ReviewLung involvement in connective tissue diseases: A comprehensive review and a focus on rheumatoid arthritis
Introduction
Lungs are often involved in connective tissue diseases (CTDs), with a noticeable effect on morbidity and mortality. The term “interstitial lung disease” (ILD) embraces a group of disorders characterized by inflammation and possibly pulmonary interstitial fibrosis, whose progression results in impaired oxygen transfer and scarring of the lung.
An ILD may be the first sign of a CTD and may precede extrapulmonary manifestations by years. ILDs may occur in all CTDs (overall incidence of 15%) and most often in Systemic Sclerosis (SSc), which justifies autoimmune screening in all patients with apparent idiopathic ILDs. A population-based study reported that 3.5% of patients with Rheumatoid Arthritis (RA) were diagnosed as having ILD prior to RA diagnosis [1]. Their prognosis and treatment varies depending upon the underlying CTD and radiological and histopathological patterns [2]. Around 25% of ILDs occur during “undifferentiated” CTDs (UCTDs), making it hard to distinguish them from an idiopathic interstitial alternative or a lung-dominant CTD [3].
A combination of patterns is frequently observed. Therefore finding abnormalities in more than one compartment upon imaging, histological or clinical analysis is a possible trait of an underlying CTD (Table 1). ILDs may be asymptomatic, but may be identified with high resolution computed tomography (HRCT) or pulmonary function tests (PFTs) [4] that are essential in determining the clinical significance of lung impairment [5]. However clear parameters for ILD staging have only been developed for SSc [3]. Very-low-radiation dose HRCT is much more sensitive in detecting changes in the parenchyma than chest X-rays [6], and can identify interstitial involvement in otherwise healthy asymptomatic patients, as reported by Winklehner et al. [7]. Detailed analysis has shown good correspondence between HRCT abnormalities and histopathological sub-classification in cases where lung biopsy was carried out [8]. Bronchoalveolar Lavage (BAL) may be useful in excluding infections, although there is still some concern over whether BAL cellular profiles have a prognostic meaning [9], [10].
Section snippets
The 2002 American Thoracic Society/European Respiratory Society Revised Classification
The American Thoracic Society/European Respiratory Society (ATS/ERS) revised the original classification in 2002 replacing the term ILD with diffuse parenchymal lung disease (DPLD), thus emphasizing that the parenchyma is the first site of damage and shifting the emphasis from histopathology to pathophysiology. These disorders are classified into four groups: 1) DPLDs of known association (drugs, CTDs, environmental and occupational exposure), 2) granulomatous DPLDs (such as sarcoidosis), 3)
Idiopathic usual interstitial pneumonia vs. idiopathic non-specific interstitial pneumonia
Distinguishing UIP from NSIP has important prognostic implications: idiopathic UIP/IPF has a poor prognosis and lacks an appropriate treatment, whereas idiopathic NSIP has a good prognosis, with a five-year mortality rate of under 18% [28], and responds to anti-inflammatory treatment. The NSIP pattern affects middle-aged women, is more common in CTDs [29] and is found in several disorders, such as hypersensitivity pneumonitis [28]. The histopathology of fibrotic NSIP is characterized by
Rheumatoid arthritis and interstitial lung disease
RA is the most frequent CTD, with a prevalence of 1–2% in the general population and female to male ratio of 3:1. Extra-articular manifestations are found in nearly 50% of RA patients [68], including splenomegaly, pericarditis, skin ulceration, subcutaneous nodules, increased rate of atherosclerotic artery disease and a multiplicity of pleuropulmonary manifestations [3]. Several studies [69], [70], [71], [72], [73], [74], [75], [76] have reported impairment of one or more parts of the
Therapy
Every lung treatment strategy must include supportive care. Best supportive and palliative care approaches always play a central role and include:
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treatment of gastroesophageal reflux
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pulmonary rehabilitation
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low doses of opiates when dyspnoea is immovable
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oxygen therapy when mild to severe hypoxia occurs at rest and during exercise, and
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annual influenza and regular pneumococcal vaccination are recommended to reduce the risk of pulmonary infection.
Conclusions
All new RA patients should be assessed by establishing their basic respiratory history (smoking, cough and dyspnoea) and by examination (nail clubbing and basal crackles). Those with possible ILD and patients commencing methotrexate and anti-TNF biologic agent have to perform a chest X-ray and undergo PFTs (spirometry and DLCO). According to the British Society for Rheumatology guidelines, HRCT is required if abnormalities are found in order to determine whether the extent of lung involvement
Disclosure statement
The authors declare no conflicts of interest.
Take-home messages
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ILDs complicate the natural course of CTDs and have a negative prognostic value.
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RA-ILD has a more aggressive behavior than other CTD-ILDs, which resembles IPF.
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It is important to detect ILDs during CTDs promptly in order to start treatment early.
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