Abstract
Lung involvement in systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) has extensively been outlined with a multiplicity of different manifestations. In SLE, the most frequent finding is pleural effusion, while in pSS, airway disease and parenchymal disorders prevail. In both cases, there is an increased risk of pre-capillary and post-capillary pulmonary arterial hypertension (PAH) and pulmonary venous thromboembolism (VTE). The risk of VTE is in part due to an increased thrombophilic status secondary to systemic inflammation or to the well-established association with antiphospholipid antibody syndrome (APS). The lung can also be the site of an organ-specific complication due to the aberrant pathologic immune-hyperactivation as occurs in the development of lymphoma or amyloidosis in pSS. Respiratory infections are a major issue to be addressed when approaching the differential diagnosis, and their exclusion is required to safely start an immunosuppressive therapy. Treatment strategy is mainly based on glucocorticoids (GCs) and immunosuppressants, with a variable response according to the primary pathologic process. Anticoagulation is recommended in case of VTE and multi-targeted treatment regimens including different drugs are the mainstay for PAH management. Antibiotics and respiratory physiotherapy can be considered relevant complement therapeutic measures. In this article, we reviewed lung manifestations in SLE and pSS with the aim to provide a comprehensive overview of their diagnosis and management to physicians taking care of patients with connective tissue diseases.
Keywords
Introduction
The lungs are often affected in connective tissue diseases (CTDs), with a variable degree of severity and protean clinical presentations by virtue of the complex anatomo-functional characteristics of the respiratory apparatus. Among the CTDs, systemic sclerosis (SSc) has the highest prevalence of clinically overt pulmonary involvement with a prevalence ranging between 70% and 90% of cases; 1 similarly, in idiopathic inflammatory myopathies, and in particular anti-synthetase syndrome, the prevalence is remarkable. 2 In systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS), pulmonary involvement has been reported with a variable prevalence according to the diagnostic method and criteria used.3–8 In SLE and pSS, the immune-inflammatory process may affect not only the lung parenchyma but also pleural layers, respiratory muscles, and the pulmonary vascular system with different pathogenetic mechanisms. This often requires a comprehensive clinical and laboratory evaluation and a multi-disciplinary management to correctly characterize the extension of the organ impairment and to provide the best management. Besides, it is important to remind that the respiratory abnormalities may additionally be due to complications associated with the immunosuppressive therapy such as pulmonary drug-related toxicity9,10 or, more frequently, recurrent infections. In pSS, they may also derive from a malignant evolution of an underlying lymphoproliferative disorder.
In this review, we provide an overview on the diagnosis and management of pulmonary manifestations in patients with SLE and pSS with the aim of raising the awareness of lung involvement among physicians taking care of SLE and pSS patients.
Search strategy
A narrative literature search was conducted to address research questions related to pulmonary manifestations in SLE and pSS patients. We considered different databases such as PubMed, Google Scholar, and Cochrane Library searching for case series, case reports, clinical trials, and review articles on lung involvement in SLE and pSS. Additional references were identified by searching the bibliographies of retrieved articles. We performed a keyword search restricted to the title of the articles, using terms relating to SLE, pSS, lung involvement, and treatment of lung involvement in CTDs. The date of publication was not used as an entry selection criterion. Articles were reviewed according to the article title and abstract, with all article types taken into consideration if they provided data relevant to the research questions.
Pulmonary involvement in SLE
SLE is a chronic autoimmune multi-systemic disease with a complex and multi-factorial pathogenesis, mostly affecting young women and characterized by a relapsing-remitting course. Organ involvement can be highly heterogeneous, and the respiratory system, along with skin, kidney, joints, and blood system, is frequently affected.3,4
Pleuritis is definitely the most common manifestation, but other different vascular and parenchymal abnormalities have been reported (Table 1). The prognosis greatly varies according to the type of manifestation and on the response to the currently available therapies.
Lung involvement in SLE.
BAL, bronchioalveolar lavage; BOOP, bronchiolitis obliterans organizing pneumonia; DLCO, diffuse lung CO; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; NSIP, non-specific interstitial pneumonia; PFT, pulmonary function test; RHC, right heart catheterization; SLE, systemic lupus erythematosus; UIP, usual interstitial pneumonia.
