Systemic Lupus Erythematosus and Lung Involvement

Journal of
Clinical Medicine
Review
Systemic Lupus Erythematosus and Lung Involvement: A
Comprehensive Review
Jae Il Shin 1,† , Keum Hwa Lee 1,† , Seoyeon Park 2,† , Jae Won Yang 3,† , Hyung Ju Kim 2 , Kwanhyuk Song 2 ,
Seungyeon Lee 2 , Hyeyoung Na 2 , Yong Jun Jang 2 , Ju Yun Nam 2 , Soojin Kim 2 , Chaehyun Lee 2 , Chanhee Hong 2 ,
Chohwan Kim 2 , Minhyuk Kim 2 , Uichang Choi 2 , Jaeho Seo 2 , Hyunsoo Jin 2 , BoMi Yi 2 , Se Jin Jeong 2 , Yeon
Ook Sheok 2 , Haedong Kim 2 , Sangmin Lee 2 , Sangwon Lee 2 , Young Soo Jeong 2 , Se Jin Park 4 ,
Ji Hong Kim 1,5, * and Andreas Kronbichler 6
1 Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
2 Yonsei University College of Medicine, Seoul 03722, Republic of Korea
3 Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
4 Department of Pediatrics, Eulji University School of Medicine, Daejeon 34824, Republic of Korea
5 Department of Pediatrics, Gangnam Severance Hospital, Yonsei University College of Medicine,
Seoul 26426, Republic of Korea
6 Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
* Correspondence: kkkjhd@yuhs.ac
† These authors contributed equally to this work.
Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan
manifestations, including pleuropulmonary involvement (20–90%). The precise mechanism of pleu-
ropulmonary involvement in SLE is not well-understood; however, systemic type 1 interferons,
circulating immune complexes, and neutrophils seem to play essential roles. There are eight types of
pleuropulmonary involvement: lupus pleuritis, pleural effusion, acute lupus pneumonitis, shrinking
lung syndrome, interstitial lung disease, diffuse alveolar hemorrhage (DAH), pulmonary arterial hy-
Citation: Shin, J.I.; Lee, K.H.; Park, S.;
pertension, and pulmonary embolism. DAH has a high mortality rate (68–75%). The diagnostic tools
Yang, J.W.; Kim, H.J.; Song, K.; Lee, S.;
for pleuropulmonary involvement in SLE include chest X-ray (CXR), computed tomography (CT),
Na, H.; Jang, Y.J.; Nam, J.Y.; et al.
Systemic Lupus Erythematosus and
pulmonary function tests (PFT), bronchoalveolar lavage, biopsy, technetium-99m hexamethylprophy-
Lung Involvement: A lene amine oxime perfusion scan, and (18)F-fluorodeoxyglucose positron emission tomography. An
Comprehensive Review. J. Clin. Med. approach for detecting pleuropulmonary involvement in SLE includes high-resolution CT, CXR, and
2022, 11, 6714. https://doi.org/ PFT. Little is known about specific therapies for pleuropulmonary involvement in SLE. However,
10.3390/jcm11226714 immunosuppressive therapies such as corticosteroids and cyclophosphamide are generally used.
Rituximab has also been successfully used in three of the eight pleuropulmonary involvement forms:
Academic Editor: Gerard Espinosa
lupus pleuritis, acute lupus pneumonitis, and shrinking lung syndrome. Pleuropulmonary manifes-
Received: 12 September 2022 tations are part of the clinical criteria for SLE diagnosis. However, no review article has focused on
Accepted: 4 November 2022
the involvement of pleuropulmonary disease in SLE. Therefore, this article summarizes the literature
Published: 13 November 2022
on the epidemiology, pathogenesis, diagnosis, and management of pleuropulmonary involvement
Publisher’s Note: MDPI stays neutral in SLE.
with regard to jurisdictional claims in
published maps and institutional affil- Keywords: systemic lupus erythematosus; autoimmunity; pleuropulmonary; lung; review
iations.
1. Introduction
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with poten-
This article is an open access article
tial multiorgan involvement, including pulmonary involvement, arthritis, photosensitive
distributed under the terms and rashes, glomerulonephritis, and cytopenia [1,2]. SLE is an extremely heterogeneous disease,
conditions of the Creative Commons and its pathophysiology remains unknown [3]. The lack of pathognomonic molecular
Attribution (CC BY) license (https:// markers or nonspecific constitutional symptoms delays the early diagnosis and treatment
creativecommons.org/licenses/by/ of SLE [4]. This complex clinical feature and unknown pathophysiology make the diagnosis
4.0/). of SLE difficult. In 2019, the European League Against Rheumatism (EULAR)/American
J. Clin. Med. 2022, 11, 6714. https://doi.org/10.3390/jcm11226714 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2022, 11, 6714 2 of 23
College of Rheumatology (ACR) developed new SLE classification criteria, including one
obligatory entry criterion (positive antinuclear antibody (ANA)) followed by additional
weighted criteria grouped into seven clinical (constitutional, hematologic, neuropsychiatric,
mucocutaneous, serosal, musculoskeletal, and renal) and three immunologic (antiphospho-
lipid antibodies, complement proteins, and SLE-specific antibodies) domains, weighted
from 2 to 10 [5].
Pleural effusion is included in the current EULAR/ACR criteria. Pleuropulmonary
manifestations, including pleural effusion, are part of the clinical criteria and are highly
prevalent in SLE [6]. Many (50–70%) patients with SLE experience pulmonary complica-
tions ranging from subclinical pleural effusion to life-threatening alveolar hemorrhage [6],
and 4–5% have pulmonary manifestations as presenting symptoms [7]. Pulmonary manifes-
tations in children occur less frequently than in adults; however, they could be significant
and lethal SLE complications [8,9]. Various studies have reported that patients with SLE
may have symptoms of subtle or absent pulmonary dysfunction, suggesting a subclini-
cal disease [10–13]. One multiethnic United States cohort study (LUMINA XLVIII) [14]
reported that 7.6% and 11.6% of patients had permanent lung damage 5 and 10 years after
SLE diagnosis, respectively. Age, pneumonitis, and anti-ribonucleoprotein (anti-RNP) anti-
bodies are positively correlated with the early development of permanent lung disease [14].
In another retrospective (RELESSER) cohort study [15], patients with pleuropulmonary
manifestations had significantly lower survival rates than those without pleuropulmonary
manifestations (82.2% vs. 95.6%, p = 0.030). Thus, SLE-related pleuropulmonary mani-
festations are potentially life-threatening in children and adults with SLE. An in-depth
understanding of SLE-related pleuropulmonary manifestations will help facilitate early
diagnosis and prevent the disease from progressing to a serious condition. Therefore, this
review aimed to describe the epidemiology, pathophysiology, diagnosis, and management
of SLE-related lung diseases, including infection and drug-induced lung injury.
2. Epidemiology
2.1. General Incidence
The term “lupus erythematosus” was initially used by physicians to describe skin
lesions in the 19th century [16]. However, the systemic characteristics, the extent of organ
involvement, and clinical heterogeneity of the disease caused by an abnormal autoimmune
response were not realized until 100 years later [17]. SLE may affect vital organs such as
the brain, blood, kidneys, and predominantly occurs in women of childbearing age [16].
The prevalence of SLE varies according to the sampling and recruitment methods used
in studies and ranges from 20 to 150 cases per 100,000 persons in the United States [16,18].
The incidence of the disease nearly tripled by the end of the 20th century owing to the
improved detection of mild SLE [19].
Geographic and racial distributions appear to affect the prevalence and severity of
SLE in clinical and laboratory settings. People with African or Asian backgrounds have
approximately two to three times higher incidence and prevalence rates in the United States
and the United Kingdom than other ethnicities [20–25]. In more detail, Asians, African
Americans, Caribbeans, and Hispanic Americans have a higher prevalence of SLE than
Caucasians [18,26,27]. Asian and African descents in European countries also show similar
results, while Africa reports the lowest prevalence of SLE [18].
Sex is the most important risk factor for SLE, as 90% of patients with SLE are women
in most studies [18]. Hormones contribute to the onset of SLE through an unknown
mechanism [17]. Cluster of differentiation 40 is located on chromosome X, one of the genes
responsible for the pathogenesis of SLE [16]. Since sex hormones have minimal effects on
children, the women-to-men ratio of patients with SLE is 3:1, while it ranges from 7 to
15:1 in adults, especially in women of childbearing age [20]. Postmenopausal women have
lower grades of sex hormones; hence, the women-to-men ratio is decreased to 8:1 in older
adults [28].
J. Clin. Med. 2022, 11, 6714 3 of 23
SLE can occur throughout life, and approximately 20% of cases are diagnosed within
the first 20 years. It is quite rare before the age of 5 years; yet, its prevalence increases
after the first decade [29–32]. The prevalence and incidence rates of SLE in adulthood
are considerably higher [16]. In patients with late-onset SLE, the women-to-men ratio
and disease activity are lower while organ damage accrual is greater, leading to higher
mortality [33].
2.2. Incidence of Pleural Involvement in SLE

