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INTRODUCTION
Pulmonary involvement occurs in over 80 percent of patients with systemic sclerosis (SSc)
and is second in frequency only to esophageal involvement as a visceral complication [1]. It
has surpassed renal involvement as the most common cause of death.
Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most
frequent major types of lung involvement. Affected patients have a poorer prognosis than
those with SSc who are free of pulmonary involvement.
The spectrum of pulmonary complications of SSc and an approach to their evaluation will
be reviewed here. The clinical manifestations, diagnosis, therapy, and prognosis of SSc-
associated ILD and PAH are discussed separately. (See "Clinical manifestations, evaluation,
and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and
"Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)"
and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk
factors, and screening".)
Two major types of SSc are commonly recognized and are based on whether the extent of
skin involvement is limited or diffuse. The type of cutaneous involvement correlates with
the risk for different types of lung involvement, although substantial overlap exists. (See
"Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)
● Diffuse cutaneous SSc is characterized by extensive skin involvement with extension of
skin sclerosis proximal to the wrists (particularly over the proximal limbs and trunk but
commonly sparing the upper back). Approximately one third of patients with SSc have
diffuse skin involvement. Patients with diffuse skin involvement due to SSc have a
greater likelihood of developing interstitial lung disease (ILD; and also cardiac and
renal disease), compared with those who have limited cutaneous SSc [2-4].
● Limited cutaneous SSc is characterized by skin sclerosis restricted to the hands, distal
extremities, and, to a lesser extent, to the face and neck. Patients with limited
cutaneous SSc generally have prominent vascular manifestations and may have CREST
syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility,
Sclerodactyly, and Telangiectasia). A subset may develop ILD [2].
The most common forms of SSc lung involvement, which may occur separately or together,
are interstitial lung disease and pulmonary vascular disease. Other pulmonary
complications include pulmonary thromboembolic disease, pleural disease, aspiration
pneumonitis, airways disease, drug-induced pneumonitis, and lung cancer. More than one
of these processes may be present in a given patient.
The exact prevalence of PAH in patients with SSc is unknown, but is estimated to be 10 to 15
percent. Patients with long-standing SSc are at greatest risk for developing PAH; limited
cutaneous disease has long been thought to be a risk factor for PAH, particularly in
association with the CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal
dysmotility, Sclerodactyly, and Telangiectasia). However, PAH also occurs in patients with
diffuse cutaneous disease. Anticentromere antibodies are associated with a higher
likelihood of PAH. (See "Pulmonary arterial hypertension in systemic sclerosis
(scleroderma): Definition, risk factors, and screening", section on 'Risk factors'.)
Among patients with SSc and PAH, dyspnea on exertion is the most common initial
symptom, but early PAH can be asymptomatic. Patients with advanced PAH may have chest
pain due to right ventricular angina, and near-syncope or syncope on exertion due to
reduced cardiac reserve. Patients with PH due to ILD typically have profound dyspnea on
exertion and a history of ILD. Those with PH due to left heart dysfunction may have other
features of myocardial dysfunction such as peripheral edema, palpitations, or syncope. The
clinical features of PH associated with SSc are discussed separately. (See "Clinical features
and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical
manifestations' and "Overview of the treatment and prognosis of systemic sclerosis
(scleroderma) in adults", section on 'Myocardial fibrosis and myocarditis'.)
PVOD and/or PCH should be suspected in a patient with elevated pulmonary artery
pressures and normal or low pulmonary capillary wedge pressure (PCWP) when imaging
studies suggest pulmonary edema. In general, pulse oxygen saturation is lower during a six-
minute walk test and pulmonary artery systolic pressure (PASP) is higher (typically >45
mmHg) in PVOD than PAH. (See "Epidemiology, pathogenesis, clinical evaluation, and
diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in
adults".)
Pleural effusion — Pleural effusions have been reported in both diffuse and limited
cutaneous scleroderma, but are uncommon (less than 10 percent) and often asymptomatic
[13,14]. Among patients with SSc, potential causes of a pleural effusion include pleuritis,
heart failure, pericarditis (with tamponade), pneumonia, PCH-PVOD and cancer. Depending
on the etiology, the presentation varies from acute onset of pleuritic chest pain (pleuritis) to
progressive shortness of breath (heart failure) to an asymptomatic pleural effusion
discovered on imaging or at autopsy [13,14]. On physical examination, a pleural friction rub
may be heard in patients with SSc-associated pleuritis.