Pleuritis
Pleural involvement is the most common pleuro-pulmonary manifestation of SLE. Pleuritis, with or without pleural effusions, has been reported in up to 50% of SLE patients during the disease course 11 and in as many as 93% of autopsy series. 12 Noteworthy, it is the only pulmonary manifestation which has been included in the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE. 13 Long-standing disease, chronic damage, late-onset SLE, and positive anti-RNP and anti-Smith antibodies are associated with a nearly two-fold increased risk of developing pleuritis. 14 It occurs with chest pain in up to 45% to 60% of patients,3,15 but it can be asymptomatic and fortuitously diagnosed in routine radiographs performed for other reasons. Patients may also report fever, cough, and dyspnea. 16 Pleural effusions in SLE are often bilateral, exudative, and commonly of small entity, but may occasionally be massive. 17 Fibrothorax is a rare but potentially fatal complication of lupus pleuritis, which may require pleural decortication. 18 The differential diagnosis mainly includes infections, 19 pulmonary embolism (PE), malignancy, and congestive heart failure. When infections are excluded, high levels of C-reactive protein (CRP) in SLE patients have been associated with pleural disease or other forms of serositis during disease exacerbations.20,21 Pleural involvement is commonly observed in patients with active SLE in other organs and systems. 20 Pleural fluid analysis does not provide any specific feature; however, it can be used to rule out other conditions. 22 The fluid appearance can vary from clear, serous to bloody; physico-chemical analysis can reveal predominant polymorphonuclear cell, low glucose levels, and high levels of lactate dehydrogenase (LDH). Low complement levels and positive antinuclear antibodies (ANAs) can also be found in pleural fluid. Nonetheless, the detection of positive ANA should be interpreted with caution because a titre of ANA above 1:160 by indirect immunofluorescence has also been reported in malignant diseases. 23 Thoracoscopy may detect nodules on the visceral pleura histologically characterized by deposits of immune complexes (ICs) by immunofluorescence. 24 Treatment is mainly based on non-steroidal anti-inflammatory drugs (NSAIDs) or systemic glucocorticoids (GCs). The latters are commonly used in case of unresponsiveness to NSAIDs and/or in moderate-severe forms. In refractory cases, immunosuppressive drugs such as azathioprine (AZA), mycophenolate mofetil (MMF), 25 and methotrexate (MTX) are recommended. Finally, the anti-BlyS monoclonal antibody belimumab resulted to be effective in some cases.26–31
Parenchimal disease
Acute lupus pneumonitis
Acute lupus pneumonitis (ALP) is a rare and severe manifestation of SLE affecting 1% to 4% of patients. In some series, it is reported as the initial disease presentation in up to half cases. 32 ALP is more likely to occur during SLE flares, with multi-systemic involvement, including lupus nephritis; furthermore, anti-Ro/SSA antibodies have been associated with an increased risk of ALP. 33 In one series of 12 patients with ALP, the mortality rate was 50%, which derived from respiratory failure, infections, and thromboembolic events; among the survivors, up to one third developed chronic interstitial lung disease (ILD). 32 The clinical picture of ALP is not specific and is usually characterized by a rapid-onset severe respiratory illness, fever, cough, and dyspnea. Physical examination typically shows tachycardia, tachypnea, hypoxemia, and basilar crackles. Chest radiographs are characterized by bilateral, acinar infiltrates in the lower lobes, while high-resolution computed tomography (HRCT) shows patchy consolidation or ground glass opacities, frequently in conjunction with pleural effusion. 34 Histopathologic findings include diffuse alveolar damage, hyaline membranes, and inflammatory cells infiltrates. By immunofluorescence, granular deposits of IgG and C3 can be found within the alveolar septa.35,36
As clinical manifestations of ALP are non-specific, diagnosis can be very challenging. Viral, bacterial, and fungal infections need to be ruled out, especially the opportunistic ones if the patient is immunocompromised. Notably, in the current times, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia should be excluded as well.37,38 Other alternative diagnoses include organizing pneumonia (OP), PE, drug toxicity, diffuse alveolar hemorrhage (DAH) and malignancy. If clinical or microbiological tests are non-diagnostic, lung biopsy is recommended to confirm the diagnosis. No controlled trials have been carried out for the treatment of lupus pneumonitis and the therapeutic recommendations mainly derive from case reports and clinical practice. Broad spectrum antibiotics, including those covering encapsulated organisms, should be administrated in all patients while awaiting microbiological results. The cornerstone of treatment is represented by systemic prednisone at the dose of 1 mg/kg/day. If no response is obtained within 72 hours, intravenous (IV) pulses of GCs (i.e. 1 g of methylprednisolone per day for three consecutive days) should be administered. Steroid-sparing immunosuppressive agents, such as AZA, MMF, or cyclophosphamide (CYC), should be concomitantly started. Intravenous immunoglobulins (IVIGs) and plasmapheresis may be useful in refractory cases. 33
DAH
DAH is an uncommon but potentially fatal manifestation of SLE, occurring in less than 2% of patients, 39 in most cases during the disease course rather than at the time of the diagnosis. 40 Despite aggressive immunosuppressive therapy, the mortality rate from DAH is still high, mainly for its rapid onset and fast progression over a few days. 33 DAH is most commonly reported in young women, especially in the setting of a serologically and clinically active disease.41,42 The most relevant risk factor associated with the development of DAH is active renal disease, especially class III or IV lupus nephritis.41–44 Furthermore, a recent case-control study reported that anti-Ro/SSA antibodies, thrombocytopenia, and elevated CRP may significantly be associated with lupus DAH. 45 Antiphospholipid antibodies (aPL) are also supposed to be contributory in some patients. 46 DAH is characterized by acute or subacute dyspnea, cough, and hemoptysis in the setting of a drop in blood hemoglobin level and bilateral alveolar opacities, patchy, or diffuse, on chest radiography. The diffusing capacity for carbon monoxide (DLCO) is typically increased because of the presence of extravascular hemoglobin within the alveoli. Bronchoscopy with bronchoalveolar lavage (BAL) is commonly performed in order to confirm DAH and to rule out infections and malignancies. BAL fluid is invariably stained with blood and does not clear with continuous lavage. Hemosiderin-laden macrophages in BAL fluid are an additional common finding. The two most frequent histologic patterns described in lupus DAH include bland pulmonary hemorrhage and vasculitis of the small arterioles.41,47 Bland pulmonary hemorrhage has been suggested to be the most common cause of DAH in some series. 48 It is commonly associated with a predominant monocyte infiltration in the alveolar wall and arterial IC deposition. 48 Inflammation and necrosis of the alveolar and capillaries with a predominant pericapillary neutrophil infiltration are instead the common features of the inflammatory vasculitic pattern. 49 Since DAH may be life threatening, most patients are treated with a high dose of systemic GCs, especially IV pulses of methylprednisolone (Figure 1(a) and (b)). Some studies reported a better survival rate in patients receiving a higher dose of methylprednisolone than that conventionally used (4–8 g instead of 3 g). 50 Administration of CYC has demonstrated to improve survival, 51 also in the most severe cases requiring mechanical ventilation; 41 the combination of methylprednisolone and CYC is associated with an even increased survival rate. 52 Plasma exchange and IVIG are considered rescue therapies for refractory disease, although supportive data are limited. 48 The anti-CD20 monoclonal antibody rituximab (RTX), in addition to GCs, has proven to be effective in case reports or in registries; 53 however, if the clinical picture is from mild to moderate, MMF or AZA may be reasonably used.54,55
Areas of bilateral parenchymal consolidations with a peribronchovascular distribution localized in the inferior lobes on high-resolution computed tomography (a) and the corresponding chest radiography image (b) in a patient with organizing pneumonia in systemic lupus erythematosus.