Respiratory involvement in SLE is frequent, especially in men, as nearly 50% of
patients with SLE have lung involvement during the course of their disease, and 4–5%
present with pulmonary symptoms [7,34]. The most favorable thoracic localization involves
the pleura and ranges from an asymptomatic manifestation to pleuritic pain, present in
45–60% of patients. The latter can also be accompanied by radiographically undetectable
chest effusion [34]. The pathologic evidence of pleural fibrosis or pleuritis is 50–93%, and
pleural effusion in chest radiologic studies is 16–50% [34].
2.3. Incidence of Pulmonary Parenchyma Involvement in SLE

The clinical manifestations of lung parenchyma involvement in SLE can be acute
or chronic [34]. Some (2–9%) of the cases present with acute lupus pneumonitis (ALP)
and 3–9% interstitial lung disease (ILD) in previously undiagnosed SLE [34–36]. Diffuse
alveolar hemorrhage (DAH) is a rare but critical manifestation, with a mortality rate of
50–90%, a prevalence of 0.5–5.7%, and a women-to-men ratio of 6:1 [37–47].
3. Pathogenesis
SLE is an autoimmune disease characterized by the production of antibodies against
cell nucleus components. The primary pathological findings in patients with SLE include
inflammation, vasculitis, immune complex deposition, and vasculopathy. Multiple genes
confer susceptibility to disease development. The interaction of sex, hormonal milieu,
the hypothalamic–pituitary–adrenal axis, and defective immune regulation, such as the
clearance of apoptotic cells and immune complexes, modify this susceptibility. The loss
of immune tolerance, increased antigenic load, excess T-cell activities, defective B-cell
suppression, and shifting of Th1 to Th2 immune response causes cytokine imbalance, B-cell
hyperactivity, and the production of pathogenic autoantibodies [48].
Based on this perspective, inflammation and immune response dysregulation are
important drivers of lung pathology in autoimmune diseases [14]. The precise mechanism
of lung involvement in SLE is unknown; however, several features are associated with SLE,
such as elevated systemic type 1 interferon (IFN) levels, circulating immune complexes
(IC), and neutrophils. These factors and other unidentified mediators seem to play essential
roles in driving lung inflammation and, ultimately, fibrosis and tissue damage [49].
Patients with SLE and lung involvement have increased levels of systemic proinflam-
matory cytokines [50,51]. In patients with lung involvement, the levels of proinflammatory
cytokines such as IFN-γ, tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin 8
(IL-8), and interleukin-12 are two or three fold increased in comparison to patients without
lung involvement, and the IL-8/IL-10 ratio was 3 fold increased the level in restrictive lung
disease [50,51]. While the role of inflammation in the progression of pulmonary fibrosis is
unclear, cellular inflammation, particularly in the early stages of the disease, is consistent
with the pathological findings [50,51]. As an effect of initial inflammatory insult (injury,
infection, or antibody deposition), damaged or activated epithelial or endothelial cells
release proinflammatory cytokines or chemokines (such as TNF-a, IL-1, and IL-8), resulting
in the attraction and homing of neutrophils, followed by monocytes, macrophages, and T-
and B-lymphocytes [50,51]. In SLE, neutrophils further play a contributing role, because
they release DNA and histones in a process called NETosis, revealing autoantigens and
self-DNA to further exacerbate inflammatory responses [52]. Type 1 IFNs also play an
essential role in driving neutrophil NETosis, autoantibody production, and breaking the
J. Clin. Med. 2022, 11, 6714 4 of 23
immune tolerance in the lungs [49]. This reciprocal interaction between the initiating factors
(IFNs, autoantibodies, immune complexes, infectious insult, or injury) and downstream
responses (complement activation, neutrophil accumulation, and activation) likely plays
an essential role in driving SLE-associated lung involvement [49]. Macrophage activa-
tion syndrome (MAS) has been described in several case reports of patients with lupus;
however, its relationship is unclear and is rarely the first presentation of SLE [53–55]. In
juvenile SLE, some cases of MAS that developed in the initial stage should be treated with
immunosuppressants [56].
In recent decades, many studies have been published on the pathogenesis of SLE-
associated lung involvement (Figure 1). Table 1 summarizes the major studies on the
pathogenesis of SLE-associated lung involvement.
Table 1. Studies on the pathogenesis of lupus-associated lung involvement.
Study
Published Year Key Finding Comments
Type
Nielepkowicz- The mean IL-6 and IL-10 concentrations in the BALF and the
Goździńska A IL-10 concentration in the EBC were higher in patients with SLE
Exhaled cytokines in SLE with
et al. In vivo compared with healthy controls. Study showed that IL-6 and
lung involvement
(2013) IL-10 are involved in the pathogenesis of SLE and it is likely
[57] that IL-10 protects against pulmonary manifestations of SLE.
The pathogenesis of DAH involves opsonization of dead cells
Zhuang H by natural IgM and complement followed by complement
Pathogenesis of diffuse
et al. receptor-mediated lung inflammation. The disease is
In vivo alveolar hemorrhage in
(2017) macrophage dependent, and IL-10 is protective. Complement
murine lupus
[58] inhibition and/or macrophage-targeted therapies may reduce
mortality in lupus-associated DAH.
Neutrophil infiltration was markedly reduced in the
peritoneal lavage of pristane-treated IL-16-deficient mice and
elevated following administration of IL-16. miR-125a mimic
Smith S IL-16/miR-125a axis controls
reduced pristane-induced IL-16 expression and neutrophil
et al. In vivo/ neutrophil recruitment in
recruitment and abrogated the induced lung pathology.
(2018) In vitro pristane-induced lung
To sum up, IL-16 acts directly on the pulmonary epithelium
[59] inflammation
and markedly enhances neutrophil chemoattractant
expression both in vitro and in vivo, while the miR-125a
mimic can prevent this.
Jarrot P-A NETs are associated with the PMNs and NETs play an important pathogenic role in lung
et al. pathogenesis of diffuse injury during pristane-induced DAH. Targeting NETs with
In vivo
(2019) alveolar hemorrhage in Rh-DNase-1 inhalations could be an interesting adjuvant
[60] murine lupus therapy in human DAH.
Abbreviations: SLE: systemic lupus erythematosus, BALF: bronchoalveolar lavage fluid, EBC: exhaled breath
condensate, IgM: immunoglobulin M, DAH: diffuse alveolar hemorrhage, PMN: polymorphonuclear neutrophil,
NETs: neutrophil extracellular traps, miR: microRNAs, and Rh-DNase: recombinant human deoxyribonuclease.
J. Clin. Med. 2022, 11, 6714 5 of 23
Figure 1. Pathogenesis of lung involvement in SLE [50,51,59,60].
4. Diagnosis
4.1. Chest X-ray (CXR)
The CXR findings vary for various diseases. Pleural effusion was observed in patients
with pleural involvement [35]. In ALP, the CXR frequently demonstrates nonspecific pleural
effusions and acute development of consolidation in one or more areas (usually basal and
bilateral) [35]. Regarding chronic ILD, although patients usually have clinical symptoms
such as dyspnea on exertion, pleuritic pain, dry cough, and rales, the results may be normal
or show irregular opacities in the early stages [61]. However, in later stages, it shows
diffuse or bi-basal infiltration, pleural disease, honeycomb (coarse reticular opacities),
and diminished lung volume [35]. Regarding DAH, the radiograph might show diffuse
hemorrhage, a diffuse infiltrative opacification pattern with a slight predilection towards
the mid zones with some apical sparing [35]. In shrinking lung syndrome (SLS), a rare and
less-known SLE complication that shows diaphragmatic dysfunction and reduced diffusing
capacity for carbon monoxide (DLco), a typical finding is elevated hemidiaphragm and
reduced lung volume [62–64]. Interstitial infiltrates, pleural thickening, and basal atelectasis
can also be found, but the CXR results are normal in some cases [65,66].
As described above, previous studies on CXR findings in patients with SLE with lung
involvement were descriptive and did not report the prevalence of each manifestation.
However, in symptomatic patients, CXR results usually correlate with clinical symptoms.
As in the early stages of chronic ILD and SLS, images can demonstrate normal findings [35].
Therefore, chest radiography is the most basic imaging tool for assessing lung involvement
in SLE. However, its sensitivity for screening lung involvement in SLE is low, suggesting
the need for another diagnostic tool.
J. Clin. Med. 2022, 11, 6714 6 of 23
4.2. Computerized Tomography (CT)

