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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Pulmonology

      Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD)

      Updated: Aug 06, 2020
      • Author: Aniruddh Kapoor, MBBS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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      Overview

      Background

      Connective tissue diseases (CTDs) (also referred to as collagen vascular diseases [CVDs], because collagen is typically affected, and there may be a vascular component) are a heterogeneous group of disorders characterized by the presence of autoantibodies, such as systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis (DM)/polymyositis (PM), ankylosing spondylitis (AS), Sjögren syndrome (SS), undifferentiated connective tissue disease (UCTD), and mixed connective-tissue disease (MCTD). [1] Many experts include the antineutrophil cytoplasmic autoantibody (ANCA)-related vasculitides and Goodpasture syndrome in this group because of the presence of autoantibodies. [2]

      Similarly, interstitial lung diseases (ILDs) are a heterogeneous group of lung disorders—characterized by parenchymal lung injury as a consequence of systemic autoimmunity—classified on the basis of their radiologic as well as histopathologic features. Several etiologic factors may result in the development of ILD, including idiopathic, familial, environmental or occupation exposures, radiation, infections, or CTDs. CTDs account for 15% of ILD (CTD-ILD) [3, 4] ; they can involve the lungs either directly or through drug toxicities from their treatment. Several different components of the respiratory system may be involved, including the airways, vessels, parenchyma, pleura, and respiratory muscles. Unfortunately, ILDs are a common pulmonary complication of the CTDs and are responsible for significant mortality and morbidity. [4] In fact, the presence of ILDs in CTDs is associated with a poor prognosis. [5, 6]

      Almost all autoimmune conditions have been associated with the occurrence of ILD, and these may be the initial and possibly sole manifestation of an otherwise occult CTD. [7, 8] It has been suggested that some patients with ILD and autoimmune features who do not meet clinical criteria for CTDs may have a lung-predominant form of a CTD. [9] To address this, the European Respiratory Society and American Thoracic Society released a joint consensus statement in 2015 proposing the term "interstitial pneumonia with autoimmune features" (IPAF) be used for "idiopathic interstitial pneumonia" (IIP) with clinical features that suggest an underlying autoimmune process. [10]

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      Pathophysiology

      Although the distinct cause of interstitial lung disease (ILD) in connective disease tissue (CTD) is not known, the underlying pathogenesis is thought to be secondary to varying degrees inflammation, alveolar injury, dysregulated tissue repair, and fibroproliferation. [11] ​

      Regardless of the inciting event, the first step in the process of developing ILD is an injury to the epithelium. Epithelial injury may be secondary to a variety of causes, including microaspiration which may play a prominent role in systemic sclerosis (SSc). In the early stages of lung injury, the degree of inflammation of interstitial and alveolar spaces is associated with subsequent fibrosis. Through the activation of a variety of mediators this inflammatory response stimulates pulmonary fibroblasts, resulting in a maladaptive response, which can ultimately lead to the development of ILD. Following the initial insult, further activation of fibroblasts and myofibroblasts leads to lung fibrosis and scarring. [12]

      CTD-ILD

      ILD associated with CTDs (CTD-ILD) may display a variety of histologic subtypes, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage, lymphoid interstitial pneumonia (LIP), bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, and alveolar hemorrhage. Patients with CTD who develop drug-induced ILD may also manifest a variety of histologic patterns in lung biopsy specimens. [13] The frequency of each histologic pattern varies, depending on the underlying CTD.

      SSc, a chronic disease with multisystemic involvement, is characterized by widespread collagen deposition. Fifty percent of patients with SSc go on to develop clinically significant lung disease (SSc-ILD). [14] In fact, high-resolution computed tomography (HRCT) scanning demonstrates consistent findings in more than 65% of these patients, and pulmonary function tests (PFTs) are abnormal in 93% of SSc patients. [15] On the basis of skin involvement, SSc has been typically characterized into diffuse cutaneous or limited cutaneous. The diffuse form, associated with the anti-topoisomerase (Scl 70), is more strongly associated with lung disease than the limited form. However, skin involvement does not mirror lung involvement, and ILD can also occur in the limited cutaneous form. Histologically, SSc is most commonly associated with the NSIP pattern, whereas the UIP pattern is less common. [16]

      Rheumatoid arthritis (RA), the most common of the inflammatory arthropathies, is associated with joint stiffness and arthritis. However, as it is a systemic disorder, RA also has numerous nonarticular manifestations, including ILD. The diagnosis of ILD in RA (RA-ILD) is associated with significant morbidity and mortality. [8] In contrast to SSc-ILD, the most common interstitial pathologic pattern in patients with RA is an initial manifestation of peribronchial follicles with lymphocytic aggregation, which progresses to diffuse fibrosis and honeycombing. [17, 18] Other reported pulmonary manifestations of RA include OP, rheumatoid nodules, and pleural effusions. Vasculitis and pulmonary hypertension have also been reported. [19]