SLE-associated ILD
Chronic systemic lupus erythematosus–associated interstitial lung disease (SLE-ILD) is a rare manifestation of the disease, which affects up to 9% of patients.3,56–58 SLE-ILD can occur after one or more episodes of ALP or in a more insidious fashion. 32 Although no clinical or serologic markers have strongly been associated with the development of chronic SLE-ILD, 59 a recent systematic review demonstrated a potential association with late-onset disease.60,61 Non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), OP, lymphocytic interstitial pneumonia (LIP), follicular bronchiolitis, and nodular lymphoid hyperplasia have all been reported in association with SLE. 62 NSIP is the most common radiologic pattern, 58 while UIP and OP are fairly unusual62,63 (Figure 2(a) and (b)). SLE-ILD commonly occurs with a decreased exercise tolerance, non-productive cough, dyspnea, and basilar crackles at physical examination. 64 The diagnosis is often based on clinical and radiological findings, but it is crucial to rule out other possible causes of respiratory symptoms, such as infections, malignancy, and congestive heart failure. Pulmonary function tests (PFTs) are characterized by a restrictive pattern, defined by a decrease in forced vital capacity (FVC), total lung capacity, and DLCO. Chest radiographs may show the presence of ILD, but HRCT is the milestone for confirming lung interstitial involvement and for defining its radiologic pattern, which in turn correlates with a specific histopathologic diagnosis.
Diffuse ground glass opacities, air-bronchogram images, and bilateral pleural effusion on high-resolution computed tomography in a patient with hemorragic alveolitis in systemic lupus erythematosus before (a) and after (b) methylprednisolone pulses and high-dose intravenous glucocorticoid therapy.
In recent years, novel serum biomarkers have been tested for evaluating ILD in SLE and other CTDs. 65 Among them it has to be mentioned Krebs von den Lungen-6 (KL-6), surfactant protein-A (SP-A), surfactant protein-D (SP-D), CC-chemokine ligand 18 (CCL18), and matrix metalloproteinase 7 (MMP7). In the future, they may be used for diagnosis, assessing the severity of disease, prediction of progression, and treatment responses in CTDs-ILD. 65
There are no definite guidelines for the management of SLE-ILD, and the therapeutic approach depends on the type, severity, and rate of progression of lung involvement. Patients with fibrotic ILD are less likely to benefit from anti-inflammatory or immunosuppressive therapy, while they may take advantage from the use of antifibrotic agents. A recent clinical trial in patients with progressive fibrosing ILDs of different etiologies, including autoimmune diseases, showed a decrease in the rate of decline of lung function with the use of the antifibrotic agent nintedanib.66,67 With exception of fibrosing forms, the mainstay of therapy is high-dose prednisone (1 mg/kg/day) followed by gradual tapering. In a case series, 58 the treatment with prednisone was associated with an improvement of respiratory symptoms and DLCO in the majority of patients. Steroid-sparing agents commonly used for the treatment of ILD in CTDs include AZA, MMF, RTX, and CYC. However, data on the use of immunosuppressive drugs in SLE-ILD are insubstantial.68–70 For patients affected with mild to moderate forms, AZA or MMF may be considered, while in the severe or rapidly progressive cases, CYC or RTX should be preferred. In the setting of a severe ILD flare, characterized by hypoxemia and marked impairment by PFTs, high dose of systemic GCs (i.e. methylprednisolone 1 g for 3 days) should be administered, in association with RTX or CYC, switching to another immunosuppressive agent such as AZA or MMF for maintenance therapy. 70
Pulmonary thromboembolic disease
Notably, SLE patients have an increased risk of developing venous thromboembolic events in the pulmonary circulation.71,72 Yusuf et al. 71 found that among hospitalized patients the risk of pulmonary venous thromboembolism (VTE) is higher in SLE patients compared to those without autoimmune diseases. Membranous nephropathy and aPL positivity are well-established risk factors for VTE, in particular the presence of aPL carries a six-fold increased risk of VTE. 73 Indeed, thrombotic events frequently occur in the setting of antiphospholipid antibody syndrome (APS), whose prevalence in SLE is estimated to be around 30%.74–76 Noteworthy, recurrent episodes of VTE may lead to chronic thromboembolic pulmonary disease and, eventually, pulmonary arterial hypertension (PAH). Therapy of pulmonary thromboembolism is mainly based on anti-coagulants. Initial management does not differ if the patient is aPL positive or negative. 33
PAH
PAH is a rare and life-threatening pulmonary manifestation of SLE, much more frequent in SSc or mixed connective tissue disease (MCTD). 77 It is defined, on right heart catheterization (RHC), by a mean pulmonary artery pressure greater than 25 mmHg at rest and a normal pulmonary capillary wedge pressure when classified as pre-capillary. 78 Pulmonary hypertension can be secondary to a variety of diseases, such as ILD leading to hypoxemia, thromboembolic disease, pulmonary veno-occlusive disease (PVOD), 79 left-heart-sided valvulopathies, and sleep apnea disorder. On this regard, the World Health Organization has proposed a classification of the different forms of pulmonary hypertension into five groups based on the underlying cause. 80 In a cross-sectional study of 283 patients with SLE, pulmonary hypertension was observed in 4% of patients, based on Doppler echocardiography, while severe PAH (pulmonary systolic pressure by echocardiography >40 mmHg) was noted in about 1%. 81 In most cases, SLE diagnosis precedes the detection of PAH but its early prevalence may be underestimated due to the lack of overt clinical symptoms in the early phase. 82 The strongest association of PAH in the setting of SLE is with Raynaud’s phenomenon (RP), occurring in up to 60% of cases. 83 Other reported associations are with positive rheumatoid factor (RF), anti-ribonucleoprotein (RNP) antibodies, and serum endothelin-1 levels.84,85 The clinical picture of PAH is characterized by exertional dyspnea, fatigue, non-productive cough, and, in advanced disease, symptoms of cor pulmonale. Physical examination findings commonly include a loud second pulmonary heart sound and a left parasternal lift. A chest radiography can show cardiomegaly and a pronounced pulmonary artery segment. PFTs in PAH commonly show normal lung volumes with a decrease in DLCO. The six-minute walk distance (6MWD) is reduced, in association with oxygen desaturation ⩾5%, often with an inflated heart rate response. 