Early diagnosis of pulmonary involvement in patients with SLE can be achieved using
high-resolution CT (HRCT). In adults, 70% of patients with SLE showed abnormal findings
on HRCT, such as thickened interlobular septa (44%), parenchymal bands (44%), subpleural
bands (21%), bronchiectasis (21%), and bronchial wall thickening (21%) [67]. CT imaging
in symptomatic children with SLE also shows ground-glass opacity (GGO) (33%), mosaic
appearance (27%), pleural irregularity (27%), and bronchial wall thickening (27%) [68].
Some children with SLE without clinical manifestations of pulmonary diseases also showed
HRCT findings, such as GGO, consolidation, and pleural irregularity [68]. Therefore, HRCT
helps to detect early-stage pulmonary involvement in symptomatic and asymptomatic
patients with SLE.
A study from China showed GGO in ten (55.6%) patients, interlobular septal thicken-
ing in nine (50.0%), bilateral diffuse infiltrates in nine (50.0%), pleurisy/pleural effusion in
eight (44.4%), fibrotic streaks in six (33.3%), and patchy infiltrates in five (27.8%) (Figure 1).
Most abnormalities were bilaterally distributed (94.4%) in the lower lobes (82.3%) or sub-
pleural regions (61.1%) (Figure 2) [69].
Figure 2. HRCT scans of the SLE patients with pulmonary involvement. Arrow indicate the shape
of lung lesion of HRCT (A) Fibrotic streak. (B) Reticular pattern. (C) Mosaic perfusion. (D) Pleural
thickening. (E) Ground glass opacity. (F) Subpleural interlobular septal thickening (The CC-BY
Creative Commons attribution license, Dai G, Li L, Wang T, Jiang W, Ma J, Yan Y, Chen Z. Pulmonary
Involvement in Children With Systemic Lupus Erythematosus. Front Pediatr. 2021 Feb 2; 8:617137.
doi: 10.3389/fped.2020.617137. PMID: 33604317; PMCID: PMC7884320) [69].
Patients with pulmonary fibrosis, such as ILD, had GGO, and the extent of the disease,
according to the CT, correlates well with the spirometric values, such as forced expira-
tory volume in the first forced expiratory volume/forced vital capacity (FEV1/FVC) and
DLco [70]. The results suggest that CT imaging is helpful for patients with SLE with
pulmonary involvement owing to its relatively precise expectation of pulmonary func-
tion. Furthermore, some HRCT findings of patients with ILD correlated with open lung
biopsy [67]. In some cases, patients with SLE (21%) were diagnosed with ILD using
HRCT while there were no significant changes in the CXR and pulmonary function test
(PFT) results [67]. Therefore, abnormal HRCT changes allow the diagnosis of pulmonary
involvement which is undetectable by other diagnostic tools.
4.3. Pulmonary Function Test

PFT can be an effective diagnostic tool for patients with SLE and subclinical pul-
monary disease. PFT allows the early detection of patients with SLE with pulmonary
involvement, because they show low DLco without any respiratory clinical manifesta-
tions [71]. Furthermore, some patients with SLE only showed a reduction in DLco without
J. Clin. Med. 2022, 11, 6714 7 of 23
any abnormalities in imaging studies [71]. Among the measured spirometric values, such
as the FVC, FEV1/FVC ratio, total lung capacity (TLC), and functional residual capacity
(FRC), the most prevalent PFT impairment was DLco [71]. The broad availability of PFT
makes it the preferred method; however, it has some limitations, such as abnormal results in
patients with obstruction, restriction, or abnormal diffusing capacity [72]. Therefore, some
patients with SLE and pulmonary involvement may not be detected using PFT. In such
cases, other imaging tools or the six-minute walk test, which evaluates the total distance
walked, oxygen desaturation, and the patient-reported Borg Dyspnea Scale after walking
back and forth down a 30-m hallway, can help to detect pulmonary diseases [72].
4.4. Biopsy
In patients with pleural involvement, fibrosis, lymphocytic and plasma cell infiltration,
and fibrinous pleuritis were detected, and anti-IgG, anti-IgM, and anti-C3 nuclear patterns
were seen in the immunofluorescence tests [73]. ALP shows alveolar wall damage, necrosis,
inflammatory cell infiltration, edema, hemorrhage, and hyaline membranes [73]. The pre-
dominant finding in DAH is bland hemorrhage, capillaritis, immune complex deposition,
and neutrophils in the alveolar walls at lower rates [45,47].
However, a biopsy is only used when the diagnosis is uncertain and other findings are
nonspecific [73]. Postoperative complications, morbidity, and mortality are factors limiting
the use of lung biopsy [74].
4.5. Bronchoalveolar Lavage (BAL)

BAL is mainly used to exclude other causes of respiratory compromise. It can be
used to rule out infection as an underlying cause of ALP, and BAL shows an increase in
cellularity because of the activation of polymorphonuclear cells in such cases [51]. One
study showed the predominance of lymphocytes and neutrophils in ILD; however, SLE
without pulmonary symptoms showed a predominance of macrophages [75]. In patients
with nonspecific symptoms, BAL is useful to confirm DAH, which is defined as ≥20% of
hemosiderin-laden macrophages in bronchoalveolar lavage fluid (BALF) [76–78].
4.6. FDG-PET
In 2020, a study showed that a high FDG uptake in pulmonary arterial hypertension
(PAH) in patients with SLE correlated with SLE disease activity and the immune/inflammatory
status (C3 and C4 levels) [79]. Thus, FDG-PET may assess intrapulmonary disease activity
markers in patients with SLE-PAH [79].
4.7. Dynamic Magnetic Resonance Imaging (MRI)

