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

Updated: Aug 07, 2020
Author: Aniruddh Kapoor, MBBS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

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 (SJS), 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]

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]

Stevens-Johnson syndrome (SJS) is an autoimmune disorder characterized by the presence of chronic inflammation and lymphocytic infiltration of lacrimal and salivary glands. Pulmonary involvement in SJS involves lymphocytic infiltration, causing NSIP and, less commonly, LIP (SjS-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]

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 Stevens-Johnson syndrome (SJS), 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]

SJS, one of the more common autoimmune disorders, can occur as either primary SJS or secondary SJS in the context of another autoimmune disease. The prevalence of primary SJS is 3.9 per 100,00 cases. As with the other CTDs, SJS 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]

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.

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 ot 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)

 

Presentation

History

A thorough history including present respiratory symptoms, their onset and duration, as well as other systemic manifestations are crucial in diagnosing connective tissue disease-associated interstitial lung disease (CTD-ILD). Chronic cough and dyspnea, especially dyspnea on exertion, represent the initial presenting complaints in patients with CTD-ILD. However, patients are often asymptomatic early in the disease course.

Furthermore, a careful history of occupation, environmental exposures, smoking, radiation exposure, and drug use is needed to make a correct diagnosis. Actively seek extrapulmonary symptoms, including—but not limited to—rashes, telangiectasias, skin thickening, and nail pitting (which can be found in scleroderma); musculoskeletal or joint pain (which can be found in RA); and Raynaud symptoms (discoloration of the fingers and/or toes in response to triggers such as cold or stresss). It has been suggested that a multidisciplinary approach, including consultation with a pulmonologist and rheumatologist, is the gold standard for the diagnosis of ILD.[47]

A history of smoking is important because this habit can exacerbate the underlying CTD. A detailed history of previously used medications is also needed to exclude the possibility of drug-induced lung disease. Certain CTDs (eg, systemic lupus erythematosus [SLE]) run in families; therefore, a detailed family history is important in these cases. A patient’s previous employment history and environmental exposures may be helpful to differentiate CTD from ILD that is secondary to occupational exposure.

The clinical manifestations of CTD depend on the underlying CTD (see below); as a group, almost all CTDs cause diffuse ILD. Predominant symptoms of all CTDs include insidious onset of dyspnea, cough, hypoxia and, in the later stages of ILD, hypoxemia. Occasional chest pain is also reported.

Systemic lupus erythematosus

The clinical diagnosis of SLE is based on the presence of at least 4 of the following 10 features:

  • Rash

  • Discoid lupus

  • Photosensitivity

  • Oral ulcers

  • Arthritis

  • Serositis

  • Renal disorders

  • Neurologic disorders

  • Hematologic disorders

  • Immunologic disorders

SLE can involve any part of the respiratory system[48] and can cause acute pneumonitis (1-9% of cases), ILD (25%), pleuritis and pleural effusions (50-80%), an increased incidence of bacterial pneumonia, diffuse alveolar damage (1-2%), pulmonary hypertension (9%) and thromboembolism, diaphragmatic dysfunction with reduced lung volumes,[49] shrinking lung syndrome, and acute reversible hypoxemia syndrome.[50]

Pleural disease is the most common lung abnormality; effusion occurs in 50-70% of cases.[51] Pleural effusions are usually small, bilateral, and exudative. Fibrothorax due to lupus pleuritis is a rare complication.

Pneumonia, usually of bacterial origin, is the most common cause of pulmonary infiltrates in SLE patients. It may be related to immunosuppression by the disease itself or it may be due to the drugs used for its treatment. Lupus pneumonitis occurs in 5% of cases and is characterized by fever, cough, pleurisy, dyspnea, pulmonary infiltrates on radiography, hypoxia, and pleural effusion.

Diffuse alveolar hemorrhage (DAH) due to capillaritis is rare (occurring in 1-2% of cases) and associated with high mortality.[52, 53] It is characterized by fever, cough, dyspnea, hypoxia, and hemoptysis. The presentation is similar to that of acute lupus pneumonitis; however, in DAH, the diffusion capacity of the lung for carbon monoxide (DLCO) is usually high, and lupus nephritis is present. The diagnosis is typically made by bronchoscopy with bronchoalveolar lavage, which shows progressively bloody lavage fluid and hemosiderin-laden macrophages.

Diaphragmatic dysfunction or pleuritic chest pain with restriction of respiration has been suggested but not confirmed as a cause of shrinking lung syndrome. Patients have shortness of breath, and chest radiographs show loss of lung volume with no evidence of interstitial fibrosis or significant pleural disease. Furthermore, patients with chronic interstitial pneumonitis usually present with an insidious onset of dyspnea, chronic hypoxia, nonproductive cough, and recurrent pleuritic chest pain.

Pulmonary hypertension is less common with SLE than with other CTDs (eg, scleroderma [SD] or mixed connective-tissue disease [MCTD]). Symptoms of pulmonary hypertension include dyspnea (which increases with exercise), fatigue, weakness, and right-side heart failure.

Acute reversible hypoxemia is rare in SLE patients; it manifests as acute hypoxia with negative chest radiography findings and no evidence of pulmonary emboli. Pulmonary leukoaggregation and complement activation are thought to be the causes of this acute hypoxemia. Antiphospholipid antibodies can cause thromboembolic events in patients with SLE.