86 When PAH is caused by advanced ILD, lung volumes will show a restrictive pattern. Transthoracic Doppler echocardiography can be useful for PAH screening because it allows to estimate pulmonary artery pressures and right atrial and right ventricular size and function. 81 However, RHC is required for a definitive diagnosis. Common histological findings in SLE-related PAH are represented by thickening of the arterial media and subintima in addition with angiomatoid lesions of the pulmonary muscular arteries and IC deposition in the arterial wall.87,88 Rare cases of pulmonary vasculitis have been reported. 89 The management of SLE-associated PAH is similar to that of other CTDs or the idiopathic form. 90 General measures for patients affected with PAH may include oxygen, exercise, and diuretics. The main pharmacological approach is based on endothelin receptor antagonists, phosphodiesterase type-5 inhibitors (PDE5 inhibitors), and vasodilators. Monotherapy with a single-class agent can be administered, although the combination of oral drugs belonging to different classes is preferred in clinical practice to obtain a synergic effect and, at the same time, to reduce the risk of adverse effects by administering lower doses of each drug. Among the endothelin receptor antagonists used for PAH, there are the non-selective agents, bosentan, and macitentan, and the selective agent ambrisentan. Sildenafil, tadalafil, and vardenafil are PDE5 inhibitors with vasodilatory effects. A study examining the effect of oral sildenafil in 19 patients with SLE-associated PAH found that sildenafil-treated patients had a mean increase in 6MWD of 42 meters compared with a decrease of 13 meters in the placebo group after 12 weeks of treatment. 91 The combination of ambrisentan and tadalafil has been associated with a significant decrease in the rate of clinical failure compared to monotherapy with either drugs alone. 92 Data on the use of immunosuppressive therapy in SLE-associated PAH are inconclusive, but those patients with PAH secondary to ILD or pulmonary vasculitis may benefit from immunosuppressive agents. 93 In this regard, single studies reported a successful treatment of PAH with CYC 94 or RTX 95 but randomized clinical trials are needed to confirm these findings. 96
Shrinking lung syndrome
Shrinking lung syndrome (SLS) is an uncommon but well-recognized complication of SLE and other autoimmune diseases 97 such as SSc, pSS, and rheumatoid arthritis (RA). 98 SLS affects from 0.5% to 1.53% of all lupus patients, 99 in most cases 4 to 5 years after the initial diagnosis. 100 Pleural involvement, positive anti-double-stranded-DNA (dsDNA), and anti-RNP antibodies are associated with the development of SLS. 101 Different etiologies have been proposed, but the precise pathophysiological mechanism has yet to be demonstrated. 102 It is possible that myopathy or myositis of the diaphragms may lead to muscular disfunction; 103 however, this hypothesis is in contrast with some reports suggesting a normal diaphragm function in most patients with SLS. 104 Another hypothesis postulates a phrenic nerve damage or paralysis.105,106 Some other reports suggest a possible role of chronic pleural inflammation leading to lung hypo-inflation and altered lung compliance.107,108 SLS commonly occurs with dyspnea and/or chest pain, reduced lung volumes by PFTs, and diaphragm elevation by X-ray. For establishing the diagnosis of SLS parenchymal diseases, infections and PE need to be excluded. GC therapy and immunosuppressants are reported to improve both pulmonary function and symptoms.108–110 RTX and CYC have been successfully used for the treatment of SLS,111–113 while the efficacy of theophylline or other beta-adrenergic agonists is still controversial. 114 Finally, physiotherapy for pulmonary rehabilitation may also be helpful. 103
Lung infections
Lung infections can be considered one of the most relevant causes of morbidity and mortality among hospitalized patients affected with SLE 115 and one of the most common causes of lung involvement in SLE patients. High disease activity, disease duration, and use of immunosuppressants are recognized risk factors for the development of lung infections. 116 Furthermore, a mean daily dose of 15 mg of prednisolone at the onset of pneumonia is reported to be an adjunctive threatening of death. 117 Deficiencies in the complement system, impaired chemotaxis and phagocytosis of macrophages, and homozygosity for mannose-binding lectin variant polymorphisms put SLE patients at high risk for a variety of bacterial (especially encapsulated organisms) and opportunistic lung infections.117–119 Nevertheless, functional asplenia, which is reported in up to 5% of SLE patients, may also play a role. 120 The most common causes of lung infection in a Canadian study were P. aeruginosa, H. influenzae, S. marcescens, K. pneumoniae, and Legionella species; 121 other potential causes include Cytomegalovirus, disseminated Herpes simplex, and Pneumocystis jirovecii.122,123 According to EULAR recommendations, vaccination against pneumococcal disease and influenza should be strongly encouraged for most people with SLE and other autoimmune rheumatic diseases. 124
Pulmonary involvement in pSS
pSS is defined as an autoimmune epithelitis specifically characterized by impairment of exocrine glands (mainly lacrimal and salivary) due to inflammatory infiltrate. 125 It also shows extra-glandular, multi-organ involvement126,127 and respiratory manifestations (Table 2) are among the most prevalent extra-glandular complications affecting 9% to 75% of patients 128 according to the detection methods and patient selection criteria.129–131 Upper airway disorders with dryness in nasal and oropharyngeal mucosa are definitely among the most frequent manifestations and are due to mucosal dryness, mucus viscosity disorders, and impaired mucociliary clearance caused by the long-standing inflammation that finally leads to atrophy of the submucosal glands of the airway mucosa. 132 Chronic obstructive pulmonary disease133–136 and bronchial hyperresponsiveness137,138 have also an increased prevalence in pSS patients in respect to general population. Respiratory and lung involvement have proven to significantly decrease the quality of life and are associated with increased mortality.8,139
Lung involvement in pSS.