An MRI can confirm pleuritis in SLE-associated shrinking lung syndrome. Dynamic
MRI sequences on forced voluntary ventilation can confirm the physiological movements of
the diaphragms and all auxiliary respiratory muscles [80,81]. The evaluation of diaphragm
dome motion using a dynamic contrast-enhanced lung MRI might be a useful second-line
tool to reinforce clinical suspicion in cases of diagnostic difficulty. It is not as widely used
as other imaging studies; however, a dynamic MRI can sufficiently diagnose this disease.
4.8. Summary
The diagnosis of pulmonary involvement is made by using different imaging tools [67].
However, using a single tool to define pulmonary involvement is insufficient. For example,
there is little evidence for the use of PFT as a screening method, as lung involvement is
uncommon and is mostly acute [82]. Reductions in DLco and the maximum voluntary
ventilation are generally not helpful to evaluate if pulmonary involvement is present [82].
Therefore, pulmonary screening in SLE should include chest CT and PFTs, which are mildly
invasive, easily available, and can sometimes detect early manifestations before symptoms
occur. Additional studies, such as a dynamic MRI, should be performed for lung-involved
diseases with poor prognoses (Table 2).
J. Clin. Med. 2022, 11, 6714 8 of 23
Table 2. Summary of the characteristics of the diagnostic tools to diagnose pulmonary involvement
in SLE.
Key Finding Comments Ref

CXR findings vary upon diseases, and usually CXR is the most basic imaging method, and its
CXR [35,61–66]
correlate with clinical symptoms [35]. sensitivity is low.
70% of the patients showed abnormal findings such CT imaging is useful to make an early diagnosis of
CT as interlobular septa thickening, parenchymal bands, pulmonary involvement, and it provides precise [67,68,70]
etc [67]. expectation of pulmonary function [64].
PFT provides an option to early detect of
DLco shows the most prominent abnormality among
PFT pulmonary involvement in SLE patients, but it [71,72]
the spirometric values [71]
lacks sensitivity [71,72].
Pleural involvement shows results such as fibrosis,
Biopsy is rarely used in the diagnostic work-up; it
lymphocytic/plasma cell infiltration, etc. ALP show
is used only when the diagnosis is unclear and
Biopsy alveolar wall damage and necrosis, etc. [45,47,73]
other findings are nonspecific, and it is avoided
Bland hemorrhage is predominantly found in DAH
due to postoperative complications [45].
[45,47,73].
It shows increased cellularity in ALP,
lymphocytic/neutrophilic predominance in ILD, BAL is mainly performed to exclude other causes
BAL [35,51,75–77]
predominance of macrophage in SLE, and the such as infections [35].
presence of hemosiderophage in DAH [35,51,75–77].
SLE disease activity and immune/inflammatory
It can be the potential marker for intrapulmonary
FDG-PET status is correlated with high FDG uptake PAH in [79]
disease activity in SLE-PAH patients [79].
patients with SLE [79].
Dynamic MRI sequences on forced voluntary Magnetic resonance imaging-confirmed pleuritis in
Dynamic MRI ventilation can confirm physiologic movements of systemic lupus erythematosus-associated shrinking [80,81]
both diaphragms and all auxiliary respiratory muscles lung syndrome
Abbreviations: CXR: Chest X-ray, CT: computed tomography, SLE: systemic lupus erythematosus, PFT: pulmonary
function test, DLco: diffusing capacity for carbon monoxide, ALP: acute lupus pneumonitis, DAH: diffuse alveolar
hemorrhage, BAL: bronchoalveolar lavage, ILD: interstitial lung disease, FDG: fluorodeoxyglucose, PET: positron
emission tomography, PAH: pulmonary arterial hypertension, and MRI: Magnetic Resonance Imaging.
5. Types of Pulmonary Involvement

SLE can cause various pulmonary diseases, such as pleural effusion/pleuritis, shrink-
ing lung syndrome, acute pneumonitis, DAH, chronic ILD, and pulmonary hyperten-
sion [35]. Pleuritis is the most common intrathoracic disease in SLE, which presents with
chest pain, cough, dyspnea, and pleural effusion [34,83]. ALP and DAH are acute pul-
monary diseases resulting from damage to the alveolar–capillary unit [83], while ILD is a
chronic pulmonary disease that causes pulmonary fibrosis [83]. We summarize the clinical
manifestation, treatment, sequelae, and outcomes according to the type (Table 3).
5.1. Lupus Pleuritis

5.1.1. Clinical Manifestation
Pleuritis, also known as pleurisy, is an inflammation of the pleural tissue that causes
sharp chest pain (pleuritic pain), which worsens during breathing. Pleuritis with or without
pleural effusion is the most common feature of acute pulmonary involvement in SLE [84].
It is characterized by chest pain, dyspnea, shortness of breath, cough, and possibly fever.
Pleuritis is often difficult to diagnose without pleural effusion on a chest X-ray. Pleural
friction rubbing may facilitate the diagnosis of pleuritis [84]. A pleural US or HRCT
combined with serological markers for SLE activity can confirm pleuritis in vague cases [85].
Pleural effusion in SLE is often bilateral (50%), and the amount is usually small to
moderate. The pleural fluid appearance varies from clear serous to serosanguineous and
bloody [84]. It is an exudate characterized by elevated lactate dehydrogenase and a white
blood cell count of 3000–5000 cells/mL, with a predominance of neutrophils or mononuclear
cells [83]. Hemopneumothorax has been described in patients with lupus pleuritis; however,
spontaneous pneumothorax is uncommon [86]. Fibrothorax is a rare complication that can
lead to dyspnea and shortness of breath by preventing lung expansion [87].
J. Clin. Med. 2022, 11, 6714 9 of 23
5.1.2. Treatment
Treatment options for lupus pleuritis differ depending on the severity of symptoms.
Mild pleuritis can be treated with NSAIDs [88]. If a patient has difficulty enduring the
gastrointestinal side effects of NSAIDs, the dosage may be adjusted [88], and NSAIDs
should be avoided in patients with impaired kidney function. Antimalarials such as
hydroxychloroquine may be added in some cases [89].
Systemic corticosteroids are the drugs of choice for patients with severe lupus pleuritis.
Hunder et al. found that five out of six patients with lupus pleuritis treated with corticos-
teroids experienced a rapid disappearance of pleural effusions [90]. Winslow et al. reported
that effusions in 10 out of 11 patients subsided quickly after treatment [91]. If the volume
of pleural fluid is large, aspiration may be required to alleviate respiratory difficulties [87].
Cyclophosphamide should be considered for patients who do not respond to corticos-
teroids or have concomitant kidney involvement [88]. Other options include mycophenolate
mofetil (MMF) and rituximab. Kariem et al. showed that MMF lowered the extrarenal and
renal symptoms in patients with SLE who did not respond to conventional therapies [92].
In another study by Ng et al., two out of seven patients with lupus pleuritis experienced
improvement after depleting B cells with rituximab [93].
Intravenous immunoglobulin (IVIg) is not the mainstay treatment for lupus pleuritis;
however, Meissner et al. reported that 1 month of IVIg therapy effectively decreased pleural
effusion in patients with SLE and severe pleuritis [94]. Sherer et al. also reported that a
combined therapy of IVIg and cyclosporin alleviated massive pleural effusion [95]. These
reports suggest the utility of IVIg in patients with severe lupus; however, further studies
are needed to confirm its clinical effectiveness.
A pleurectomy may be needed in rare cases of patients with refractory pleural effusion
who do not respond to immunosuppressive drugs [96]. Sichan et al. successfully treated
such patients by performing open surgical pleurectomy [96].
5.1.3. Sequelae and Outcomes