See Systemic Lupus Erythematosus for more information.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is commonly associated with pleural disease (in 20-40% of cases), interstitial pneumonitis (5-10%), nodules (1%), interstitial fibrosis (similar to idiopathic pulmonary fibrosis [IPF]), bronchiolitis obliterans organizing pneumonia (BOOP), and pulmonary vasculitis. Pleural effusions in RA, unlike those in SLE, are usually small, unilateral, and asymptomatic.

RA-ILD occurs most commonly in middle-aged men and is usually associated with severe arthritis and high serum levels of rheumatoid factor (RF). Risk factors include male sex, older age, and a history of cigarette smoking. Clinically, patients develop an insidious onset of dyspnea with occasional dry cough.

The underlying pathologic pattern is usually nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP). Pulmonary vasculitis can cause pulmonary hypertension. RA-ILD is usually slowly progressive; however, approximately 10% of patients die of progressive respiratory failure. Also, the findings of ILD can be present before the onset of articular disease.

See Rheumatoid Arthritis for more information.

Scleroderma

The lungs are the second most common organ involved in scleroderma (SD) (also referred to as progressive systemic sclerosis [PSS]), after the esophagus. SD can be divided into two types: limited (CREST syndrome [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia]) and diffuse. ILD is more prevalent in diffuse SD (30-90%), whereas pulmonary hypertension is more common in limited SD (10%).

ILD in SD patients manifests as an insidious onset of dyspnea, hypoxia, and fatigue. Later, as the disease progresses, it becomes indistinguishable from IPF. It should be noted that SD-ILD follows a less progressive course than IPF does and has a better long-term prognosis.

Pulmonary hypertension (see the image below) is fatal in SD patients. It can occur alone or in combination with ILD. Dyspnea on exertion is the most common symptom, followed by syncope or right-sided chest pain.

Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Pulmonary hypertension is a complication of various collagen vascular diseases, referred to as connective tissue diseases. This lung biopsy specimen demonstrates severe interstitial fibrosis and medial fibrosis, as well as smooth muscle hyperplasia of a pulmonary arteriole, features that are compatible with pulmonary hypertension.

Less commonly, SD can cause pleural disease, aspiration pneumonia, spontaneous pneumothorax, bronchiectasis, and drug-induced pulmonary toxicity (eg, methotrexate-mediated ILD).

See Scleroderma for more information.

Sjögren syndrome

Sjögren syndrome (SS) consists of the triad of keratoconjunctivitis sicca, xerostomia, and parotid swelling. It can be divided into two forms: primary (when other connective-tissue diseases are not present) and secondary (when other connective-tissue diseases are present). Pulmonary involvement (eg, pleuritis or vasculitis) is more common in secondary SS, whereas ILD is more common in primary SS.

Pleuropulmonary manifestations of SS include tracheobronchial gland inflammation, pleuritis, lymphoid interstitial pneumonia (LIP), NSIP, UIP, BOOP, and follicular bronchiolitis. Focal lymphoid hyperplasia (pseudolymphoma, a nonmalignant extraglandular lesion characterized by infiltrates of mature lymphocytes) and lymphoma (non-Hodgkin lymphoma) are more common in these patients.

See Sjogren Syndrome for more information.

Polymyositis/dermatomyositis

Polymyositis (PM)/dermatomyositis (DM) is less commonly associated with pulmonary lung disease.[54, 55] ILD occurs in 10% of patients with PM/DM (PM/DM-ILD). Patients with PM/DM-ILD tend to have shorter survival than patients without lung involvement. These patients present acutely with normal creatine kinase levels despite myositis.[55, 56]

Infections are the most common form of pulmonary disease in PM/DM patients.[54, 55] Several mechanisms have been proposed, including weakness of the respiratory muscles, aspiration, lymphocytopenia, and immunosuppression from the drugs used to treat PM/DM.

See Polymyositis and Dermatomyositis for more information.

Mixed connective-tissue disease

Mixed connective tissue disease (MCTD) is a rare autoimmune disorder that causes signs and symptoms of other CTDs. Clinical and laboratory findings overlap those of PSS, SLE, and PM/DM. For this reason, MCTD is sometimes referred to as an overlap disease.

The lungs are commonly affected in persons with MCTD; most patients are asymptomatic, but they may present with an insidious onset of dyspnea, dry cough, and chest pain. Pulmonary hypertension is the most common cause of death in patients with MCTD.[57]

See Mixed Connective-Tissue Disease for more information.

Ankylosing spondylitis

Ankylosing spondylitis (AS) involves the lungs in 1% of patients (AS-ILD). Upper lobe and apical lung fibrosis is seen, usually 10 years or more after the onset of the disease. In 3.5% of cases, AS can cause aortic root dilatation and aortic valve regurgitation.

See Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy for more information.

Physical Examination

In addition to a detailed history, a thorough physical examination has a central role in the early diagnosis patients with CTDs.

Alhough often obscure, "velcro crackles" are an easily identifiable and key physical examination finding in the diagnosis of CTD-associated ILD (CTD-ILD). Previous data suggest that crackles, or rales, are auscultated in 60% of patients with biopsy-proven interstitial pneumonias.[58]

Specific physical findings depend on the underlying CTD, and they may be limited to the chest or may involve other body organs (see the images and Table 1 below).

Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Note the heliotrope rash in a woman with dermatomyositis.
Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This image reveals Gottron papules and nail-fold telangiectasia in a patient with dermatomyositis.
Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This image shows the classic malar rash (butterfly rash), with distribution over the cheeks and nasal bridge. Note that the fixed erythema (sometimes associated with mild induration, as seen here) characteristically spares the nasolabial folds.