DLCO, diffuse lung CO; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; LIP, lymphocytic interstitial pneumonia; NSIP, non-specific interstitial pneumonia; OP, organizing pneumonia; PAH, pulmonary arterial hypertension; PFT, pulmonary function test; pSS, primary Sjogren’s syndrome; RHC, right heart catheterization; UIP, usual interstitial pneumonia.
Airway disorders
Bronchiolitis
Bronchiolitis is the most frequent airway disease in pSS, and it is classified into three main types: follicular bronchiolitis, chronic bronchiolitis, and bronchiolitis obliterans. Lung biopsy–proven prevalence reaches 12% of cases (29% of patients have histopathologic changes consistent with follicular bronchiolitis, 21% with chronic bronchiolitis, and 7% with bronchiolitis obliterans), but frequency increases to 29% with HRCT evaluation. 140 It traditionally occurs with cough and dyspnea, which may be the first manifestation of pSS in up to 36% of patients. 141 The course of bronchiolitis in pSS is typically fairly mild; however, severe cases have been reported.141,142 Follicular bronchiolitis has been specifically linked to CTDs, such as pSS and RA. It traditionally occurs with cough and dyspnea, even without objective clinical signs of lung involvement. PFT findings may be normal or show either a restrictive or obstructive pattern. Radiographically, it appears as a reticular or reticulonodular pattern on HRCT 143 (Figure 3(a) and (b)), while histopathologically, it is characterized by the presence of hyperplastic lymphoid follicles with reactive germinal centers distributed along bronchovascular bundles. 144 Bronchiolitis obliterans is defined by a mosaic pattern with air trapping on HRCT. 142 Chronic bronchiolitis and bronchiolitis obliterans present with a spectrum of histological changes such as lymphocytic infiltration of small airways, bronchiolar smooth muscle hypertrophy, obstruction of bronchioles with mucus or even complete obliteration of bronchioles with scarring; these aspects are often indistinguishable from other etiologies. 139 There are scant data on the effect of therapy on bronchiolitis in pSS. Macrolides (most commonly azithromycin 250 mg 3 days a week for 2–3 months 145 ), inhaled GCs and inhaled bronchodilators may strongly improve the respiratory status of patients. 146 GCs and RTX could be an option for follicular bronchiolitis147–149 while a combination of hydroxychloroquine and MMF had been administered to patients with constrictive bronchiolitis showing stability or slight improvement of respiratory function. 142
Reticular pattern during inspiration (a) and expiration (b) on high-resolution computed tomography in a patient affected with follicular bronchiolitis in primary Sjögren’s syndrome.
Bronchiectasis
Radiographically evident bronchiectasis has been described in 23% to 54% of patients with pSS.150,151 Patients with bronchiectasis tend to be older at pSS diagnosis, have a higher frequency of hiatal hernia and a lower prevalence of anti-Ro/SSA antibodies but increased presence of anti-smooth muscle cell antibodies. 152 Most patients usually show cylindrical shape bronchiectasis and have lower lobe–predominant disease. 152 Clinical symptoms are variable and non-specific: dry cough, isolated dyspnea, and hemoptysis in rare occasions. In addition, patients with bronchiectasis have a higher frequency of respiratory infections (56% vs 3%) and pneumonia (29% vs 3%). 152 Treatment is based on strategies to relief from secretions 145 like mucolytic agents and expectorants, nebulized saline or hypertonic saline, oscillatory positive expiratory pressure, postural drainage, and mechanical high-frequency chest wall oscillation therapies. Chronic administration of macrolides in patients without non-tuberculous mycobacterium colonization or infection is also advisable. 145
Parenchymal involvement
Interstitial lung disease (pSS-ILD)
ILD prevalence among pSS patients is around 20% when defined by HRCT or reduced FVC and/or DLCO. Besides HRCT, which is the gold standard, quantitative CT (QCT) analysis may be a promising tool to assess pSS-ILD and its severity. It is based on software providing highly accurate and operator-independent measurements, termed QCT indices, which have been rapidly validated in systemic autoimmune diseases. Quantitative lung assessment methods are capable of distinguishing limited ILD from extensive ILD, which is responsible for poor prognosis in pSS. 153 ILD prevalence increases along with the disease duration (10% after 1 year from diagnosis, up to 47% after 15 years of disease) but in 10% to 51% of patients, it occurs years before pSS onset. 154
Symptoms as non-productive cough and dyspnea are observed in 40% to 66% of patients but are not specific; 24% to 48% of patients are completely asymptomatic.154,155 Physical examination is often unremarkable but fine bibasilar end-inspiratory “velcro-like” crackles at auscultation may lead to ILD suspicion. 156 Digital clubbing, weight loss, focus score ⩾4 in minor salivary gland biopsy, lower albumin-to-globulin ratio, higher levels of IgM, LDH, Erythrocyte Sedimentation Rate (ESR), and positive anti-Ro52 antibodies are frequently found in pSS-ILD patients.157,158 Older age, smoking, increased ANA titer and CRP level, and RF have been reported as potential risk factors for the development of ILD. 157 Patients with non-sicca-onset pSS-ILD less commonly have hypergammaglobulinemia, increased RF or positive anti-SSA, and anti-SSB antibodies compared with patients with sicca-onset pSS-ILD, 159 making ILD recognition challenging. In a patient with pSS and suspected ILD, an oximetry testing is part of the patient’s initial evaluation; further investigations include HRCT with expiratory views and PFTs with DLCO measurement which should be performed and followed initially at 3- to 6-month intervals for at least 1 year because of variable natural history of the disease progression. 145 Discordance between baseline PFT abnormalities, degree of symptoms, and HRCT findings can be observed: 160 the incidence of parenchymal HRCT changes appear to be earlier and greater in frequency than what clinical symptoms would indicate; moreover, HRCT findings are not always accompanied by substantial alterations in PFTs. 160 In early involvement, it is easy to observe a decrease in DLCO with a preserved FVC because inflammation, affecting the alveolar membrane, causes an impairment of gas-exchange function with preserved lung volumes. 