● Airflow limitation – Airflow limitation has been noted on pulmonary function testing
in a small portion of patients with SSc, and cigarette smoking is thought to be a
contributing factor [24,25]. However, nonsmokers can also manifest airflow limitation.
In a series of 46 patients with SSc, airflow limitation (decreased forced expiratory
volume in one second/forced vital capacity [FEV1/FVC] with a reduction in FEV1 below
80 percent predicted) was noted in 5 of 34 nonsmokers (15 percent) and 4 of 12
current or exsmokers (33 percent) [24]. The cause of airflow limitation in these patients
is not known.
Clinically apparent bronchiectasis may increase the risk of serious infection and
warrants careful evaluation when the use of immunosuppressive drugs is considered
[30].
Lung cancer — The risk of lung cancer appears to be increased in patients with SSc,
especially those with ILD, and can occur independently of cigarette smoking. In a series of
17 patients with SSc and lung cancer, 13 had adenocarcinoma, 12 had underlying ILD, 11
were current or former cigarette smokers, and 8 had antibodies to topoisomerase [31]. In
addition, 13 had other pulmonary nodules noted on CT prior to the diagnosis of lung
cancer, although the nature of the noncancerous lung nodules was not further specified.
The evaluation of lung nodules is discussed separately. (See "Diagnostic evaluation of the
incidental pulmonary nodule".)
The potential association of SSc and cancer is discussed separately. (See "Clinical
manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on
'Other disease associations'.)
All patients with SSc should be screened for interstitial lung disease (ILD) and pulmonary
hypertension (PH) at presentation and periodically thereafter. The rationale for screening is
based on the frequent occurrence of these lung diseases and their high morbidity; studies
to show improved outcomes among screened patients are lacking [34,35].
In concert with current guidelines, we typically screen for these processes with a clinical
assessment, N-terminal pro-brain natriuretic peptide (NT-proBNP) or BNP, pulmonary
function tests (PFTs), and high resolution computed tomography (HRCT). While some
guidelines also include a Doppler echocardiogram, we reserve this test for selected patients
[35]. Further testing is based on the results of these initial tests.
Clinical assessment — The clinical assessment for lung involvement should include the
following: inquiry about symptoms such as cough, sputum production, dyspnea on
exertion, exertional presyncope, syncope, ankle swelling, and chest pain; a complete history
regarding cigarette smoking, medication use, and occupational and domiciliary exposures
to fumes and chemicals.
Patients are examined for physical signs of lung involvement, including tachypnea, crackles
(rales), pleural friction rub, an increased A wave in the jugular venous pulse, increased
pulmonic component of the second heart sound or a right ventricular S4, a right ventricular
heave, a pulmonary arterial "tap," a murmur suggestive of tricuspid regurgitation, and
peripheral edema.
Worsening dyspnea and/or cough in a patient with SSc should also arouse suspicion for
aspiration due to gastroesophageal reflux and/or esophageal dysmotility. Additional
considerations include infection, thromboembolism, or superimposed left heart failure.
(See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on
'Esophageal involvement' and "Clinical manifestations and diagnosis of systemic sclerosis
(scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)
In one study, elevated NT-proBNP levels in SSc patients had a sensitivity and specificity of 90
percent for the presence of PAH [36]. This has been confirmed by several studies that have
also demonstrated a correlation between NT-proBNP levels and the tricuspid gradient,
mean pulmonary arterial pressure, pulmonary vascular resistance, and survival [34,37-39].
However, patients with SSc can also have myocardial dysfunction that could contribute to
the elevation of BNP.
The role of antibody testing in assessing an individual patient’s risk for pulmonary
complications is not well-established. The antibodies associated with SSc are discussed
separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in
adults", section on 'Laboratory testing'.)