Table 1. Important Physical Findings in Connective Tissue Diseases (Open Table in a new window)

CTD

Skin and Musculoskeletal System

Lungs

Heart

Salivary Glands

Eyes

RA*

Subcutaneous nodules, digital ulcers, nail-fold infarcts

Bibasilar Velcro crackles, signs of pulmonary hypertension, pleural effusion

Pericarditis, myocarditis

N/A

N/A

SLE*

Malar rash, alopecia, livedo reticularis, erythema, telangiectasia, capillary infarcts, polyarthritis

Pleural effusion or rub, pneumonitis, cor pulmonale, diaphragmatic weakness

Pericarditis, myocarditis, CAD

N/A

N/A

SD

Thickening of skin of face, fingers, and hands; Raynaud phenomenon and ischemic changes of fingertips

Cor pulmonale, inspiratory "Velcro crackles" at lung bases

Restrictive pericardial disease, conduction defects, CHF

N/A

N/A

SS*

Secondary SS can manifest similarly to RA and SLE

Secondary SS can manifest similarly to RA and SLE

N/A

Xerostomia, parotid gland swelling

Keratoconjunctivitis sicca

PM

Proximal muscle weakness

Respiratory muscle failure

N/A

N/A

N/A

DM

Heliotrope rash of eyelids, Gottron papules

Respiratory muscle failure

N/A

N/A

N/A

AS

Sacroiliitis

Restriction in chest expansion, pulmonary apical fibrosis

Aortic insufficiency

N/A

Anterior uveitis

* ​Mixed connective tissue disease (MCTD) can manifest with the signs and symptoms of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or Sjögren syndrome (SS).

AS = ankylosing spondylitis; CAD = coronary artery disease; CHF = congestive heart failure; CTD = connective-tissue disease; DM = dermatomyositis; PM = polymyositis; SD = scleroderma.

Interstitial pneumonia with autoimmune features (IPAF)

in IPAF associated with CTD, specific clinical features suggestive of an underlying CTD are present, but they do not allow for the diagnosis of a defined CTD. For example, Raynaud phenomenon, palmar telangiectasia, distal digital tip ulceration, and digital edema are specific physical findings that are often seen in systemic sclerosis (SS) but rarely seen in idiopathic interstitial pneumonia (IIP). Similarly, the features of digital fissuring (“mechanic hands”) and a fixed rash on the digital extensor surfaces (Gottron sign) are hallmarks of the anti-synthetase syndrome or SS-myositis overlap associated with PM-Scl antibody positivity. Inflammatory arthropathy is characterized by symptoms or signs of peripheral joint synovitis, but joint pain alone lacks specificity.[10]

 

DDx

Diagnostic Considerations

As previously mentioned, a multidisciplinary approach to the diagnosis and treatment of connective tissue disease-associated interstitial lung disease (CTD-ILD) is of paramount importance. A thorough history and physical examination should be supplemented by chest radiography, serum biomarkers and, occasionally, histopathology.

It is essential to make an effort to exclude the diagnosis of underlying CTD or interstitial pneumonia with autoimmune features (IPAF) in a patient presenting with ILD, as previous data have shown improved outcomes regardless of the histopathologic diagnosis.[9, 45]

Differential Diagnoses

 

Workup

Laboratory Studies

Laboratory studies are helpful in the setting of connective tissude disease-associated (CTD) interstitial lung disease (ILD) (CTD-ILD). At least 15% of patients with ILD have evidence of underlying CTD.[3]

Antibody testing

Various antibodies detected in the serum of patients with CTD help in determining the diagnosis and the prognosis (see Table 2 below).

Table 2. Autoantibodies in Connective Tissue Diseases (Open Table in a new window)

Autoantibody

RA

SLE

SD

SS

PM/DM

AS

MCTD

IPAF # [10]

RF

+

+

+

+

Rare

-

+

Possible

ANA

+

+

+

+

Rare

-

+

(speckled)

Possible

ds-DNA

-

+

-

-

-

-

-

Possible

Anti centromere

-

-

+ (limited)

Rare

Rare

-

-

Possible

Scl-70

-

-

+ (diffuse)

 

Rare

-

-

Possible

Anti-Jo

-

-

-

Rare

+ (ILD)

-

-

Possible

ANCA

Rare

Rare

-

-

-

-

-

-

Smith antibody

-

+

-

-

-

-

-

Possible

Anti-Ro/SSA and anti-La/SSB

-

-

-

+

-

-

-

Possible

Anti-U1-RNP and anti-UN-70 kd

-

-

-

-

-

-

+

Possible

Anti-CCP

+

-

-

-

-

-

-

Possible

ANA = antinuclear antibody; ANCA = antineutrophilic cytoplasmic antibody; AS = ankylosing spondylitis; CCP = cyclic citrullinated peptide; DM = dermatomyositis; ds-DNA = double-stranded DNA antibody; ILD = interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; MCTD = mixed connective-tissue disease; PM = polymyositis; RA = rheumatoid arthritis; RF = rheumatoid factor; RNP = ribonucleoprotein; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome.

 

Anemia of chronic disease can be found in persons with rheumatoid arthritis (RA), whereas systemic lupus erythematosus (SLE) can cause leukopenia, lymphopenia, thrombosis, and thrombocytopenia. The erythrocyte sedimentation rate (ESR) and creatine kinase levels may be high in patients with polymyositis (PM)/dermatomyositis (DM). Total complement levels and a high ESR may be present in patients with SLE who present with an acute lupus flare.

