expert roundtables

Management of Interstitial Lung Disease Associated With Connective Tissue Disease

by Charles D. Burger, MD; Steven D. Nathan, MD; and Justin Oldham, MD, MS

Overview

Connective tissue disease–associated interstitial lung disease (CTD-ILD) represents a nexus of subspecialty interests, where multidisciplinary care can offer many advantages. With regard to pulmonary hypertension (PH), a distinction with CTD-ILD is that there may be uncertainty as to whether the PH falls into group 3 or group 1.

Q:

How is CTD-ILD best managed, and what are some important points for multidisciplinary care?

Charles D. Burger, MD

Professor of Medicine, Mayo Clinic College of Medicine
Consultant, Pulmonary, Allergy, Sleep, and Critical Care Medicine
Medical Director, Pulmonary Hypertension Clinic
Medical Director, Lymphangioleiomyomatosis Clinic
Mayo Clinic
Jacksonville, FL

“Ultimately, a multidisciplinary approach leads to more tailored decisions on the selection of medications, and the management of side effects, as well as improved coordination of care by the pulmonary and rheumatology subspecialists.”

Charles D. Burger, MD

A multidisciplinary approach to CTD-ILD, combining the efforts of pulmonologists and rheumatologists, is important across a range of issues. This type of approach fosters a larger view of the patient as a whole human being, with potentially multiple manifestations of their disease that may impact their lives and/or require lifelong treatment.

Bidirectional communication between pulmonology and rheumatology also brings distinct insights to the point of care more quickly and efficiently, and patients tend to be appreciative of that. For example, my background is primarily in pulmonary vascular disease, and keeping up with all of the medications for treating PH over the decades has been part of this niche; likewise, rheumatologists today really have seen an explosion in disease-modifying biologics, and these agents have implications for the inflammatory state and therefore the ILD component of the CTD. So, having that communication with rheumatologists enables a more tailored and coordinated approach to both diagnosis and treatment.

Patients with systemic sclerosis (SSc) are at risk for both ILD and PH, which may occur together or in isolation. Several PH screening guidelines have been developed. DETECT and ASIG, for instance, are 2 screening algorithms that have shown good sensitivity. Additionally, the majority of patients with SSc have esophageal dysfunction, and with that there is the potential for severe gastroesophageal reflux disease and damage to the lungs through microaspiration, which can impact candidacy for lung transplantation.

Polymyositis/dermatomyositis may be associated with nonspecific interstitial pneumonitis, which seems both clinically and radiographically to be an entity that is in the inflammatory state. It has historically been more responsive to corticosteroids, and advancements have been made in identifying the potential for other immunomodulatory agents, so, again, that ongoing coordination between pulmonary and rheumatology is important.

Ultimately, a multidisciplinary approach leads to more tailored decisions on the selection of medications, and the management of side effects, as well as improved coordination of care by the pulmonary and rheumatology subspecialists.

Steven D. Nathan, MD

Medical Director
Advanced Lung Disease and Transplant Program
Inova Fairfax Hospital
Falls Church, VA

“We have a lower threshold to screen for PH in CTD-ILD than in an entity such as IPF. Additionally, there may be some uncertainty regarding whether the PH in CTD-ILD is true group 1 (ie, PAH) vs group 3 PH resulting from the lung disease. This is not the case for an entity such as IPF, which is group 3 by definition.”

Steven D. Nathan, MD

The extent to which pulmonology and rheumatology may be involved in CTD-ILD treatment and management differs on a case-by-case basis. In one patient, joint manifestations may be present in addition to lung manifestations, with both being addressed simultaneously by both specialists. Conversely, lung disease may be the only manifestation in another patient, in which case the lung disease would often be the driver of treatment for that patient.

