSc-ILD. The US Food and Drug Administration (FDA) has recently approved tocilizumab subcutaneous injection for slowing the rate of decline in pulmonary function in adult patients with SSc-ILD. Autologous stem cell transplantation may have a role in select cases of SSc-ILD. Summary CTD-ILD is a challenging area with diverse entities and variable outcomes. High-resolution CT is the investigative modality of choice. Treatment decisions need to be individualized and are based on patient symptoms, lung function, radiologic abnormalities, and the risk of disease progression. Precision medicine may play an important role in determining the optimal therapy for an individual patient in the future. Keywords Lung fibrosis · Connective tissue disease · Interstitial pneumonia with autoimmune features · CTD-ILD · Treatment Introduction Interstitial lung disease (ILD) occurring in a person with a known or classifiable connective tissue disease (CTD) is termed CTD-ILD. Approximately 15% of ILDs will have This article is part of the Topical Collection on Interstitial Lung Disease * Rohini Handa Sakir Ahmed 1 Department of Clinical Immunology & Rheumatology, Kalinga Institute of Medical Sciences (KIMS), KIIT University, Bhubaneswar, India 2 Indraprastha Apollo Hospitals, New Delhi, India a background CTD [1]. Very often presence of ILD is the major determinant of mortality in a patient with a CTD [2••]. In systemic sclerosis (SSc), around 30% have symptomatic ILD and this is associated with 10-year mortality of 40% [3, 4]. For rheumatoid arthritis, severe interstitial lung disease is often reported in 2–8% while active case finding estimates are around 8–80% [5–7••]. In mixed connective tissue disease (MCTD), around 50% have ILD on CT imaging [8]. Again, in idiopathic inflammatory myositis (IIM) cohorts, there is a wide variation in the prevalence of ILD from 20 to 78% depending on the methods used to define ILD [9]. At times, a patient may have an ILD with some features of CTDs such as Raynaud or ANA (anti-nuclear antibody) positivity but not meet the criteria for any CTD. Previously, different names have been proposed for such entities such as lung dominant CTD [10]. However, with the description of the criteria for interstitial pneumonia with autoimmune 13 Vol.:(0123456789) Current Pulmonology Reports features (IPAF), this term is now widely used in the literature [11••]. The emergence of the concept of IPAF stems from the recognition that the presence of autoimmune features predicts response to treatment, and hence, favourable prognosis [12]. Thus, clinical significance is attached to the differentiation of CTD-ILD and IPAF from idiopathic pulmonary fibrosis (IPF). IPF to CTD-ILD appears to be a continuous spectrum bridged by IPAF [13]. The component of autoimmunity is most prominent CTD-ILD, lesser in IPAF and minimal in IPF. This implies that immunosuppressant therapies have better outcomes in CTD-ILD than in IPAF, and possibly are harmful in IPF [14]. The last decade has seen a sea change in the concept of treatment of CTD-ILD from stem cell transplantation for systemic sclerosis (SSc)–ILD to the change in the dogma of avoiding methotrexate in CTD-ILD [3, 15]. Also, of the antifibrotic agents for IPF, nintedanib has shown promise even in CTD-ILD [16••]. The precipitous arrival of the COVID19 has shown that the presence of ILD is an additional risk factor necessitating rational use of immunosuppressants in such patients [17]. Literature Search Strategy A literature search was made on Scopus and MEDLINE/ Pubmed with search terms “connective tissue disorder” or equivalent terms, “interstitial lung disease” or equivalent terms; “interstitial pneumonia with autoimmune features” and “management” or “treatment.” The search was restricted to the last 3 years. The bibliography of selected articles was also scanned for additional relevant articles. The authors have focussed on recent articles but have included older articles also if they have particular relevance to current treatment strategies as per recommendations for a biomedical review [18]. promoter region polymorphisms have been associated with ILD at large, and also with RA-ILD [20]. In rheumatoid lung disease, the same mucosal pathological factors associated with precipitation of arthritis such as smoking or air pollutants and microbiota may also contribute to the genesis of bronchial epithelial injury [21]. Transforming growth factor-β (TGF-β), endothelin-1, and platelet-derived growth factor (PDGF) are major players in the pathogenesis of fibrosis in the setting of SSc. These lead to an endothelial mesenchymal transition (EMT) of the epithelial cell that predisposes to fibroblasts converting to myofibroblasts and leading to fibrosis [22]. The role of autoantibodies has been proposed but not fully established [23]. Knowledge of Pathogenesis Helps in Management Elucidating the pathogenesis enables the evolution of targeted therapies [24]. The initial trials targeting TGF-β or its receptors met with mixed success [25, 26]. This might have been due to the pleiotropic effects of TGF-β as well as various redundant canonical and non-canonical downstream pathways. However, exploring the role of interleukin-6(IL-6) has led to good results with the IL-6 receptor antagonist tocilizumab. The use of subcutaneous tocilizumab led to both improvement of the modified Rodnan skin score and stabilization of functional vital capacity (FVC) [27••]. Similarly, interleukin-17 and PD-1 (programmed cell death protein1) have a role in SSc-mediated fibrosis [28]. Since there are clinical (...truncated)