Schirmer and Rose Bengal staining

The Schirmer test may be used to screen for dry eyes secondary to decreased tear production in patients with Sjögren syndrome (SS). Similarly, Rose Bengal staining of the cornea can detect keratitis associated with SS.

Radiology

Radiologically, connective tissue disease (CTDs) may manifest as a focal or a diffuse pulmonary abnormality. The type and frequency of the lung abnormalities vary with the specific disease (see Table 3 below).

Table 3. Radiologic Patterns of Connective Tissue Diseases (Open Table in a new window)

Radiologic Pattern

RA

SLE

SD

Secondary SS

PM/DM

AS

MCTD

IPAF  [10]

Pleural effusion

+

+

+

±

-

-

+

May be present

Interstitial pneumonitis, fibrosis

UIP and NSIP patterns

+

LIP pattern

±

+

Upper apical fibrosis[59]

+

NISP, OP, LIP or NISP with OP overlap pattern

BOOP

±

+

+

+

+

±

±

 

Pulmonary nodules

Rheumatoid pulmonary nodules; uncommon, maybe 1-5 mm, single or multiple, may cavitate

-

-

Follicular lymphoid hyperplasia or lymphoma can present as lung nodules

+

-

-

 

Bronchiectasis

+

+

+

+

+

+

+

unexplained airflow obstruction, bronchiolitis or bronchiectasis.

Caplan syndrome

Coal worker pneumoconiosis, rheumatoid nodules

-

-

-

-

-

±

 

Diffuse pulmonary hemorrhage

-

+

-

-

-

-

±

 

Shrinking lung syndrome

-

Loss of lung volume at bases with no parenchymal pathology

-

-

-

-

±

 

Diaphragmatic dysfunction

-

+

-

May be present

+

-

±

 

Cysts, honeycombing

10% of patients have subpleural honeycombing; compared with IPF, it is more anterior and involves upper lobes

Uncommon

+

Present, especially in LIP

+

Upper-lobe cyst may become infected with Aspergillus species

-

 

GGO

Present, especially in NSIP

+

+

+

+

-

±

 

AS = ankylosing spondylitis; BOOP = bronchiolitis obliterans organizing pneumonia; DM = dermatomyositis; GGO = ground-glass opacification; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; LIP = lymphoid interstitial pneumonia; MCTD = mixed connective-tissue disease; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; PM = polymyositis; RA = rheumatoid arthritis; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome; UIP = usual interstitial pneumonia.

 

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma (SD), Sjögren syndrome (SS), and polymyositis/dermatomyositis (PM/DM) can cause interstitial fibrosis similar to idiopathic pulmonary fibrosis (IPF). All CTDs like IPF involve the lung bases and are subpleural, except for ankylosing spondylitis (AS), which involves the upper lobes, and RA-induced interstital lung disease (ILD). RA-ILD is differentiated from IPF on the basis of greater upper-lobe involvement, an anterior location, and the presence of reticular infiltrates finer than those associated with IPF (see the image below).

Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The high-resolution computed tomography scan of advanced-stage pulmonary fibrosis demonstrates reticular opacities with honeycombing in a predominantly subpleural distribution. This pattern can be present in rheumatoid arthritis–related interstitial lung disease, Sjögren syndrome, and scleroderma.

Radiologic features of mixed connective tissue disease (MCTD) vary across different studies. Radiologic abnormalities include subpleural honeycombing, bronchiolitis obliterans organizing pneumonia (BOOP), and pleural effusion.

Chest radiography

Chest radiographs can detect ILD; however, these may be normal initially.[60] Thus, high-resolution computed tomography (CT) scanning remains the standard when it comes to the evaluation of CTD-related ILD (CTD-ILD). Depending on the type of CTD present and the extent of lung involvement, radiography may reveal a plethora of findings, including but not limited to ground-glass opacities, reticulations, pleural effusions, pulmonary nodules, bronchiectasis, volume loss, and prominent pulmonary vessels.

SS is manifested by a reticulonodular pattern of infiltrates involving lower lung zones. This finding may reflect the presence of lymphocytic interstitial fibrosis (see the image below). HRCT scans may reveal ground-glass opacities (GGOs) and bronchiolitis obliterans.[61]

Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This chest radiograph was obtained from a patient with lymphocytic interstitial pneumonia.

Ultrasonography

Although not yet adopted as a gold standard, data exists to suggest a role for the use of lung ultrasonography.[62, 63, 64, 65] ​[66]

Echocardiography can help detect cardiac involvement, which is useful in patients presenting with heart failure and in patients with suspected pulmonary hypertension.

Computed tomography (CT) scanning

Numerous studies show high-resolution (HR) CT findings and pulmonary function test (PFT) results correlate with underlying lung histopathology in patients with CTD.[67] GGOs and consolidation may reflect the presence of interstitial pneumonia on CT scanning of the chest (see the image below). Pulmonary fibrosis is uncommon in patients with SLE; if present, it is usually patchy. The abnormalities occur mainly at the periphery of the lung and can be associated with traction bronchiectasis and honeycombing. The HRCT findings in CTD-ILD can be indistinguishable from those found in idiopathic interstitial pneumonia.

Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Ground-glass opacification (GGO) may correlate with active alveolitis and a favorable response to therapy. GGO is among the earliest features of rheumatoid arthritis–induced interstitial lung disease.