Pleural diseases, especially lupus pleuritis, cause severe lung restriction and fibrotho-
rax in chronic and refractory pleuritis [87]. Patients with acute pleurisy normally present
with severe chest pain, dyspnea, fever, cough, and friction rub [97]. With pleural effusion
and pleuritis, some patients were initially not diagnosed with SLE but with other pul-
monary diseases. In one study, out of 14 patients diagnosed with lupus pleuritis, only five
were diagnosed with SLE on admission. The rest were initially diagnosed with pulmonary
embolism, congestive heart failure, and other pulmonary manifestations [97]. Lupus pleu-
ritis was finally diagnosed based on a pleural fluid analysis and clinical presentation,
indicating an SLE diagnosis. Since lupus pleuritis was misdiagnosed and inadequate
treatment was provided, some patients developed rare complications, such as fibrothorax.
Fibrothorax is a state of progressive pleural fibrosis that leads to limited lung expansion
and dyspnea [87]. In one study, pleural stripping, also known as decortication, effectively
treated thickened visceral pleura [87]. Lupus pleuritis has good treatment outcomes. In a
study of 119 patients involving 127 pleuritis/pleural effusion episodes, 93% of the patients
responded to corticosteroids, and out of these, 94% completely responded to the initial
treatment. Relapse only occurred in approximately 13% of patients, and none progressed
to fibrotic disease [98]. Lupus pleuritis is the most common pulmonary complication of
SLE; however, its prognosis and treatment response are good.
5.2. Pleural Effusion

According to the EULAR/ACR_2019 criteria, the only criterion that is related to lung
involvement is pleural effusion, and the definition of this criterion is evidenced by imaging
techniques: ultrasound, X-ray, CT scan, and MRI [5]. Pleural effusion in SLE may be caused
by autoimmune pleuritis, but it cannot be easily distinguished from other causes, such as
J. Clin. Med. 2022, 11, 6714 10 of 23
infections, heart disease, and tuberculosis [6]. Therefore, more detailed criteria for pleural
effusion should be established.
5.2.2. Treatment
Usually, SLE-associated pleural effusion responds quickly to corticosteroids [99]. How-
ever, persistent steroid-resistant pleural effusion can occur in some cases. Various methods
have been used to treat these cases. Some cases of SLE-associated steroid-resistant pleural
effusion have been successfully treated with tetracycline pleurodesis [100,101]. A case of
SLE-associated refractory massive pleural effusion was successfully treated with pleurec-
tomy [102].

No study with a statistically meaningful sample size was found regarding the sequelae
and outcomes of SLE-associated pleural effusion.
5.3. Acute Lupus Pneumonitis (ALP)

ALP is an uncommon SLE manifestation [103]. The clinical presentation of ALP is sim-
ilar to that of acute interstitial pneumonia, characterized by the acute onset of fever, cough,
and dyspnea [104]. Sometimes, hemoptysis is accompanied by tachypnea, tachycardia,
inspiratory crackles, and hypoxemia during the physical examination. Half of the patients
with ALP experience pneumonitis as the initial SLE manifestation [104]. Diffuse alveolar
damage, alveolar edema, hyaline membrane formation, and mononuclear cell infiltration
can be found during histopathological examination. Immunoglobulin and complement
deposition may be present in capillary walls [105,106]. Alveolar hemorrhage may also
be noted, whereas vasculitis is uncommon [104]. Chest X-rays reveal diffuse or patchy
opacities, predominantly in the lower lung zones. A differential diagnosis is needed to
rule out infection, organizing pneumonia, pulmonary embolism, drug toxicity, DAH, heart
failure, and malignancy [106].
5.3.2. Treatment
Empirical broad-spectrum antibiotic therapy should be administered without delay
because of the high incidence of infection [107]. After infectious etiologies are excluded,
aggressive immunosuppressive therapy must be initiated. High doses of intravenous
methylprednisolone, oral corticosteroids, and intravenous cyclophosphamide can be consid-
ered [91]. In addition, successful treatment with rituximab has been reported [108]. Plasma
exchange and intravenous immunoglobulins have been used in refractory cases [109].

Acute lupus pneumonitis is a complication of SLE that occurs in 1–12% of patients.
It is a life-threatening condition characterized by nonspecific alveolar damage, necrosis,
inflammatory cell infiltration, and edema [51]. Studies have not been reported since 1975,
indicating that, out of 12 cases with acute lupus pneumonitis, six patients survived, and
most had residual interstitial infiltrates that led to chronic interstitial pneumonitis [104].
Specific studies related to acute lupus pneumonitis have not been conducted; however,
the current treatment with ventilators and plasma exchange has improved its prognosis.
Patients are at risk of persistent pulmonary function abnormalities and restrictive lung
disease in cases of infection [51]. The patient’s clinical presentation is similar to that of
acute interstitial pneumonia. No specific treatment is available; however, most patients are
treated with broad-spectrum antibiotics.
J. Clin. Med. 2022, 11, 6714 11 of 23
5.4. Diffuse Alveolar Hemorrhage

DAH varies in its clinical intensity, ranging from mild to severe, potentially life-
threatening pulmonary hemorrhage. Patients experiencing DAH present with dyspnea,
cough, fever, blood-stained sputum, and sometimes hemoptysis, with symptoms devel-
oping rapidly within a few hours or days [78]. Typical conditions include a drop in the
hemoglobin level and diffuse lung infiltrates visible on chest X-rays or high-resolution chest
CT [78]. Infections can be associated with DAH and should be ruled out as a differential
diagnosis [36]. BAL is useful for confirming DAH when ≥ 20% of hemosiderin-laden
macrophages in BALF are present [78].
5.4.2. Treatment
There are no specific treatment guidelines for DAH; however, high-dose methylpred-
nisolone is often used [110]. Cyclophosphamide is another option, but its effectiveness is
controversial. Zamora et al. found that cyclophosphamide caused increased mortality [38],
which might have been confounded by an indication bias. In other studies, plasma ex-
change was used in combination with cyclophosphamide or methylprednisolone; however,
its effectiveness as a monotherapy has not been established [77].

The mortality rate of patients with SLE and pulmonary hemorrhage is very high.
Evidence suggests a mortality rate of 68–75% [111,112] during follow-up. The latter study
showed that the same proportion (75%) required mechanical ventilation [112]. Mortality
is related to several factors. First, patients who experience severe dyspnea and require
mechanical ventilation are at a higher risk of mortality [111,112]. This results from severe
dyspnea associated with severe lung failure, and patients with long-term mechanical
ventilation have a higher risk of ventilator-associated pneumonia [112]. Second, kidney
failure in patients with pulmonary hemorrhage also contributes to poor outcomes [42].
Third, patients with neuropsychiatric complications are at a high risk of mortality [113].
Other factors such as thrombocytopenia, infections, age, and multi-organ failure scores also
cause higher mortality [111].
However, recent studies have shown that the early and aggressive treatment of pa-
tients presenting with pulmonary hemorrhage can increase their survival rates [114]. This
includes management with high-dose steroids, IVIG, and cyclophosphamide [76]. Infec-
tions occur concomitantly in approximately 57% of patients with pulmonary hemorrhage;
therefore, managing these patients with the appropriate antibiotics is important to lower
the mortality rate [115]. In addition, alternative and experimental therapeutic approaches,
such as umbilical cord-derived mesenchymal stem cell transplantation, have been shown
to improve outcomes [116,117].
5.5. Interstitial Lung Disease (ILD)

The true prevalence of SLE-associated interstitial lung disease (SLE-ILD) is unknown;
however, a prevalence rate of 3–9% has been reported [103,107,118]. Nonspecific interstitial
pneumonia (NSIP), organizing pneumonia, lymphocytic interstitial pneumonia (LIP), follicular
bronchiolitis, nodular lymphoid hyperplasia, and usual interstitial pneumonia are associated
with SLE. Among these, NSIP is the most common [119]. Patients with SLE-ILD typically show
an insidious onset of chronic nonproductive cough, dyspnea, decreased exercise tolerance,
and basilar crackles on physical examination, but some patients are asymptomatic [120]. By
identifying these clinical features, a SLE-ILD diagnosis is made on a clinical basis and by
HR CT confirming ILD; while excluding other causes, such as infection, drug toxicity, and
heart failure [119]. The serological markers for SLE did not show a good correlation with the
development of ILD, but they helped confirm the SLE diagnosis [107].
J. Clin. Med. 2022, 11, 6714 12 of 23
5.5.2. Treatment
SLE-associated ILD treatment is mainly based on expert opinion [121]. Recent treat-
ment algorithms suggest induction therapy with corticosteroids alone or with cyclophos-
phamide or MMF and maintenance therapy with azathioprine or MMF.