There are several distinctions that can be drawn between the approach to patients with CTD-ILD as opposed to an entity such as idiopathic pulmonary fibrosis (IPF). One is that we have a lower threshold to screen for PH in CTD-ILD than in an entity such as IPF. Additionally, there may be some uncertainty regarding whether the PH in CTD-ILD is true group 1 (ie, pulmonary arterial hypertension [PAH]) vs group 3 PH resulting from the lung disease. This is not the case for an entity such as IPF, which is group 3 by definition. As Dr Burger noted, CTD can cause ILD but it may also cause PAH, and the 2 may coincide in the same patient, or just 1 of the 2 may develop, or neither may develop. Thus, annual screening for PH is recommended for patients with CTDs such as SSc. If present, group 1 (PAH) tends to be more severe than group 3 PH, and we do have US Food and Drug Administration–approved therapies for group 1. Clinicians are faced with the difficult conundrum as to whether PH is due to the lung disease or a primary vasculopathy that would have developed independent of the lung disease.

Justin Oldham, MD, MS

Assistant Professor of Medicine
Director, Interstitial Lung Disease Program
University of California, Davis
Sacramento, CA

“Patients with SSc or mixed CTD will generally develop group 1 PH at a higher prevalence than those with an idiopathic inflammatory myopathy or rheumatoid arthritis. So, understanding the CTD that you are dealing with will also inform the comorbid work-up.”

Justin Oldham, MD, MS

As relates to factors linked to the development of pulmonary vascular disease in ILD, most of what we see is group 3, but in those with CTD-ILD, group 1 is certainly a possibility and understanding that not all patients with CTD will develop PH at the same prevalence is important. Patients with SSc or mixed CTD will generally develop group 1 PH at a higher prevalence than those with an idiopathic inflammatory myopathy or rheumatoid arthritis. So, understanding the CTD that you are dealing with will also inform the comorbid work-up.

There was an abstract based on a phase 3 study of tocilizumab for the treatment of SSc. The primary end point was not met, but lung function preservation was seen in patients with SSc-ILD treated with tocilizumab when compared with the placebo group.

First-line therapy in patients with non-IPF ILD and in those with mixed inflammatory fibrotic lung diseases, such as CTD or hypersensitivity pneumonitis, is a big unknown at this point.

References

Almaaitah S, Highland KB, Tonelli AR. Management of pulmonary arterial hypertension in patients with systemic sclerosis. Integr Blood Press Control. 2020;13:15‐29. doi:10.2147/IBPC.S232038

Coghlan JG, Denton CP, Grünig E, et al; DETECT Study Group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340-1349. doi:10.1136/annrheumdis-2013-203301

Denton CP, Lin CJF, Goldin J, et al. Lung function preservation in a phase 3 trial of tocilizumab (TCZ) in systemic sclerosis (SSc). Eur Respir J. 2019;54(suppl 63):RCT1883. doi:10.1183/13993003.congress-2019.RCT1883

Distler O, Highland KB, Gahlemann M, et al; SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518‐2528. doi:10.1056/NEJMoa1903076

Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177. doi:10.1016/j.rec.2016.01.002

Khanna D, Lin CJF, Kuwana M, et al. Efficacy and safety of tocilizumab for the treatment of systemic sclerosis: results from a phase 3 randomized controlled trial [abstract 898]. Arthritis Rheumatol. 2018;70(suppl 10). Accessed July 14, 2020. https://acrabstracts.org/abstract/efficacy-and-safety-of-tocilizumab-for-the-treatment-of-systemic-sclerosis-results-from-a-phase-3-randomized-controlled-trial/

Mena-Vázquez N, Godoy-Navarrete FJ, Manrique-Arija S, et al. Non-anti-TNF biologic agents are associated with slower worsening of interstitial lung disease secondary to rheumatoid arthritis. Clin Rheumatol. 2020 Jun 16. doi:10.1007/s10067-020-05227-9

Oliveira RP, Ribeiro R, Melo L, Grima B, Oliveira S, Alves JD. Connective tissue disease-associated interstitial lung disease. Pulmonology. 2020 Feb 11. doi:10.1016/j.pulmoe.2020.01.004

Thakkar V, Stevens WM, Prior D, et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther. 2012;14(3):R143. doi:10.1186/ar3876

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