RA is associated with the following four CT scan patterns:

  • Usual interstitial pneumonia (UIP)

  • Nonspecific interstitial pneumonia (NSIP)

  • Bronchiolitis[68]

  • Organizing pneumonia (OP)[69]

The most common CT scan features of RA-related lung disease are GGOs and reticulation.[18, 70] RA can manifest as rheumatoid nodules, Caplan syndrome (rheumatoid nodules ≤5 cm, mostly involving the upper lungs in coal miners and resembling coal worker pneumoconiosis).[71] In a smoker who has RA and presents with lung nodules, lung cancer should be ruled out first.[72]

In patients with SD, HRCT scanning frequently shows evidence of interstitial pneumonitis and fibrosis, mainly involving the lower lobes, in a predominantly peripheral and posterior distribution.

PM/DM-induced lung disease is rare (5%). The most common pattern of ILD is symmetric and predominantly basal reticulation. HRCT scanning is remarkable for revealing prominent interlobular septa, patchy consolidation, and honeycombing. Patients with an acute presentation have GGOs and consolidation, in contrast to the reticulation and honeycombing seen in patients with the chronic type of ILD.

Nuclear imaging

Gallium scanning results may be abnormal in patients with CTDs, probably as a consequence of alveolitis. However, the role of gallium scanning in the diagnosis or prognosis of CTDs is not well established.

Pulmonary Function Tests

Pulmonary function testing (PFTs) include spirometry, lung volumes, diffusion capacity of the lung for carbon monoxide (DLCO), and arterial blood gas (ABG) measurements.

Most connective tissue diseases (CTDs) cause a restrictive lung disease pattern with a decrease in total lung capacity (TLC), residual volume (RV), functional residual capacity (FRC), and DLCO.[73] Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) (ie, the FEV1/FVC ratio) may be normal or increased. However, bronchiolitis obliterans may cause an obstructive ventilatory defect (reduced FEV1/FVC ratio and FEV1, increased RV and RV/TLC ratio).

Arterial blood gas (ABG) analysis may reveal hypoxemia at rest. Arterial oxygen desaturation may occur with exercise. A 6-minute walk test with pulse oximetry provides a measure of oxygen desaturation and helps to detect disease progression.

Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) results are not diagnostic in patients with connective tissue diseases (CTDs), but they are diagnositic in excluding infections and can help narrow a differerential diagnosis.[74]

Studies have been performed to determine the importance of cell counts in BAL samples; patients with increased neutrophil counts tend to have a worse prognosis than those with increased lymphocyte counts.[75] BAL results seem to correlate with the underlying lung pathology.[76, 77] Similarly, BAL lymphocytosis may predict responsiveness to corticosteroids. Most patients with underlying interstitial lung disease (ILD) have lymphocytosis in BAL fluid. Finally, BAL is valuable for excluding infections that can mimic CTDs.

Biopsy

As with other interstitial lung diseases (ILDs), a transbronchial biopsy is usually inadequate for diagnosis, given the often patchy distribution of histologic findings. Alhough lung biopsies would provide a histopathologic diagnosis, they are often not required.

High-resolution computed tomography (HRCT) scanning results correlate well with the pathology of the underlying connective tissue disease (CTD).[78] However, open lung biopsy is needed in atypical cases,[79] depending on the clinical and functional status of the patient. Video-assisted thoracoscopic surgery is usually preferred.

Histologic Findings

The most common histopathologic findings in patients with connective disease tissues (CTDs) are nterstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), follicular bronchiolitis, diffuse alveolar hemorrhage (DAH), and lymphoid interstitial pneumonia (LIP).

Usual interstitial pneumonia

Histologic findings in UIP include fibroblastic foci with alternate areas of normal lung tissue, fibrosis, and honeycombing (see the image below). The distribution is peripheral, subpleural, and basal. These findings may be seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and mixed connective tissue disease (MCTD).

Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The histologic image is from a patient with usual interstitial pneumonitis. Subpleural and paraseptal inflammation are present, with the appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal (or nearly normal) alveoli interspersed between fibrotic areas are hallmarks of this disease. In addition, the lung architecture is completely destroyed. This pattern can be present in rheumatoid arthritis–induced interstitial lung disease and is generally associated with a poor prognosis.

Nonspecific interstitial pneumonia

Histologic findings in NSIP include varying proportions of interstitial inflammation and fibrosis, which may be divided into cellular and fibrosing and are patchy with intervening normal lung tissue.[80] The distribution is peripheral, subpleural, basal, and symmetric. These findings may be seen in SLE, RA, DM/PM, and MCTD.

Lymphoid interstitial pneumonia

Histologic findings in LIP include infiltration of T cells, plasma cells, and macrophages, as well as lymphoid hyperplasia that is usually diffuse and predominantly septal. The distribution is diffuse. These findings may be seen in Sjögren syndrome (SS) and MCTD.

Organizing pneumonia

Histologic findings in OP include patchy intraluminal organizing fibrosis in air spaces, with preservation of lung architecture. The distribution is bronchovascular. These findings may be seen in SLE, scleroderma (SD), SS, and PM/DM.

Diffuse alveolar hemorrhage

Histologic findings in DAH include hyaline membrane formation, damaged type II pneumocytes, alveolar edema, and fibroblastic proliferation. Distribution is diffuse. These findings may be seen in SLE, RA, SD, and PM/DM.

Interstitial pneumonia with autoimmune features (IPAF)

The histopathologic features included within the morphologic domain criteria for IPAF are only those considered to be highly associated with, but not diagnostic for, the presence of CTDs. These are the primary patterns of NSIP, OP and LIP and the secondary features of interstitial lymphoid aggregates with germinal centers and diffuse lymphoplasmacytic infiltration, with or without lymphoid follicles.[10]

 

Treatment

Approach Considerations

In patients with suspected connective tissue disease (CTD)-associated interstitial lung disease (ILD) (CTD-ILD), referral to a center with expertise in management of CTD-ILD is recommended. A multidisciplinary approach to help guide management includes collaboration with pulmonologists, rheumatologists, radiologists, and pathologists. Furthermore, referral to centers with expertise in pulmonary hypertension on lung transplantation may be required, depending on the individual clinical context.