      Systemic lupus erythematosus (SLE) is an inflammatory disorder of unknown etiology that affects multiple systems, including frequent involvement of the pulmonary system, of which pleuritis and pleural effusions are the most common. [20] Fortunately, ILD appears to be less common in SLE. Acute lupus pneumonitis, a rare but life-threatening condition, has been described as having a nonspecific diffuse alveolar damage and a mortality of 50%. [21] Other infrequent manifestations of SLE include diffuse alveolar hemorrhage, pulmonary arterial hypertension, and extrapulmonary restriction known as "shrinking lung syndrome."

      The inflammatory myopathies polymyositis and dermatomyositis (PM/DM) are frequently associated with pulmonary complications. [22] As with the other CTDs, the underlying cause of myopathy-associated ILD (IM-ILD) is often unknown. However, the final common pathway appears to be a cellular inflammatory process that fails to terminate. Several hypotheses have been described as the initial trigger. For example, viral infections, such as coxsackie, influenza, echovirus, human immunodeficiency virus, and human T-cell leukemia virus, have been shown to be associated with myositis. Also, there is an increased prevalence of hepatitis C seropositivity in patients with PM/DM. Furthermore, the treatment of PM/DM with immunosuppression has resulted in a rapidly progressive ILD in association with cytomegalovirus. Other possible triggers for the cause of ILD in PM/DM include the human leukocyte antigen (HLA)-haplotype, especially HLA-DRB1. [23]

      Sjögren syndrome (SS) is an autoimmune disorder characterized by the presence of chronic inflammation and lymphocytic infiltration of lacrimal and salivary glands. Pulmonary involvement in Sjögren syndrome involves lymphocytic infiltration, causing NSIP and, less commonly, LIP (SS-ILD). [24]

      Less is known about the pathogenesis of ILD in other forms of CTDs, including mixed connective tissue disease (MCTD), ankylosing spondylitis (AS) and undifferentiated connective tissue disease (UCTD).

      CTD risk factors

      Risk factors for the development of CTDs are as follows:

      • Genetic susceptibility: Many individuals have a genetic predisposition for developing CTDs; in persons with scleroderma (SD) class II, major histocompatibility complex (MHC) associations raise the risk of idiopathic pulmonary fibrosis (IPF); a genetic predisposition is also found in persons with Sjögren syndrome SS), including familial clustering and an association with HLA-Dw2 and HLA-Dw3; and AS is strongly associated with HLA-B27. [25, 26] A 2019 report found a significant association for acute-onset diffuse CTD-ILD (AoDILD) and deleterious rare alleles in the NPL gene, as well as an increase in the deleterious rare allele frequency in eight other candidate genes (NPPA, PGAP1, SEC24A, DEFA4, DEFA3, SLC25A37, TMOD2, HILPDA) in patients with AoDLD. [27]

      • Hormonal influence: Pregnancy exacerbates various CTDs, including SLE and RA, suggesting that hormones (especially estrogen) play an important role. [28]

      • High titers of rheumatoid factor (RF) and the presence of rheumatoid nodules: These factors are also associated with an increased prevalence of pulmonary fibrosis in persons with RA.

      • Cigarette smoking (>25 pack-year): This factor increases the risk of ILD in patients with RA. [29]

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      Epidemiology

      Due to the heterogeneity of connective tissue diseases (CTDs) and interstitial lung disease (ILD), the exact frequency of CTD-associated ILD (CTD-ILD) is unknown. However, depending on the epidemiologic study used, the overall incidence of CTD-ILD is estimated to be 15%; about 10-90% of patients with CTDs will have lung involvement in their lifetimes. [4] The frequency of ILD had been reported to be 45% in systemic sclerosis (SSc), 20-30% in rheumatoid arthritis (RA), 20-50% in polymyositis/dermatomyositis (PM/DM), up to 25% in Sjögren syndrome, and 2-8% in systemic lupus erythematosus (SLE). [14]

      The prevalence of SSc is 26 cases per 100,000 population in the United States, [30, 31, 32] mainly affecting females aged 40-60 years. A genetic clustering exists. An epidemiologic study of full-blooded Choktaw Native Americans revealed a prevalence of 469 per 100,000 person, the highest of any subgroup in the study. [33]

      SLE has a prevalence of 30-50 per 100,000. Its incidence is more frequent in patients with Black, Asian, or Hispanic ethnicities. [34] About 90% of patients are women and of childbearing age. [35] The occurrence of ILD in SLE (SLE-ILD) appears to be 3%. [21]

