Detecting Connective Tissue Disease-Associated Interstitial Lung Disease: What Are Current Screening Strategies?

Kimberly Showalter, MD, MS; Jessica K. Gordon, MD, MS


January 19, 2022

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Medscape &

Dr Kimberly Showalter

Interstitial lung disease (ILD) is a leading cause of morbidity and mortality among individuals with systemic sclerosis (SSc)[1] and also negatively affects survival for those with other connective tissue diseases (CTD), including rheumatoid arthritis (RA),[2] Sjogren’s syndrome,[3] and myositis.[4] Symptoms of ILD include cough and shortness of breath; however, some patients, even those with a high burden of radiographic ILD changes, may have few or no symptoms.[5]

Dr Jessica Gordon

Further, it is increasingly recognized that early identification and treatment is key to improving outcomes for individuals with CTD-ILD. Indeed, currently approved treatments have been shown to prevent ILD progression rather than yield large improvements in pulmonary function. Therefore, it is essential for rheumatologists and other treating physicians to recognize known risk factors associated with ILD development and progression and to screen at-risk patients with appropriate testing.

Incidence, Risk Factors, and Screening for CTD-ILD

Systemic Sclerosis. Depending on the modality of detection used, ILD may be present in >80% of individuals with SSc. Risk factors for progressive SSc-ILD include male sex; African American race; diffuse subtype; anti-Scl-70 autoantibody positivity; nucleolar ANA; elevated C-reactive protein; baseline forced vital capacity (FVC) <70% of predicted; baseline diffusing capacity of carbon monoxide (DLCO) <55% of predicted; and greater extent of fibrosis on high-resolution computed tomography (HRCT) (>20%).[6,7,8,9]

All patients with SSc, regardless of pulmonary symptoms, should be screened for the presence of ILD. In addition to a thorough history of physical exam, complete pulmonary function tests (PFT) are recommended. The pattern of PFT abnormality can help differentiate the type of pulmonary involvement in an individual; however, normal parameters at baseline do not exclude the presence of ILD, as PFTs have suboptimal sensitivity for the detection of SSc-ILD.[5,10] In a patient with normal baseline PFTs, but with other risk factors (eg, diffuse cutaneous SSc [dcSSc] or Scl-70 positivity), HRCT should be performed.

In very low-risk patients (those with early limited cutaneous SSc), one could consider following annual PFTs rather than HRCT imaging. Chest x-ray imaging is insensitive and does not rule out ILD. Patients without ILD on HRCT at baseline should be followed longitudinally with PFT, as often as every 4-6 months in high-risk individuals within the first 3-5 years of disease, and at least annually in all dcSSc patients.

Rheumatoid Arthritis. The prevalence of RA-ILD varies widely between studies (1%–58%) and may precede joint involvement in up to 20% of individuals.[11,12] Known risk factors for RA-ILD include smoking, older age, male sex, and high titer anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF).[13,14] Serum KL-6 (a glycoprotein expressed on pneumocytes) has also been shown to be associated with RA-ILD, when adjusting for clinical risk factors,[15] and genetic risk factors have also been described.[16] Physicians should assess for pulmonary disease with detailed history and exam at follow-up appointments; however, no specific studies have yet validated a screening approach for RA-ILD in asymptomatic individuals.[17] If RA-ILD is suspected clinically, the diagnosis may be confirmed by chest HRCT and PFTs.

Sjögren syndrome. An estimated 10%–20% of individuals with Sjögren's have pulmonary complications, including ILD.[3] In 2021, a consensus guideline was released for management of Sjögren-associated ILD.[18] This guideline recommends screening patients with Sjögren's without respiratory symptoms by (1) performing a chest x-ray at baseline, (2) evaluating clinically for pulmonary involvement at each visit, and (3) considering full PFT. If an individual has normal PFT and chest x-ray, no further work up is recommended and patients should be followed clinically. If patient has abnormal chest x-ray or PFT, an HRCT scan of the chest is recommended. For patients with Sjögren's with a cough, physicians should assess for lung disease with (1) full PFT and (2) chest HRCT. If those tests are unremarkable, physicians should consider other causes of cough, including gastroesophageal reflux and xerotrachea. 

Myositis. The prevalence of pulmonary parenchymal disease among individuals with myositis has been estimated to be between 20%–86%.[4] In a large meta-analysis of 834 patients and 1245 controls, risk factors for myositis-associated ILD were older age, arthritis, fever, Jo-1 antibody, anti-MDA-5 antibody, and elevated inflammatory markers (C-reactive protein and erythrocyte sedimentation rate).[19] Conversely, malignancy was associated with a reduced risk for myositis-associated ILD (odds ratio, 0.35; 95% CI, 0.18 - 0.72; P = .004).[19] Patients with inflammatory myositis should be clinically assessed for pulmonary involvement, including a focused history regarding respiratory symptoms and physical exam. Abnormal exam findings or respiratory symptoms should prompt imaging studies (eg, chest HRCT) and PFTs.

Together these may differentiate between ILD and respiratory muscle weakness, the latter of which causes restrictive PFT without pulmonary parenchymal abnormalities on HRCT imaging. Some experts also advocate for screening HRCT in all patients at high risk for ILD, such as those with MDA-5 or anti-synthetase antibodies. There is no correlation with muscle and skin disease,[4] and so physicians should assess organ-specific disease activity independently.

In conclusion, it is essential for physicians to be aware of known ILD risk factors, symptoms, and screening recommendations when caring for patients with connective tissue diseases. This knowledge will facilitate a timely diagnosis of pulmonary involvement and will enable early treatments to improve patient outcomes.

Kimberly Showalter, MD, MS, is an assistant professor in the department of medicine at Weill Cornell Medical College and assistant attending physician in the division of rheumatology at Hospital for Special Surgery, New York City. Jessica K. Gordon, MD, MS, is an associate professor of clinical medicine at Weill Cornell Medical College and associate attending physician in the division of rheumatology at Hospital for Special Surgery, New York City.

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