Thoracic Manifestations in Connective Tissue Disease: A Review

Thoracic manifestations are common in connective tissue disease (CTD) — also called collagen vascular disease — which includes syndromes as diverse as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma or systemic sclerosis (SSc), dermatomyositis (DM)/polymyositis (PM), Sjögren’s syndrome (SS), ankylosing spondylitis (AS), and mixed connective tissue disease (MCTD).^1-3 These pathologies are all immunologically-mediated systemic inflammatory disorders characterized by antibody profusion and organ damage, with the lungs as a common target.^1,4,5

Pulmonary and thoracic symptoms often coincide with the initial presentation of CTD, although some appear years before clinical manifestations arise. The patterns vary widely, and may be idiopathic features of the original disorder or occur as a result of drug toxicity or opportunistic infections associated with treatments.¹

Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the two most commonly identified thoracic conditions associated with CTD; both are associated with high morbidity and mortality rates.^1,2,5

Interstitial lung disease

It may be difficult to separate idiopathic ILD from ILD associated with CTD because of irregular patterns of presentation and similar morphology on thoracic high-resolution computed tomography (HRCT) images,  although some distinguishing features have been identified.^1,4,5 According to a 2016 review, arthropathy on imaging is suggestive of RA, while disproportionate esophageal dilation and pulmonary artery enlargement to lung fibrosis indicates SSc. In addition, soft tissue calcification points to DM or SSc, and pleural or pericardial effusion or thickening to SLE.⁵

Differential diagnosis generally relies on clinical and demographic features; CTD-related ILD is more frequent in younger, female patients, and more likely to demonstrate multicompartmental thoracic involvement of lung parenchyma, airways, pleura, vasculature, and pericardium, when compared with idiopathic cases. The presence of Raynaud’s syndrome, articular involvement, or mediastinal lymphadenopathy is indicative of extrathoracic symptoms that point to CTD involvement.^4,6,7 Serologic tests may help identify treatment-related causes, which can confuse HRCT readings.^6-8

ILD Subtypes

• Nonspecific interstitial pneumonia (NSIP) is the most common type of CTD-related ILD, occurring more frequently than idiopathic ILD in the presence of SSc, DM/PM, or MCTD, and sometimes manifesting earlier than other symptoms.^5,9,10 Researchers therefore recommend that “CTDs … be thoroughly investigated in patients who present with an NSIP pattern of ILD without extrathoracic manifestations of CTD.”⁵
• Usual Interstitial Pneumonia (UIP) is the most common form of ILD seen in RA and the second most common ILD. UIP presents histopathologic and radiologic evidence of heterogeneous patterns of patchy fibrotic scarring and honeycombing alternating with normal lung tissue.^1,5
• Although NSIP and UIP may appear similar on HRCT, NSIP responds better to corticosteroid therapy and has a better prognosis than UIP.¹
• Other prominent, but less common forms of CTD-related ILD include organizing pneumonia (OP), and lymphoid interstitial pneumonia (LIP).

Pulmonary Arterial Hypertension (PAH)

PAH is characterized by a mean resting pulmonary artery pressure ≥25 mmHg with pulmonary capillary wedge pressure ≤15 mmHg, and is often comorbid with SSc with or without ILD.¹³

Implications of Thoracic Abnormalities by CTD

Each CTD is associated with a unique set of abnormalities detected on HRCT. By teasing out the differences, clinicians can attempt to optimize responses to available therapies.

Rheumatoid arthritis affects 1% of the global population, favoring women age 25 to 50 at a 3:1 ratio, with higher risks of pulmonary manifestations in men, and about two-thirds of patients remaining asymptomatic using standard physiologic testing.¹⁴ Risks increase with smoking. Mortality in patients with RA and ILD is 3-fold higher than in individuals with RA only. A number of drugs used to treat RA may lead to the appearance of symptoms associated with ILD and increase the risks of opportunistic infections, thus initiating a cycle of chronic lung disease.

The most common HRCT-detected thoracic abnormalities in RA include bronchial wall thickening, which is detected in 12% to 92% of cases, and bronchial dilation in 30% to 40% of individuals.^3,15,16 Other CT features are distributed in patterns unique to each patient, including parenchymal micronodules reported in 15% to 20%, reticular abnormality in 10% to 20%, pleural opacity in 16%, ground glass opacities in 15% to 25%, honeycombing in 10%, and consolidation in 5%. ^3,15,16

In SSc, up to 75% of patients are found to have ILD on autopsy, nearly 80% in the form of NSIP. Patients with UIP tend to fare worse, as fibrotic NSIP has shown limited response to treatment.^4,5,7

More than 50% of DM/PM cases have thoracic manifestations  — most commonly NSIP and OP  — and are associated  with high rates of morbidity and mortality. ⁵ Patients with SSc will most often develop NSIP, although LIP, UIP, OP and amyloidosis are also reported. Pleural involvement is rare, but patients with SSc have a 16- to 44-times higher risk of developing lymphoma — usually non-Hodgkin’s lymphoma — with a good prognosis. ^5,17-19 Pleural involvement is also rare in AS, in which radiologic changes tend to progress slowly over many years.³

In contrast, pleural disease is the most common thoracic feature of SLE, presenting as chest pain, fever, cough, and dyspnea. Pleural infections such as community-acquired pneumonia are associated with high rates of morbidity and mortality in these patients.⁵ At the same time, ILD is rare in SLE, with 3% of patients affected.⁵

In MCTD, which captures mixed, overlapping features from several CTDs, both radiographic and clinical evidence tends to support thoracic involvement in 20% to 80% of cases. As with SLE, SSc, RA, or DM/PM, ILD, and PAH are the most significant complicating thoracic manifestations, with NSIP being the most common ILD pattern observed.¹

Summary

Despite tremendous heterogeneity among CTDs and substantial overlapping thoracic manifestations, careful attention to histologic and radiographic subtleties of thoracic presentations can help make important distinctions between idiopathic thoracic disease and CTD-related forms and better inform therapeutic decisions.

References

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