154 Therefore, DLCO is highly sensitive to predict the presence of ILD while FVC is more useful for assessing the disease extent. 161 A novel non-invasive tool based on lung ultrasound examination could be helpful for screening of pSS-ILD involvement 154 because plain chest radiographs are insufficient to detect early abnormalities. 160 Imaging features of pSS-ILD are complex and include variable combination of ground glass opacities, reticular abnormalities, consolidation, honeycombing, cysts, nodules, and also bronchiectasis. 140 Surgical lung biopsy is not routinely recommended but may be considered in neoplastic and non-neoplastic lymphoproliferative disorder for ruling out cancers, amyloidosis, suspected infection failing empiric therapies, and when less invasive testing is not diagnostic. 145 Notably, there are cases of lymphoma and amyloidosis presenting with a radiographic pattern similar to LIP; thus, tissue biopsy is essential to ascertain a LIP diagnosis.162–164 The most common ILD pattern is NSIP, found in 41% to 45% of pSS-ILD patients, 162 followed by UIP in 10%, OP in 4%, and LIP which has been classically linked to pSS and occurring in 4% to 9% of cases.156,158 The remaining have combined HRCT patterns. 158 Guidelines for evaluation and management of pulmonary disease in pSS have recently been published. 145 No standard definition exists for staging, but EULAR Sjogren’s syndrome disease activity index (ESSDAI), imaging, and PFTs could drive the initiation of therapy. 165 No treatment or serial observations is suggested for mild disease activity; for moderate-severe disease activity, oral corticosteroids plus MMF, or AZA as first-line GCs-sparing or as adjunctive agents is recommended. 165 If there is no satisfactory response, it is advisable to perform a critical review of HRCT to determine whether the primary pattern is fibrotic or inflammatory; in the latter case, RTX, calcineurin inhibitors, tacrolimus over cyclosporine A (CsA), or CYC are available options. 145 For progressive fibrotic ILD, it is possible to consider an antifibrotic therapy, such as nintedanib, which is approved by the Food and Drug Administration (FDA) for progressive fibrotic lung disease in SSc. 145 More specifically, NSIP pattern shows good response to GCs (0.5–1 mg/kg/day tapered over months to 5–7.5mg/day) associated with other drugs as AZA or CYC 149 while UIP is considered as an irreversible lung disease with a high risk of progression despite immunosuppressive therapy.162,166 In patients with OP, it is reported a good initial response to GC therapy using adjunctive immunosuppressive agents such as AZA, CsA, infliximab, RTX, and tocilizumab in refractory cases.140,165,167,168 LIP seems to be a reversible lung disease with a potential risk of progression through the development of honeycombing 164 although the majority of patients with LIP treated with GCs remain clinically stable or improve. Other immunosuppressive agents such as AZA or CYC have been used but with variable response 169 and RTX has been reported as effective. 149 Other experimental therapies are under study for pSS and may be of potential usefulness also for lung involvement in light of the common systemic immunological mechanisms underlying the disease. Belimumab could be an option in consideration of the critical role of B-cell activating factor (BAFF) and of B-cells in the pathogenesis of pSS. Moreover, the combination of RTX and belimumab, based on previous experience26,170–172 is currently being explored for pSS and may be considered for patients with severe lung involvement; 173 belimumab given immediately before RTX should be useful against tissue lymphoid inflammation because the first drug, by depleting local BAFF, can facilitate the action of the second. 174
Ianalumab, an IgG1 monoclonal antibody against BAFF-R, is currently under study for salivary gland invovement. 175 Abatacept, a CTLA-4 monoclonal antibody that modulates T-cell co-stimulation, has been shown to give some benefit in pSS improving disease activity scores and reducing lymphocytic foci, local T-cells and gammaglobulins; 176 it might be also beneficial in pulmonary pSS. Iscalimab, a monoclonal antibody targeting CD40/CD40 L pathway which is key factor in the organization of the germinal centers, could become a viable option. 177 Direct inhibition of inflammatory cytokines may be of potential benefit in pulmonary pSS as well. Interleukin (IL)-17 has shown to play an important role in the pathogenesis of pSS because an increased number of IL-17 Ralfa-expressing T-cells have been found in minor salivary glands in pSS patients. 178 Type-I interferon has in turn a key role in pSS pathogenesis and could be a potential target in pulmonary pSS.179–181 In addition, blocking downstream signaling of pro-inflammatory cytokines through use of Janus kinase (JAK) inhibitors may be effective as recent evidence suggests it may also influence BAFF signaling. 182 There is some evidence on the efficacy of JAK inhibitors in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (IPF). It would be important to explore their role even in pulmonary pSS.139,183,184 Data on prognosis of pSS-ILD are heterogeneous. Risk factors associated with death are decreased FVC and forced expiratory volume (FEV1), severe lung involvement, 185 and higher number of reticulations on HRCT, number of lymphoblastic foci in biopsy, and high CO2 arterial pressure. 154 By multivariate analysis, low O2 arterial pressure, presence of microscopic honeycombing, 140 and severity of fibroblastic foci on surgical lung biopsy 186 seem to be independently associated with worse survival. Patients with pre-existing ILD are at risk of acute exacerbation. 187 UIP pattern is at higher risk for this complication 188 with a rate of mortality up to 50% at 3 months from onset. 189 Treatment of acute exacerbations is commonly based on high-dose GCs in monotherapy or in association with CYC, oral tacrolimus, or CsA usually along with broad spectrum antibiotic therapy because of the challenging differential diagnosis with bilateral pneumonia. Recently, reduction of acute exacerbations risk in IPF employing nintedanib has been reported.156,190
Lymphoma and pseudolymphoma