Pulmonary function testing — All patients should have PFTs (spirometry, lung volumes,
and a single breath diffusion capacity for carbon monoxide [DLCO]) performed at the time
of their initial presentation [35,40,41]. These tests assess for a restrictive pattern on lung
volumes (forced vital capacity [FVC] and/or total lung capacity <80 percent of predicted) and
reduced gas transfer. In addition, a six minute walk test with or without ambulatory
oximetry can be helpful for monitoring lung function over time. (See "Overview of
pulmonary function testing in adults".)
The combination of reduced lung volumes and a reduced DLCO suggests ILD, although a
reduced DLCO with normal lung volumes can be seen in early ILD. On the other hand, a
DLCO less than 65 percent of predicted in the absence of significant lung volume
abnormalities or a decrease in DLCO ≥20 percent in a year suggests PH, particularly in a
patient with long standing limited cutaneous SSc. The FVC/DLCO ratio is another way to
assess whether the degree of impairment of gas transfer is greater than what would be
expected on the basis of ILD. A ratio of FVC/DLCO percent predicted >1.6 suggests
pulmonary hypertension [35].
Analysis of the combination of all PFT parameters is necessary to minimize the risk of false
negative results [42-44]. As an example, in a series of 102 patients with SSc, 40 of 64 (62
percent) patients with ILD by HRCT had a normal FVC, including patients with
radiographically advanced ILD [42]. However, combining the all the PFT parameters and
using a DLCO threshold of 80 percent, the rate of false negative results was reduced to
under 25 percent. These data support the inclusion of HRCT in screening SSc patients for
ILD.
Imaging — For virtually all patients with a new diagnosis of SSc, we obtain chest imaging to
screen for the presence of ILD. We obtain an HRCT scan rather than a conventional chest
radiograph due to the greater sensitivity of the HRCT [42,45]. We include prone images to
evaluate for dependent atelectasis that can mimic ILD and expiratory images to assess air
trapping. (See "High resolution computed tomography of the lungs", section on 'Clinical
application of HRCT'.)
The HRCT scan of the chest is examined for the presence and distribution of ground glass
opacities ( image 1), reticular opacities, "honeycombing" ( image 2), bronchiectasis, and
emphysematous blebs or bullae. The most common pathologic pattern in SSC-associated
ILD, nonspecific interstitial pneumonia (NSIP), is associated with the HRCT finding of ground
glass opacities in a peripheral distribution, while the earliest HRCT change is usually a
narrow, often ill-defined, subpleural crescent of increased density in the posterior
(dependent) segments of the lower lobes. The evaluation of patients with HRCT evidence of
ILD is discussed separately. (See "Clinical manifestations, evaluation, and diagnosis of
interstitial lung disease in systemic sclerosis (scleroderma)".)
The prognostic utility of HRCT screening for SSc-ILD is supported by several studies [43,46-
48]. As an example, in a prospective study of 305 patients with SSc, absence of changes
suggestive of ILD on baseline HRCT predicted continued absence on repeat HRCT and
minimal worsening of FVC three years later, while the presence of such changes correlated
with progression of lung disease [43]. It has been suggested that the presence of ILD at
baseline appears to have an adverse impact on patient outcome in SSc [45].
Radiographic imaging studies are often normal in SSc patients with early PH, so they are not
helpful for screening. However, an enlarged pulmonary artery and attenuation of the
smaller pulmonary vessels may be seen with more advanced disease. Right ventricular
enlargement (diminished retrosternal space) and right atrial dilatation (prominent right
heart border) can also be seen. (See "Clinical features and diagnosis of pulmonary
hypertension of unclear etiology in adults", section on 'Imaging'.)
The echocardiographic features of PH are summarized in the figures ( figure 1). The
results of Doppler echocardiography may be expressed as the pulmonary artery
systolic pressure (PASP) or the tricuspid regurgitant jet velocity (TRV), where PASP = 4
(TRV)2. In general, an echocardiographically-estimated PASP exceeding 35 to 40 mmHg
should be considered elevated, which would correlate approximately with a tricuspid
regurgitant velocity >2.9 m/sec ( figure 1 and image 3). However, the sensitivity
and specificity of Doppler echocardiography for detecting PAH varies with the
estimated PASP or right ventricular pressure (another method to estimate PASP)
chosen as a threshold [49]. As an example, Doppler echocardiography with a threshold
of an estimated right ventricular systolic pressure >35 mmHg has a sensitivity of 94
percent and a specificity of 73 percent. (See "Clinical features and diagnosis of
pulmonary hypertension of unclear etiology in adults".)