The treatment of CTD-ILD requires immunosuppression with either steroid or steroid-sparing agents.

Lung transplantation may be an option for those with end-stage lung disease.

Issues to consider

Patients with CTD-ILD often present with poor quality of life; however, therapy is also associated with severe adverse effects. Thus, treatment is generally initiated when symptoms become clinically significant or progressive. The mainstay of therapy requires immunosuppression either through steroids or steroid-sparing agents.

Prolonged treatment with corticosteroids leads to a large number of comorbidities such as diabetes mellitus, hypertension, osteoporosis, and psychiatric disease. Therefore, all efforts should be made to decrease the steroid burden as soon as possible.

However, immunosuppressive agents are not without risk either. For example, cyclophosphamide, a cytotoxic immunosuppressant has been shown to cause hemorrhagic cystitis and is even associated with malignancy. Because the CTD-ILDs are a heterogeneous population, the addition of steroid-sparing medications should be considered, depending on the CTD being treated. Lastly, if a patient shows a progressive deterioration in lung function or shows no slowing in this decline, discontinuation of the immunosuppressive medications should be considered.

Most patients are treated in an outpatient setting. Chest radiography, the 6-minute walk test, arterial blood gas determinations (ie, arterial oxygen tension [PaO2]), and pulmonary function tests (PFTs)—especially forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO)—are monitored after therapy is started. Subspecialty consultations including pulmonologists and rheumatologist should be considered early in the management of these diseases. Transfer to a higher level of care is indicated if the diagnosis is in doubt or if treatment is ineffective.

Educate patients about the natural history, progression, and treatment of the disease. Before any immunosuppressive medication is started, the potential adverse effects, the duration of therapy, and the chances of success should be discussed with the patient.

Medical Care

As mentioned previously, immunosuppression is the cornerstone of the medical management of connective tissue disease (CTD)-associated interstitial lung disease (ILD) (CTD-ILD). These drugs include corticosteroids and corticosteroid-sparing medications, such as azathioprine, cyclosporine, cyclophosphamide, and methotrexate.

Glucocorticoids

Glucocorticoids have often been tried as first-line therapy for a variety of CTD-ILDs, although the optimal dose or duration of prednisone is unknown. In systemic sclerosis (SSc), glucocorticoids have been tried as monotherapy and in combination with other immunosuppression. These combinations appear to show improvement in both pulmonary and nonpulmonary complications of SSc.

Corticosteroid-sparing agents

Cyclophosphamide,mycophenolate mofetil

Cyclophosphamide, an alkylating agent, can be used with or without steroids in the treatment of SSc. A scleroderma lung study that compared oral cyclophosphamide and placebo showed 1 year of cyclophosphamide was associated with a significant but modest improvement in dyspnea and lung function.[81] Common adverse effects of cyclophosphamide therapy in the study included hematuria, leukopenia, neutropenia, anemia, and pneumonia. In addition, a small prospective, multicenter, randomized control trial conducted in patients with granulomatosis with polyangiitis showed intravenous pulse cyclophosphamide may be not only as effective as oral cyclophosphamide but also may avoid some of the systemic toxicity.[82]

In an attempt to reduce the toxicity associated with cyclophosphamide, the Scleroderma II Trial compared it with mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase.[83] Mycophenolate mofetil exerts a cytostatic effect on B and T cell lymphocytes. In this trial, no significant difference was noted in forced vital capacity (FVC), the primary outcome. However, the investigators noted that although both study drugs showed an improvement in FVC (2.88% in the cyclophosphamide group and 2.19% in the mycophenolate mofetil group), those who received mycophenolate appeared have better drug tolerance as evidenced by a 43.8% withdrawal in the cyclophosphamide group and a 28.9% withdrawal in the mycophenolate group.[83] Nonetheless, mycophenolate mofetil is associated with several adverse effects, such as diarrhea (most common), bone marrow suppression, and progressive multifocal leukoencephalopathy.

Tacrolimus, sirolimus

Tacrolimus and sirolimus are calcineurin inhibitors, drugs that inhibit the action of calcineurin and thus impair T cell lymphocytes by impairing the transcription of cytokines such as interleukin 2. These agents have been used in the maintenance of immunosuppressions for several years. More recently, multiple retrospective studies have evaluated their use in either steroid-resistant ILD associated with the inflammatory myopathies or as adjunctive immunosuppression with steroids in these conditions.[43] Calcineurin inhibitors are associated with several adverse effects, including nephrotoxicity, hypertension, neurotoxicity including posterior reversible encephalopathy syndrome, increased risk for infections, and malignancy.