Patients with pSS are at higher risk for developing non-Hodgkin lymphoma 191 with a relative risk of 44.4191,192 and a lifetime risk around 5% to 10%. 69 The mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype,193–195 secondary to lymphocytic infiltration of polyclonal B- and T-cells evolving into a monoclonal B-cell proliferation.194,196 Well-known risk factors include purpura, parotid enlargement, hypocomplementemia, type-II cryoglobulinemia,197–199 CD4 T-cell lymphopenia, and low CD4/CD8 ratio.193,194 Lymphoma is more frequently described in salivary and lacrimal glands and in the lymph nodes. Pulmonary localization comprises 20% of all lymphomas in patients with pSS, 149 and it is usually a low-grade extra nodal marginal B-cell lymphoma of the MALT type.
However, even if it is not routinely searched, it may also originate from a salivary gland B-cell clone previously expanded in that microenvironment, and then further expanding and becoming malignant by a second trigger in the lung microenvironment. 200
Symptoms generally include cough, slowly progressive dyspnea, and traditional B symptoms (fever, night sweats, and weight loss). Radiographic findings comprise solitary or multi-focal nodules or masses, bilateral alveolar infiltrates, interstitial opacities, airspace consolidation, or ground glass attenuation, all having been described with a mild predilection for the lower lobes. 201 Mediastinal lymphadenopathy and pleural effusions may accompany parenchymal abnormalities. Biopsy is necessary for definitive diagnosis202,203 because HRCT features in MALT lymphoma can be indistinguishable from benign lymphoproliferative processes. The average 5-year survival rate is 65% to 90% 204 and watchful waiting without specific treatment is reserved for asymptomatic cases. Treatment is indicated for patients with bulky lymphadenopathies and/or splenomegaly, risk of local compressive disease resulting in organ dysfunction, significant cytopenia from bone marrow compromise, and/or rapid disease progression. 205 Overt lymphomas require specific hematological treatment based on RTX and chemotherapy regimens.165,206
Pseudolymphoma, or pulmonary nodular lymphoid hyperplasia, is a localized lymphoproliferative non-malignant disease 207 characterized by infiltration of mature polyclonal lymphocytes and plasma cells. 164 It is typically asymptomatic, although it can present with cough and dyspnea and is most commonly seen in patients with isolated sicca symptoms. 130 It generally appears as a solitary nodule or mass on HRCT. 208 If mediastinal lymphadenopathy or the presence of pleural effusions is noted, a diagnosis of lymphoma should be considered, and histological confirmation is mandatory. Pseudolymphoma generally regresses after treatment with GCs or immunosuppressive therapy but rarely it progresses to lymphoma.209,210
Pulmonary amyloidosis
Amyloidosis is a heterogeneous group of disorders associated with extracellular deposition of fibrillar plasma proteins 211 whose type is determinant for clinical classification. Pulmonary involvement in pSS occurs in light-chain (AL) amyloidosis, whereas reactive (AA) and hereditary forms are uncommon. The two commonly seen patterns include nodular and septal amyloidosis. It is a rare complication of pSS, 130 and a literature review 212 reports 37 cases identified with a median delay of 7 years from pSS diagnosis. Most patients are symptomatic presenting cough or dyspnea 212 along with fatigue, weakness, 213 hemoptysis, 214 and pleuritic chest pain. 215 Identified associated abnormalities include immune thrombocytopenia, 216 cryoglobulinemia, 213 RP, 130 APS, 217 renal disease, 218 and lymphoma.212,216 The most common form of pSS-related pulmonary amyloidosis is the localized nodular type; 212 it usually occurs alone but may also be associated with pulmonary lymphoma, 219 reflecting the localized clonal proliferation of B-lymphocytes or plasma cells secreting light chains. 220 Radiologically, it presents with large, calcified, randomly distributed, irregular, smooth-bordered nodules 221 alone or in association with LIP.140,213,215 Surgical lung biopsy is generally required to establish the diagnosis.212,222 The prognosis is unknown, and there are no data to support any definitive therapeutic option. Observation alone may be sufficient in patients with localized nodular amyloidosis. The efficacy of GCs is anecdotal, and the improvement observed may reflect a favorable response of the underlying NSIP or LIP to GCs therapy. 212
Cystic lung disease (CLD)
Lung cysts are defined by the presence of clearly demarcated airspaces surrounded by thin (<2 mm) walls. CLD has been noted in up to 20% patients with pSS, being mostly subclinical and with limited impact on outcome. Cysts are mostly bilateral with the majority located in the middle lung.139,223 Association between anti-SSB/La antibodies and the presence of lung cysts has been reported: 224 anti-SSB/La has a higher diagnostic specificity for pSS than does anti-SSA/Ro alone, supporting the fact that CLD is a specific feature of pSS even though the pathogenic role of anti-La/SSB antibodies remains to be determined. 225 Lung cysts have been associated with LIP, amyloidosis, or MALT B-cell lymphoma. As lung cysts in pSS are not attributable to active disease, they do not require immunosuppressive therapy. 225
Sarcoidosis
The prevalence of sarcoidosis in patients with pSS has been estimated at between 1% and 2%.226,227 Parotid enlargement can be part of a rare sarcoid manifestation, called Heerfordt’s syndrome and characterized by the presence of facial nerve palsy, parotid gland enlargement, anterior uveitis, and low-grade fever. It is important to differentiate if sarcoidosis mimics or coexist with pSS even though making a differential diagnosis may be difficult due to similar clinical manifestations at onset including respiratory symptoms. 228 Hence, it is necessary focusing on three specific aspects: the existence of extra-glandular features, the immunologic profile, and the histologic analysis of minor salivary glands. 227
Recently, the ultrasound-guided parotid biopsy in pSS allows differentiation with sarcoidosis. 229
The correct diagnosis has important therapeutic and prognostic implications: lung sarcoidosis frequently resolves spontaneously without significant residual functional impairment, whereas pSS pulmonary involvement frequently requires immunosuppressive treatment beyond GCs 228 and often leads to permanent defects.