In a retrospective, a multicenter study from Japan, including 55 patients with SLE-
related interstitial pneumonia, the overall 5-year survival rate was 85.3% [122]. Fifty-one
out of fifty-five patients were treated for interstitial pneumonia, all of whom had received
corticosteroids, and twenty-two out of these received immunosuppressive medications.
Among the prognostic factors, smoking, thrombocytopenia, and the extent of lung fibrosis
(extent scores of 2 or 3) on HRCT predicted worse outcomes [122].
In lupus-associated pneumonitis, another type of ILD, progression to respiratory fail-
ure is common and results in high mortality [111]. ALP may develop as part of a generalized
SLE flare, typically in patients with multisystem involvement, including nephritis, arthritis,
pericarditis, and pleuritis. Fulminant ALP levels may also occur during pregnancy. Patients
with ALP may have an acute onset of fever, dyspnea, and cough with scanty expectoration,
hemoptysis, and pleuritic chest pain [111]. The symptoms include cyanosis and bi-basilar
rales [111]. Furthermore, the arterial blood gas analysis results showed hypoxia in almost
all the patients. DAH can occur concomitantly, although DAH may also occur in other
SLE-related entities, including antiphospholipid syndrome, and distinguishing between
these entities can be challenging [123]. In addition, it is difficult to accurately estimate the
exact incidence and outcome statistics of SLE-associated ILD, because many patients with
lupus and transient pleural diseases do not show symptoms, and a diagnosis is often made
late in the disease course.
5.6. Shrinking Lung Syndrome

Shrinking lung syndrome (SLS) was first described by Hoffbrand and Beck in 1965 [124].
SLS is a rare SLE complication. Its estimated prevalence is <1% [65,125]. The appearance
of SLS as the primary respiratory SLE symptom is very rare [126,127]. Few cases show
that SLS was diagnosed at the time of SLE diagnosis. SLS is usually discovered after SLE
diagnosis (the mean delay between SLE and SLS diagnosis is approximately 67 months) [66].
The sex ratio showed a higher prevalence in women [66]. All patients with SLS complained
of respiratory symptoms such as dyspnea, coughing, and pleuritic chest pain [66,124]. SLS
is characterized by a progressive decrease in lung volume on PFT and no evidence of
interstitial disease or significant pleural disease on the chest CT [65,127].
5.6.2. Treatment
There are no clinical guidelines for SLS owing to its rare incidence. However, many
cases of SLS associated with SLE have been treated with glucocorticosteroids monotherapy
or in addition with other immunosuppressive agents, such as cyclophosphamide, azathio-
prine, MTX, and mycophenolate mofetil [66,81,128]. Theophylline and beta-agonists can
help with diaphragmatic weakness [129–131]. Rituximab has also been used successfully
as a monotherapy or with cyclophosphamide and beta-agonists, especially in steroid-
refractory cases [81,132,133]. Other drugs have been used successfully after steroid failure;
however, in a retrospective study by Robles-Perez et al., 6/18 patients reported adverse
effects of rituximab [134]. Belimumab is approved for non-renal SLE, and a case report
showed improvement in SLS symptoms; however, further studies are needed [135].

The etiology of SLS has been explained by the relationship between diaphragmatic
weakness resulting from inflammatory myopathy and phrenic neuropathy. Elevation of the
diaphragm leads to dyspnea and reduced lung volumes. Treatment with corticosteroids
J. Clin. Med. 2022, 11, 6714 13 of 23
and immunosuppressive therapy showed good response rate. However, in some patients,
diaphragmatic weakness persists after treatment and requires surgical treatment [136].
Most patients exhibit acute symptomatic improvement and reversible pulmonary function.
In a study of 55 patients, 18% had no functional sequelae, the rest showed significant clinical
improvement, and none required long-term oxygen therapy [81]. Most patients are usually
healed from SLS; however, they must be aware of the associated complications, such as
pneumonia, that can impact further prescription of immunosuppression and thus efficacy.
5.7. Pulmonary Arterial Hypertension

PAH is not included in any pre-existing SLE diagnostic criteria; however, it is a rare
complication with increasing recognition in patients with SLE. PAH must be accurately
diagnosed and promptly treated, as it may lead to irreversible changes in the right ventricle
or lung capillaries, causing high mortality in patients with PAH [137]. In large cohort
studies, approximately 2–5% of patients with SLE were diagnosed with PAH [138,139]. The
delay period between the diagnosis of SLE and PAH was approximately 3–5 years [138,140].
The 5-year survival rate was 70–80% [138,140].
Several efforts have been made to elucidate the clinical and laboratory risk factors and
predictors of PAH in patients with SLE. Systemic hypertension, high fibrinogen levels, and
the presence of serositis and thrombocytopenia are clinical risk factors, indicating that SLE
complications in other organ systems may contribute to the pulmonary manifestations of
SLE [138,139]. Scleroderma-like nailfold capillary patterns and the Raynaud phenomenon
are also important risk factors for PAH in patients with SLE, in line with the well-established
connection between scleroderma and PAH [141,142]. Many studies have found that high
levels of anti-SSA/SSB, anticardiolipin, and anti-RNP antibodies predict a higher incidence
of PAH [140,142,143]. High levels of anti-U1-RNP antibodies also indicate longer survival
periods despite the higher incidence of SLE in patients with PAH [140].
5.7.2. Treatment
Immunosuppressive therapies based on intravenous cyclophosphamide have been suc-
cessfully used in several studies. As such, intravenous cyclophosphamide and prednisolone
reduce the pulmonary artery pressure [144,145]. In addition to immunosuppressive ther-
apies, vasodilators are also effective [146,147]. Multiple studies have demonstrated the
efficacy of intravenous epoprostenol (prostacyclin) in normalizing the pulmonary artery
pressure in patients with SLE and PAH [148,149]. Bosentan improved the New York Heart
Association class and exercise tolerance [150,151]. A case of SLE-associated severe PAH
treated with sildenafil was reported in 2003 [152]. A double-blinded study conducted in
2007 showed that sildenafil could improve exercise tolerance, hemodynamic measures, and
the World Health Organization functional class in patients with SLE-associated PAH [153].