Azathioprine

Azathioprine, a generally well-tolerated immunosuppressant, exerts its effect by halting DNA replication by incorporating itself into DNA metabolism. Azathioprine has been extensively used to maintain remission in antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis. In fact, in this cohort, azathioprine is considered first line after induction therapy with cyclophosphamide.[84, 85] Although data are limited, retrospective studies seem to suggest azathioprine is associated with the stabilization of pulmonary function in patients with CTD-ILD.[43]

Rituximab

Rituximab, a monoclonal antibody that targets the CD20 antigen, is used in the treatment of several autoimmune diseases. In ANCA vasculitis, a French prospective, randomized, controlled study that compared rituximab to the first-line therapy (azathioprine) found rituximab was superior to azathioprine in maintaining remission.[86] Another prospective, randomized, controlled trial showed rituximab to be as effective as cyclophosphamide in the induction of remission in ANCA vasculitis.[87] In fact, in the cohort of patients with relapsing disease, rituximab may be more effective than cyclophosphamide. Similarly, rituximab may be an option in refractory CTD-ILD. An ongoing study comparing cyclophosphamide and rituximab for the treatment of CTD-ILD is expected to be completed in 2021.[88]

Other medications have been tried in the treatment of RA-related ILD, including methotrexate,[89] leflunomide, and biologic inhibitors (eg, tumor necrosis factor–α [TNF-α] inhibitors). Hagiwara et al described a case in which an acute exacerbation of preexisting ILD occurred after the administration of etanercept for RA.[90]

Pirfenidone, nintedanib

Pirfenidone and nintedanib are antifibrotic drugs used in the management of idiopathic pulmonary fibrosis (IPF).

In September 2019, nintedanib received FDA approval in the treatment of ILD associated with SSc after being shown to slow the rate of decline in pulmonary function.[91, 92] Nintedanib is a tyrosine kinase inhibitor (TKI) that targets growth factors (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR] 1-3, colony-stimulating factor 1 receptor [CSFIR]) that are implicated in the pathogenesis of ILDs.

Nintedanib gained approval for chronic fibrosing ILDs with a progressive phenotype in March 2020. Unclassifiable ILDs, autoimmune ILDs, chronic hypersensitivity pneumonitis, sarcoidosis, myositis, Sjögren syndrome, coal worker pneumoconiosis, and idiopathic forms of interstitial pneumonias (eg, idiopathic nonspecific interstitial pneumonia) are among the diseases that may develop a progressive form of chronic fibrosing ILD.

Approval of nintedanib for chronic fibrosing ILDs was based on the INBUILD phase 3 clinical trial (N = 663). INBUILD was the first clinical trial of ILDs to group patients based on the clinical behavior of their disease rather than the primary clinical diagnosis. Results showed nintedanib slowed pulmonary function loss by 57% (107 mL/year) across a range of patients compared with placebo (P < 0.001). In patients with usual interstitial pneumonia (UIP)-like fibrotic pattern shown by high-resolution computed tomography (CT) scaning, nintedanib slowed the loss of pulmonary function by 61% (128.2 mL/year) compared with placebo (P < 0.001).[93]

Secondary pulmonary hypertension in patients with CVD is usually resistant to treatment and is associated with poor prognosis.Current guidelines recommend using the same classes of pulmonary hypertension drugs and treatment algorithm as in idiopathic pulmonary arterial hypertension (PAH).[94] Patients should be referred a pulmonary hypertension center.

Hematopetic stem cell transplantation

Hematopetic stem cell transplantation (HSCT) has emerged as a novel approach to the management of advanced SSc.[43] HSCT aims to reduce the activity of abberent T cells and B cells through aggressive immunosuppression followed by transplantation of a renewed and more tolerant immune system.[95] Although three randomized controlled trials have shown survival benefit, improvement in FVC, skin thickening, and health quality of life, the phase 3 trial comparing cyclophosphamide and HSCT is pending.

Surgical Care

Lung transplantation is the only available treatment for refractory connective tissue disease (CTD)-associated interstitial lung disease (ILD) (CTD-ILD) related with progressive fibrosis. Despite this, many centers are reluctant to perform lung transplantations in patients with CTD because of the concern for extrapulmonary disesae. However, a retrospective study from South Korea showed similar survival rates for CTD-ILD relative to idiopathic pulmonary fibrosis (IPF).[96] In patients with disease refractory to treatment or who have extensive fibrosis, it is recommended that patients are referred to a transplant center for evaluation.

 

Guidelines

Guidelines Summary

Idiopathic Pulmonary Fibrosis (IPF)

In 2018, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society released their clinical practice guidelines on the diagnosis of idiopathic pulmonary fibrosis, as outlined below.[97, 98]

Obtain a detailed history for possible environmental exposures or medication use to exclude potential causes of interstitial lung disease (ILD).

Perform serologic testing to exclude connective-tissue disease.

With newly diagnosed ILD, perform high-resolution CT (HRCT) scanning of the chest; determine if findings indicate a pattern of (1) usual interstitial pneumonia (UIP), (2) probable UIP, (3) indeterminate of UIP, or (4) alternate diagnosis.

For probable UIP, indeterminate findings, or alternate diagnosis, bronchoalveolar lavage and surgical lung biopsy are recommended; evidence is insufficient to recommend for or against transbronchial lung biopsy or lung cryobiopsy.

For a UIP pattern, bronchoalveolar lavage (cellular analysis) and surgical lung biopsy are not recommended (risks outweigh benefits); guidelines strongly recommend against transbronchial lung biopsy or lung cryobiopsy in this situation.

Multidisciplinary discussions (MDDs) should include interactions between pulmonologists, possibly rheumatologists (on a case-by-case basis), pathologists, and radiologists. MDDs are recommended with newly detected ILD of an unknown cause in patients whose findings clinically suggest idiopathic pulmonary fibrosis. MDDs likely provide the greatest benefit in situations in which HRCT patterns indicate probable UIP, indeterminate findings, or alternative diagnoses, or when clinical, histologic, or radiologic data are incongruous.