SUBSEQUENT MONITORING
Patients with no evidence of lung involvement at the time of the initial evaluation (described
above) remain at risk for developing interstitial lung disease (ILD) or pulmonary arterial
hypertension (PAH) in the future, and thus need periodic re-evaluation. Patients with diffuse
skin involvement are particularly at an increased risk for development of ILD during the first
three to five years after the onset of systemic sclerosis (SSc). In contrast, while patients with
limited skin involvement have a lower risk for early ILD, they are more likely to develop PAH,
even in later stages of their disease.
We typically follow patients with SSc at three to six month intervals to assess changes in
symptoms (eg, dyspnea or reduced exercise tolerance) or physical examination (eg,
crackles).
For the first several years after the initial diagnosis, we obtain annual pulmonary function
tests (spirometry, diffusing capacity [DLCO], exertional pulse oxygen saturation). We
decrease the frequency of pulmonary function tests (PFTs) to every two years in patients
with long-standing SSc (more than five years) if they have a normal DLCO, no dyspnea or
exercise intolerance, and in those with PFTs that have remained unchanged over several
years (more than three years).
The timing of repeat chest high resolution computed tomography (HRCT) is based on the
clinical findings and results of PFTs. Re-evaluation is performed if new symptoms or signs
develop or a decline in lung volumes or DLCO occurs.
The diagnosis of interstitial lung disease (ILD) and pulmonary vascular disease requires
careful clinical assessment in SSc, because the presenting symptoms and pulmonary
function test abnormalities overlap and because they can occur independently and in
combination. In a series of 93 patients with SSc-ILD, 29 (31 percent) had right heart
catheterization-proven pulmonary hypertension and of these, 7 had group I PH/PAH, 6 had
group II PH (left heart disease), and 16 had group III PH (due to ILD) [50]. Salient features of
the evaluation are described below.
If the DLCO is decreased substantially more than the reduction in lung volumes (eg, the
forced vital capacity [FVC]/DLCO ratio >1.6), the possibility of concomitant pulmonary
hypertension (PH) should be explored, as described below.
For patients with a diagnosis of PH by RHC, we pay particular attention to the differentiation
of the following scenarios:
● SSc-associated ILD based on HRCT scan results – The combination of ILD and PH
needs to be further classified ( table 1).
• Patients with SSc associated ILD and PH may have pulmonary arterial hypertension
(PAH, group 1) and SSc-associated ILD as independent, but simultaneous processes
[51,52]. In these patients, the severity of ILD is not sufficient to cause pulmonary
vasoconstriction due to hypoxemia. Pulse oxygen saturation (SpO 2) may decrease
on exertion, but generally not below 88 percent. (See 'Pulmonary hypertension'
above and "Clinical features and diagnosis of pulmonary hypertension of unclear
etiology in adults", section on 'Group 1 - Pulmonary arterial hypertension'.)
Once the diagnosis of SSc-associated PAH is confirmed, the assessment of the severity of
pulmonary hypertension and, in some cases, acute responsiveness to vasodilators is used
to guide treatment choices. (See "Pulmonary arterial hypertension in systemic sclerosis
(scleroderma): Treatment and prognosis".)
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Systemic sclerosis
(scleroderma)".)
● In patients with systemic sclerosis (SSc), the most common forms of pulmonary
involvement, interstitial lung disease (ILD) and pulmonary hypertension (PH), can
occur in isolation or they can coexist. Other less common pulmonary complications
include pulmonary thromboembolism, pleural effusion, spontaneous pneumothorax,
airways disease, aspiration pneumonia, lung cancer, drug-induced pneumonitis,
respiratory muscle weakness, and rarely, pulmonary veno-occlusive
disease/pulmonary capillary hemangiomatosis,. Early pulmonary involvement in
systemic sclerosis (SSc) is often asymptomatic. (See 'Types of pulmonary involvement'
above.)