      RA has a worldwide prevalence of approximately 1%, with an annual incidence of approximately 3 in 10,000 adults. [36, 37] Although RA is 2-4 times more common in women, it appears that idiopathic pulmonary fibrosis (IPF) of RA is 3 times more common in men. [38]

      Sjögren syndrome, one of the more common autoimmune disorders, can occur as either primary Sjögren syndrome or secondary Sjögren syndrome in the context of another autoimmune disease. The prevalence of primary Sjögren syndrome is 3.9 per 100,00 cases. As with the other CTDs, Sjögren syndrome has a strong female propensity and is most common in white females, with a female predominance reported to be as high as 20:1. [39]

      PM/DM is relatively rare, affecting 2-3 in 100,000 population and also more common in females. [40] Of these patients, an estimated 35-40% will develop ILD (PM/DM-ILD). Anti-synthetase syndrome, a subgroup of PM/DM associated with the presence of anti-aminoacyl-transfer RNA synthetases, represents a constellation of myositis, arthritis, Raynaud phenomenon, and ILD. In contrast to PM/DM, ILD is seen in up to 70-75% of the anti-synthetase syndrome. The most common anti-aminoacyl-transfer RNA synthetases are anti-histidyl or Anti-Jo, which is present in 20-30% patients. Other rare anti-aminoacyl-transfer RNA synthetases including anti-isoleucyl (OJ) have been described as having an even stronger association with ILD. [41]

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      Prognosis

      The development of interstitial lung diseases (ILD) in connective tissue disease (CTD) is associated with substantial morbidity. However, the mortality of CTD-associated ILD (CTD-ILD) and even interstitial pneumonia with autoimmune features (IPAF) is better than that of idiopathic ILD.

      CTD-ILD are a heterogeneous group of the disorder. Lung involvement in CTD ranges from asymptomatic subclinical disease to fibrotic lung disease that causes significant morbidity and mortality. Some patients develop a slow indolent course; however, others can develop rapidly progressive disease.

      In systemic sclerosis (SSc), most cases are associated with ILD and this remains the leading cause of death.

      In rheumatoid arthritis (RA), although ILD only occurs in approximately 10% of cases, the presence of ILD is associated with increased mortality. In patients with RA and systemic lupus erythematosus (SLE) who develop ILD, mortality appears to be 3-4 times higher than that in the general population, with a median survival of all patients with RA-ILD reported to be approximately 5 years. [42]

      In polymyositis/dermatomyositis (PM/DM), the presence of ILD has also been noted to have an association with poor outcomes. [43] In fact, in Korean patients with PM/DM, Kang et al observed ILD in 40.3% of patients, with associated poor survival. [44]

      Thus, CTD-ILD has a better prognosis than idiopathic ILD. Initially, this was thought to be secondary to a higher frequency of nonspecific interstitial pneumonia (NSIP); however, a study of 362 patients in South Korea showed improved mortality in patients with usual interstitial pneumonia (UIP) in CTD when compared to idiopathic pulmonary fibrosis (IPF). [45]

      Further data supporting this finding comes from IPAF. This subset of patients has features suggestive but not diagnostic of CTD. In a retrospective study (2006-2014), patients with IPF had a worse prognosis relative to those with IPAF, who in turn had a worse prognosis than patients diagnosed with CTD-ILD. [9] Furthermore, patients who had IPAF without the UIP pattern had improved survival compared to those who had IPAF with UIP pattern. See the image below.

      Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). In reviewing a retrospective database, Odham et al (Chicago cohort), showed a significant difference in mortality for patients with and without autoimmune features. CTD-ILD = Connective tissue disease-associated interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia. Reproduced with permission of the © ERS 2019. Eur Resp J. 2016 Jun:47(6):1767-75. DOI: 10.1183/13993003.01565-2015. Published 31 May 2016. PMID: 27103387.
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      Finally, it appears that mortality is significantly increased in patients with CTD who develop ILD and pulmonary hypertension. Takizawa et al found that in 715 patients with CTDs, ILD and pulmonary hypertension were important causes of death (37.5% and 6%, respectively). [46]

      Tools to predict patient mortality were initially developed for IPF. More recently, however, tools such as the ILD-GAP and the Du-Bois indices have been applied to CTD-ILD as well. [43]

      Complications

      Pulmonary complications of CTDs include the following:

      • Pulmonary infections

      • Drug-induced pulmonary disease

      • Pulmonary hypertension

      • ILD

      • Bronchiolitis

      • Pleuritis

      • Bronchiectasis

      • Acute respiratory distress syndrome (ARDS)

      • Pneumothorax

      • Cor pulmonale

      • Diffuse alveolar hemorrhage (DAH)

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