PAH significantly affects the survival and quality of life in connective tissue diseases,
including SLE. It is the third most common cause of death in SLE, following infection
and organ failure [154]. As other manifestations of SLE respond well to therapy, PAH is
becoming a more important cause of various morbidities and premature deaths [154].
Direct comparisons from the REVEAL registry showed that patients with connective
tissue disease-associated PAH had poorer 1-year survival than those with idiopathic PAH
(86% vs. 93%). However, patients with SLE had the best 1-year survival rates (94% vs. 82%
for scleroderma and 88% for MCTD), although all patients had comparable hemodynamic
characteristics at PAH diagnosis [155]. The study cohort was not confined to patients with
SLE; however, data from the Korean connective tissue disease (CTD)-related PAH registry,
with 174 enrolled patients (61 with SLE, 50 with systemic sclerosis, 10 with mixed CTD, 22
with rheumatoid arthritis (RA), and 31 with other CTDs), demonstrated that the overall 1-
and 3-year survival rates of CTD-PAH were 90.7% and 87.3%, respectively [156]. In that
J. Clin. Med. 2022, 11, 6714 14 of 23
study, low DLco, diabetes, and pleural effusion were poor prognostic factors, whereas
anti-U1-RNP antibodies seemed to be protective. A recent meta-analysis of six studies
encompassing 323 patients with lupus and PAH demonstrated that the pooled 1-, 3-, and
5-year survival rates were 88%, 81%, and 68%, respectively [157].
Additionally, complete autopsy studies of 90 patients diagnosed with SLE (under the
ACR diagnostic criteria for SLE) between 1958 and 2006 were performed, and their clinical
records were studied [158]. Four of ninety patients showed lesions highly suggestive of
PHT (4.4%) [158]. The SLE evolution time ranged from 15 to 23 years. Upon histological
examination, they all showed plexiform lesions and organizing microthrombosis, and three
of the patients had dilation and hypertrophy of the right ventricle of the heart. At the
time of death, three patients had Raynaud’s phenomenon, arthralgia, malar erythema, and
hypoxemia, with negative rheumatoid factor and positive ANA [158].
5.8. Pulmonary Embolism

Pulmonary embolism (PE) is a rare but potentially fatal pulmonary complication of
SLE that requires careful attention, as most of its causes can be treated. Multiple population
studies suggest that patients with SLE are significantly more susceptible to PE and related
clinical manifestations, such as deep vein thrombosis, and this association is independent
of age, sex, race, and preexisting patient comorbidities [65,159]. The overall prevalence of
PE is 1–5% in patients with SLE [159,160]. The risk factors for PE include a high body mass
index, fast progression of SLE, hypoalbuminemia, antiphospholipid antibodies, and high
doses of glucocorticoids [160].
5.8.2. Treatment
Limited amount of research has been conducted on the treatment of SLE-associated
PE; the following recommendations are generally applicable to PE. Early anticoagulation
therapy should be used when PE is diagnosed or suspected to reduce its mortality [161]. In
patients with massive PE or persistent hypotension (systolic blood pressure < 90 mmHg),
the CHEST guidelines recommend thrombolysis as a grade 2 B recommendation [162]. In
patients with massive PE, the benefits of thrombolysis usually outweigh the risks unless
there is active, uncontrolled bleeding [163].

Complete autopsy studies of 90 patients with SLE diagnosed between 1958 and 2006
and their clinical records were conducted. All patients fulfilled the ACR diagnostic criteria
for SLE [8]. Seven patients with pulmonary thromboembolism were detected, four of whom
had recurrent PE (4.4%). One case of acute PE was due to catastrophic antiphospholipid
syndrome, accompanied by multiple acute arterial and venous thromboses in several organ
systems. All patients had active lupus nephropathy at death [158].
Lifelong anticoagulation treatments may be warranted in patients with recurrent
thromboembolic disease [164]. In addition, intensive treatment with corticosteroids or
immunosuppressive agents may be required when anticoagulation monotherapy fails to
control thrombosis [164].
5.9. Drug Toxicity and Lung Involvement of SLE

ILD and ALP can be caused by multiple medications, and drug-induced lung diseases
should be differentiated from lung involvement in SLE. Several lung diseases are caused by
therapeutic agents in patients with underlying diseases such as connective tissue disease
and cancer [165]. Since imaging studies can distinguish both conditions, a history of new
medications started before evaluating lung involvement in SLE should be considered for
diagnosing ILD and ALP [166].
J. Clin. Med. 2022, 11, 6714 15 of 23
Table 3. Summary of the types of pulmonary involvement in SLE.
Clinical Symptom Treatment Outcome Summary Ref

Options vary upon the severity of symptoms.
NSAIDs can be used for mild pleuritis, and
antimalarials may be added [88,89].
Systemic corticosteroid is a treatment choice for severe Prognosis and treatment
Lupus pleuritis can be treated by
pleuritis [90]. Aspiration may be needed for massive response are good in general [98].
immunosuppressive drugs, and
pleural effusion [87]. Severe lung restriction and
has good prognosis in general.
Lupus pleuritis Cyclophosphamide, MMF, rituximab can be fibrothorax can occur. Rare [87–98]
Some rare complications can
considered for steroid-resistance or when renal complications like fibrothorax
occur, because it can be
involvement is present [88,92]. can occur, due to misdiagnosis
misdiagnosed initilally.
The use of IVIG (alone or combined with cyclosporin) and inadequate treatment [87].
has been reported, but further studies are needed
[94,95].
Pleurectomy may be needed in rare cases [96].
Pleural effusion is identified by
The criterion is imaging evidence:
imaging, and it may be caused by
US, X-ray, CT, MRI [5]. It usually shows a rapid response to corticosteroids
autoimmune pleuritis. It
Pleural effusion in SLE may be [99]. Some may have persistent steroid resistant No statistically meaningful
Pleural effusion responds well to corticosteroids. [5,6,100–102]
due to autoimmune pleuritis, but pleural effusion; in such cases tetracycline pleurodesis studies were found.
There were no studies regarding
it’s hard to distinguish it from use and pleurectomy have been reported [100–102].
the outcome of SLE-associated
other causes [6].
pleural effusion.
Empirical broad-spectrum
No studies have been reported antibiotics therapy must be given
Empirical broad-spectrum antibiotic therapy should
since 1975, but current treatment and aggressive
be initiated immediately [107].
has improved the prognosis. immunosuppressive therapy
Aggressive immunotherapy should be given after
Patients with pulmonary should be initiated after [51,91,104,
Acute lupus pneumonitis infectious etiologies are excluded; high dose IV
infection are at risk of persistent excluding infections. Studies 107–109]
methylprednisolone, oral corticosteroids, IV
abnormalities of lung function have not been reported since
cyclophosphamide, rituximab, plasma exchnage, IVIG
and restrictive lung disease 1975 about the prognosis, but
can be considered [91,108,109].
[51,104]. current options are likely
associated with better outcomes.
SLE-associated pulmonary
hemorrhage shows high
There is no well established guideline for DAH. mortality [132].
DAH is a quite common and
High-dose methylprednisolone is often used [110]. Several factors related to high
DAH is common vascular life-threatening condition,
Cyclophosaphamide alone and plasma exchange mortality are severe dyspnea, [1,6,42,76,77,
Diffuse alveolar hemorrhage involvement, and it might help to showing high mortality rate.
combined with cyclophosphamide or need for mechanical ventilation, 110–117,119]
diagnose SLE [1,6]. High-dose methylprednisolone
methylpredniosolone are used, without well defined renal failure, neuropsychiatric
can be used for treatment.
efficacy in SLE-DAH yet [77,119]. complications, etc [42,111–113].
Early and aggressive treatment
can increase survival rate [114].
J. Clin. Med. 2022, 11, 6714 16 of 23
Table 3. Cont.
Clinical Symptom Treatment Outcome Summary Ref