For serum biomarker measurements, measuring serum matrix metalloproteinase 7, chemokine ligand 18, Krebs von den Lungen-6, or surfactant protein D is not recommended solely to distinguish idiopathic pulmonary fibrosis from other ILDs, owing to high false-positive and false-negative results.

Interstitial pneumonia with autoimmune features (IPAF)

In 2015, the European Respiratory Society and American Thoracic Society released a joint consensus statement 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. Proposed classification criteria include the presence of interstitial pneumonia (by HRCT or surgical lung biopsy); alternative etiologies are excluded and the patient does not meet the criteria for a connective tissue disease; and at least one feature from two domains (clinical, serologic, morphologic) is present.[10]

The clinical domain includes specific features suggestive of an underlying CTD. While they are specific findings, their presence alone does not meet the criteria for the diagnosis of a defined CTD. These features include distal digital fissuring (i.e. “mechanic hands”), distal digital tip ulceration, inflammatory arthritis or polyarticular morning joint stiffness ≥60 min, palmar telangiectasia, Raynaud's phenomenon, unexplained digital edema, unexplained fixed rash on the digital extensor surfaces (Gottron sign).[10]

The serologic domain includes circulating autoantibodies known to be associated with CTDs. (See Table 2 in Workup) Less specific serologic markers, such as a low-titre antinuclear antibody (ANA), low-titer rheumatoid factor (RF), erythrocyte sedimentation rate, C-reactive protein or creatine phosphokinase, are not included.[10]

The morphology domain is divided into three sections: interstitial pneumonia patterns suggested by HRCT imaging, histopathologic features identified by surgical lung biopsy, or evidence of additional thoracic compartment involvement as determined by diagnostic imaging, histopathologic findings, right heart catheterization (RHC) or pulmonary function testing.[10]

When these proposed criteria were applied to 422 patients previously diagnosed with idiopathic interstitial pneumonia (IIP) or undifferentiated CTD-ILD (UCTD), 144 (34%) met IPAF criteria. The mean age was 63.2 years with a slight female predominance. IPAF cohort survival was marginally better than patients with idiopathic pulmonary fibrosis but worse than CTD-ILD. A non-usual interstitial pneumonia pattern was associated with improved survival, as was the presence of the clinical domain. A modified IPAF cohort of those meeting the clinical domain and a radiographic or histological feature within the morphological domain displayed survival similar to those with CTD-ILD.[9]

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications. Drugs used to manage connective tissue disease (CTD) associated with interstitial lung disease (ILD) (CTD-ILD) include nintedanib, corticosteroids, and antineoplastic agents.[99]

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli.

Prednisone (Deltasone, Rayos)

Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders. It has anti-inflammatory properties and produces multiple glucocorticoid and mineralocorticoid effects. Prednisone therapy is best prescribed in consultation with a pulmonary disease specialist.

Prednisolone (FloPred, Millipred, Millipred DP, Prelone)

Prednisolone elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level.

Pulmonary, Tyrosine Kinase Inhibitors

Class Summary

Nintedanib is a tyrosine kinase inhibitor that targets growth factors (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR] 1-3, colony-stimulating factor 1 receptor [CSFIR]) that are implicated in the pathogenesis of interstitial lung diseases.

Nintedanib (Ofev)

Nintedanib is indicated to slow the rate of decline in pulmonary function in patients who have interstitial lung disease (ILD) associated with scleroderma. It is also indicated for chronic fibrosing ILDs with a progressive phenotype. Unclassifiable ILDs, autoimmune ILDs, chronic hypersensitivity pneumonitis, sarcoidosis, myositis, Sjögren syndrome, coal worker pneumoconiosis, and idiopathic forms of interstitial pneumonias (eg, idiopathic nonspecific interstitial pneumonia [NSIP]) are among the diseases that may develop a progressive form of chronic fibrosing ILD.

Immunosuppressants

Class Summary

These agents inhibit key factors involved in immune reactions.

Azathioprine (Imuran, Azasan)

Azathioprine is an imidazolyl derivative of 6-mercaptopurine (6-MP). Many of its biologic effects are similar to those of the parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or 6-MP is detectable in the urine 8 hours after being taken.

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. The mechanism whereby it affects autoimmune diseases is unknown. It works primarily on T cells, suppressing hypersensitivities of the cell-mediated type and causing variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity test results are suppressed to a greater degree than antibody responses. Azathioprine works very slowly; a 6- to 12-month trial may be required before effects are observed.

As many as 10% of patients may have idiosyncratic reactions that rule out the use of azathioprine. Do not allow the white blood cell (WBC) count to drop below 3000/µL or the lymphocyte count to drop below 1000/µL. The drug is available in tablet form for oral administration or in 100-mg vials for intravenous (IV) injection.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions. Suppresses mRNA expression of Th2 cytokines (interleukins 4 and 13) in peripheral blood mononuclear cells.

Antineoplastic Agents

Class Summary

Antineoplastic agents inhibit cell growth and proliferation.

Cyclophosphamide

Cyclophosphamide is primarily used for treating several types of cancer and autoimmune disorders. It is related to the nitrogen mustard group, and its mode of action involves alkylation and cross-linking of DNA. Cyclophosphamide is used for several different types of rheumatic disease, including systemic lupus erythematosus (SLE) and sometimes rheumatoid arthritis (RA).

Methotrexate (Trexall, Rheumatrex, Otrexup, Rasuvo)

Methotrexate is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. It inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of single-carbon groups in the synthesis of purine nucleotides and thymidylate. Methotrexate therefore interferes with DNA synthesis, repair, and cellular replication.