Pulmonary VET
Patients with pSS are thought to be at increased risk for deep vein thrombosis and PE with the highest risk during the first year after pSS diagnosis.230,231 Inflammation can contribute to the development of VTE because it favors clotting, decreases the activity of natural anti-coagulant mechanisms, and impairs the fibrinolytic system. Thrombosis might be related also to the presence of antiphospholipid antibodies, being lupus anti-coagulant (LAC) an important marker for APS. 232 Treatment of PE is based on anticoagulation while the role of immunosuppressive therapy has yet to be established.
PAH
PAH is a rare but severe complication of pSS. Pre-capillary PAH is characterized by vascular proliferation and remodeling of the small pulmonary arteries resulting in a progressive increase in pulmonary vascular resistance and ultimately in right ventricular failure and death. 233 PAH in pSS can also occur as a result of PVOD, 234 valvular heart diseas, 235 or ILD. 233 The exact prevalence of PAH in pSS is unknown; one study reported echocardiographic evidence of PAH in 22% of patients, 236 nevertheless RHC represents the gold standard for the diagnosis. 237 In a recent Chinese case-control study with a cohort of 103 patients with pSS-PAH diagnosed by RHC, 238 the 1-, 3-, and 5-year survival rates were 94.0%, 88.8%, and 79.0%, respectively; a low cardiac index and an increased damage index were significantly and independently associated with survival. The main symptom is exertional dyspnea 233 which is very unspecific and sometime misleadingly associated to ILD. This determines a delay between dyspnea onset and PAH diagnosis greater than 1 year in 69% of patients.233,239 pSS-PAH has worse hemodynamic profiles on RHC than SSc-PAH and SLE-PAH, probably because diagnosis is performed in a more advanced stage of the illness. 240 Recognized associations with pSS-PAH include hypergammaglobulinemia, positive ANA, high RF level, anti-RNP antibodies, and RP. 240 Histological examination of the lungs has shown intimal and medial hypertrophy associated with plexiform lesions in the pulmonary arteries, whereas vasculitis and inflammatory infiltrates are not usually observed. 241 However, an immunologic etiology is suggested by the presence of IC in the pulmonary vessel walls of pSS–PAH patients. 241 Treatment with PAH-targeted drugs (endothelin receptor antagonists, PDE5 inhibitors, and epoprostenol) is the backbone of therapy. 233 The benefits of immunosuppressive agents such as CYC, MTX, leflunomide, tacrolimus, or AZA 231 plus GCs have been reported in several cases 242 but their effectiveness combined with PAH-target drugs requires further study.
Lymphocytic pleuritis
Pleural effusion has rarely been described in pSS.243,244 The presence of a coexisting autoimmune disease, such as RA or SLE must be excluded. 245 The pleural fluid is a lymphocytic-predominant exudate with increased levels of RF, anti-SSA, anti-SSB autoantibodies, 245 and low levels of complement. Lymphocytic infiltration of the pleura was found on pleural biopsies. 208 Controlling the systemic inflammation and use of steroid therapy is the mainstay of therapy. 244
Neuromuscular diseases with secondary lung involvement
Neuromuscular diseases with secondary pulmonary involvement have also been described in pSS.246–249 SLS, although traditionally associated with SLE, has been very rarely reported. 246 Pathogenesis is still unknown: micro atelectasis and hyaline membranes caused by surfactant deficiency, diaphragmatic myopathy or phrenic nerve neuropathy have been proposed as putative hypothesis. It is commonly characterized by dyspnea, persistent episodes of chest pain, restrictive syndrome, and the absence of significant interstitial and/or pleural disease. In one case report, it has been successfully treated with RTX. 246 Hypokalemic periodic paralysis associated with a distal renal tubular acidosis, which occurs in up to 5% of patients with pSS, can sufficiently severe to cause respiratory muscle weakness. 247 Finally, lung involvement could be secondary to proximal skeletal myopathy; 248 a case of pSS complicated with inflammatory myopathy and ILD responsive to corticosteroids therapy has been reported. 249
Footnotes
Author contributions
Roberto Depascale and Giulia Del Frate equally contributed to this work.
Conflict of interest statement
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