55 SLE-ILD patients showed
overall 5yr survival rate of 85.3% SLE-ILD includes various types
[122].Factors predicting worse of ILD, and it shows
SLE-ILD includes NSIP,
outcome include current slowly-developing respiratory
organizing pneumonia, LIP,
Treatment depends on expert opinion [121]. smoking, thrombocytopenia, symptoms. Treatment options are
follicular bronchiolitis, etc. It
Recent studies suggest corticosteroids alone or with significant lung fibrosis [122]. based on expert opinion, but [103,107,111,
Interstitial lung disease typically manifests as an
cyclophosaphamide or MMF as an induction therapy, Lupus-associated pneumonitis recent algorithms suggest the use 118–123]
insidious onset of chronic
and azathioprine or MMF as a maintenance therapy. had common progression to of corticosteroids and
nonproductive cough, dyspnea,
respiratory failure and high immunosuppressive agents. Its
decreased exercise tolerance, etc.
mortality [111]. clinical outcome is hard to
It is difficult to estimate the estimate accurately.
outcome of SLE-ILD.
SLS is rare, and it shows a large SLS is a rare condition,
There are no clinical guidelines, Corticosteroids and
female predominance [66]. All characterized by progressive
Glucocorticoid alone or with immunosuppressive immunosuppresion shows a
patients show respiratory decline of lung volumes on PFT.
agents are frequently used [66,81,128]. good response. Most will cure [65,66,81,
Shrinking lung syndrome symptoms; dyspnea, coughing, It responds well to
Theophylline, beta-agonists, rituximab alone or with from SLS, but some 124–136]
pleuritic chest pain. corticosteroids and
cyclophosphamide and beta-agonist, belimumab can complications such as
SLS causes progressive decrease immunosuppresive therapy, but
be considered [81,128–134] pneumonia can remain [81,136].
in lung volumes on PFT [65,127]. some complications may occur.
It may cause irreversible changes
Immunosuppresion based on IV cyclophosphamide PAH is the third most common PAH can cause irreversible
of right ventricle or lung
have been shown to be successful. Other options cause of death in SLE [154]. damage to heart or lung, and it
capillaries [137]. Risk factors for
Pulmonary arterial hypertension include IV cyclophosphamide with prednisolone, CTD-PAH showed poorer show high mortality rate. [137–158]
PAH include hypertension, high
immunosuppresion in combination with vasodilators, survival than idiopathic PAH Immunosuppresion can be used
fibrinogen levels,
IV epoprostenol, bosentan, and sildenafil [144–149]. [155]. as a treatment.
thrombocytopenia, serositis, etc.
PE is a rare but life-threatening
PE is rare but can be fatal, and
condition. SLE patients are
SLE patients are at risk of PE.
susceptible to PE. Risk factors Life-long anticoagulation may be
Studies on the treatment of SLE associated PE have Early anticoagulation should be
include high BMI, fast warranted. Corticosteroids or
rarely been performed. Anticoagulation therapy initiated, and some might need
Pulmonary embolism progression of SLE, immunosuppressive agents as a [8,70,158–164]
needs to be commenced [161]. Massive PE and thrombolysis. Some refractory
hypoalbuminemia, intensive treatment may be
persistent hypotension requires thrombolysis [162]. cases may need life-long
antiphospholipid antibodies, required [164].
anticoagulation or intensive
high dose glucocorticoids
treatment.
[70,159,160].
1 Abbreviations: NSAIDs: non-steroidal anti-inflammatory drugs, MMF: mycophenolate mofetil, IVIG: intravenous immunoglobulin, US: ultrasound, DAH: diffuse alveolar hemorrhage,
PAH: pulmonary arterial hypertension, CTD: connective tissue disease, PE: pulmonary embolism, BMI: body mass index, SLS: shrinking lung syndrome, PFT: pulmonary function test,
ILD: interstitial lung disease, NSIP: nonspecific interstitial pneumonia, and LIP: lymphocytic interstitial pneumonia.
J. Clin. Med. 2022, 11, 6714 17 of 23
6. Conclusions
A significant number of patients with SLE suffer from pulmonary involvement.
Pleurisy, diffuse alveolar hemorrhage, shrinking lung syndrome, interstitial lung disease,
and pulmonary arterial hypertension are the main manifestations of lung diseases. Some
patients experience critical complications, such as pulmonary hemorrhage. Therefore, the
assessment and treatment of lung involvement in patients with SLE should be performed
promptly. CXR, HRCT, and PFT are recommended as diagnostic work-up. Clinicians and
patients are less aware of the effects of SLE on their respiratory system. Moreover, exact
diagnostic criteria for lung involvement in SLE remain elusive. Thus, more attention should
be paid to the active surveillance and management of pulmonary manifestations of SLE.
Author Contributions: All authors made substantial contributions to all of the following: (1) concep-
tion and design of the study, data acquisition, or analysis and interpretation of the data; (2) drafting or
critical revision of the article for intellectual content; and (3) final approval of version to be submitted.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are available from the corresponding author on a reasonable request.
Conflicts of Interest: All authors state that they have no actual or potential conflicts of interest,
including any financial, personal, or other relationships with other people or organizations.
Abbreviations
ALP, Acute lupus pneumonitis; ANA, antinuclear antibody; BAL, bronchoalveolar lavage; BALF,
bronchoalveolar lavage fluid; BMI, body mass index; CT, computed tomography; CTD, connective
tissue disease; CXR, chest X-ray; DAH, diffuse alveolar hemorrhage; DLco, diffusing capacity for
carbon monoxide; EBC, exhaled breath condensate; FDG, fluorodeoxyglucose; IC, immune complex;
IFN, interferon; ILD, interstitial lung disease; IVIG, intravenous immunoglobulin; LIP, lymphocytic
interstitial pneumonia; miR, micro RNA; MMF, mycophenolate mofetil; NET, neutrophil extracel-
lular trap; NSIP, nonspecific interstitial pneumonia; PAH, pulmonary arterial hypertension; PE,
pulmonary embolism; PET, positron emission tomography; PFT, pulmonary function test; PMN, poly-
morphonuclear neutrophil; Rh-DNase, recombinant human deoxyribonuclease; SLE, systemic lupus
erythematosus; SLS, shrinking lung syndrome; US, ultrasound; 99m Tc-HMPAO, technetium-99m
hexamethylprophylene amine oxime.
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J. Clin. Med. 2022, 11, 6714. https://doi.org/10.3390/jcm11226714 https://www.mdpi.com/journal/jcm

2.2. Incidence of Pleural Involvement in SLE

2.3. Incidence of Pulmonary Parenchyma Involvement in SLE

Table 1. Studies on the pathogenesis of lupus-associated lung involvement.

Figure 1. Pathogenesis of lung involvement in SLE [50,51,59,60].

4.2. Computerized Tomography (CT)

4.3. Pulmonary Function Test

4.5. Bronchoalveolar Lavage (BAL)

4.7. Dynamic Magnetic Resonance Imaging (MRI)

Key Finding Comments Ref

5. Types of Pulmonary Involvement

5.1. Lupus Pleuritis

5.1.3. Sequelae and Outcomes

5.2. Pleural Effusion

5.2.3. Sequelae and Outcomes

5.3. Acute Lupus Pneumonitis (ALP)

5.3.3. Sequelae and Outcomes

5.4. Diffuse Alveolar Hemorrhage

5.4.3. Sequelae and Outcomes

5.5. Interstitial Lung Disease (ILD)

5.5.3. Sequelae and Outcomes

5.6. Shrinking Lung Syndrome

5.6.3. Sequelae and Outcomes

5.7. Pulmonary Arterial Hypertension

5.7.3. Sequelae and Outcomes

5.8. Pulmonary Embolism

5.8.3. Sequelae and Outcomes

5.9. Drug Toxicity and Lung Involvement of SLE

Table 3. Summary of the types of pulmonary involvement in SLE.

Clinical Symptom Treatment Outcome Summary Ref

Clinical Symptom Treatment Outcome Summary Ref

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