● The extent of cutaneous involvement by SSc may help predict the type of pulmonary
complications. Diffuse cutaneous SSc (extensive skin involvement with extension of
skin sclerosis proximal to the wrists) is more typically associated with ILD, while limited
cutaneous SSc (changes confined to the fingers, distal portion of the extremities, and
the face) is more likely associated with PH. (See 'Influence of diffuse cutaneous and
limited cutaneous disease' above.)
● In view of the potentially ominous prognosis of ILD and PH and the availability of
treatment, we evaluate virtually all newly diagnosed patients with SSc for ILD and PH.
(See 'Evaluation for lung disease at time of SSc presentation' above.)
● The initial evaluation for SSc lung disease includes a medical history (with careful
attention to exertional dyspnea, exercise intolerance, and other respiratory
symptoms), physical examination, measurement of plasma N-terminal pro-brain
natriuretic peptide (NT-proBNP) or BNP, pulmonary function testing (including
spirometry, lung volumes, and diffusing capacity [DLCO]), and high resolution
computed tomography (HRCT). (See 'Evaluation for lung disease at time of SSc
presentation' above.)
● Patients with no evidence of lung involvement at the time of the initial evaluation
remain at risk for developing ILD or PH in the future, and thus need periodic re-
evaluation. We typically follow patients with SSc at three to six month intervals to
assess changes in symptoms (eg, dyspnea or reduced exercise tolerance) or physical
examination (eg, crackles). In addition, we obtain annual pulmonary function tests
(spirometry, DLCO). The timing of plasma NT-pro-BNP measurement, HRCT, and
Doppler echocardiogram depends on the pattern of skin involvement at presentation,
results of initial tests, and development of clinical or laboratory abnormalities. (See
'Subsequent monitoring' above.)
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Topic 4377 Version 23.0
GRAPHICS
1 PAH
1.4.5 Schistosomiasis
5 PH with unclear and/or multifactorial mechanisms (refer to the UpToDate table on PH due to
unclear or multifactorial mechanisms)
5.3 Others
PAH: pulmonary arterial hypertension; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary
capillary hemangiomatosis; PH: pulmonary hypertension; LVEF: left ventricular ejection fraction.
Reproduced with permission of the © ERS 2019: European Respiratory Journal 53 (1) 1801913; DOI:
10.1183/13993003.01913-2018. Published 24 January 2019.
Minocycline Hydantoins
Isoniazid
Anti-inflammatory agents
Penicillamine
Abatacept
Procainamide
Azathioprine*
Illicit drugs
Cyclophosphamide*
Gold Cocaine
Leflunomide Methadone
Methotrexate* Propoxyphene
Penicillamine Miscellaneous
Sulfasalazine Bromocriptine
Antineoplastic agents
Alkylating agents
Busulfan
Chlorambucil
Cyclophosphamide*
Melphalan
Procarbazine
Antibiotics
Bleomycin sulfate
Mitomycin C
Antimetabolites
Azathioprine*
Cytosine arabinoside
Methotrexate*
Nitrosoureas
BCNU (carmustine)
CCNU (lomustine)
Methyl-CCNU (semustine)
Other
Alpha interferon
Docetaxel
Etoposide (VP-16)
Gefitinib
Nilutamide
Paclitaxel
Temsirolimus
Thalidomide*
Adapted from: Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Interstitial Lung Disease, 5th ed,
Schwarz MI, King TE Jr (Eds), People's Medical Publishing House, Shelton, 2011.
The CT scan through the lung bases in a patient with scleroderma shows bibasilar
interstitial lung disease with ground glass changes in the right lower lobe. Note also
the patulous esophagus (dashed arrow) and bilateral pleural effusions (black arrows).
The heart is also enlarged.
In the presence of TR, continuous wave Doppler interrogation can be performed across the tricuspid val
by aligning the Doppler ultrasound beam across the right heart (panel A). The Doppler shift caused by t
TR will be displayed as shown in panel B. In this example, the velocity of the TR jet is 1.9 m/s, yielding a
pressure gradient between the RV and RA of 15 mmHg ( = 4 x V2 by the Bernoulli equation). If the RA
pressure is known or can be estimated, the sum of the RA pressure and the RV to RA pressure gradient i
equal to the RV systolic pressure (which is equal to the pulmonary artery systolic pressure in the absenc
of pulmonic stenosis).
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