Version May 2024
INTRODUCTION — Sjögren's disease (SjD) is a chronic inflammatory disorder characterized by diminished lacrimal and salivary gland function and associated with lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands. In addition to causing dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), SjD can affect extraglandular organ systems including the skin, lung, heart, kidney, neural, and hematopoietic systems.
The clinical manifestations, evaluation, and diagnosis of interstitial lung disease (ILD) in SjD will be reviewed here. The clinical manifestations, classification, criteria for diagnosis, and pathogenesis of SjD and the management of interstitial lung disease (ILD) associated with SjD (SjD-ILD) are presented separately. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Diagnosis and classification of Sjögren’s disease" and "Idiopathic interstitial pneumonias: Classification and pathology".)
NOMENCLATURE
American-European criteria for SjD — The American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) criteria for the diagnosis of SjD are listed in the table (table 1). These criteria were not developed for clinical practice and not every patient who receives a diagnosis of SjD fulfills the proposed criteria. The clinical diagnosis of SjD is discussed separately. (See "Diagnosis and classification of Sjögren’s disease", section on 'Classification criteria' and "Diagnosis and classification of Sjögren’s disease", section on 'Diagnosis'.)
●Primary Sjögren's disease – Primary Sjögren's disease (pSjD) is diagnosed only when all other systemic rheumatic diseases are excluded; it predominantly affects women between 50 and 70 years of age. (See "Diagnosis and classification of Sjögren’s disease".)
●Secondary Sjögren's disease – Secondary Sjögren's disease (sSjD) refers to SjD that occurs in association with another connective tissue disease, most commonly rheumatoid arthritis, but also including systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, and inflammatory myositis. ILD that develops in a patient with sSjD is evaluated based on the primary rheumatic disease, rather than as a manifestation of sSjD. (See "Diagnosis and classification of Sjögren’s disease".)
TYPES OF INTERSTITIAL LUNG DISEASE — The types of SjD-ILD largely mirror the idiopathic interstitial pneumonias [1-5]:
●Nonspecific interstitial pneumonia (NSIP)
●Usual interstitial pneumonia (UIP)
●Cryptogenic organizing pneumonia (COP)
●Lymphoid interstitial pneumonia (LIP)
Follicular bronchiolitis can be seen on its own or in the context of NSIP or OP. Nodular lymphoid hyperplasia, primary pulmonary lymphoma, and diffuse interstitial amyloidosis are much less common [6-8].
EPIDEMIOLOGY — ILD is the most common pulmonary abnormality in primary Sjögren's disease (pSjD) [5,9-13]. SjD-ILD is more common in women than men and has a median age of onset of 60 years [14,15]. ILD appears more common among patients with pSjD than in those with secondary Sjögren's disease (sSjD), although it tends to be less severe than the ILD associated with sSjD or other rheumatic diseases [11,16,17]. The greater severity of ILD in sSjD may be due to the simultaneous effects of lung involvement due to SjD and the associated rheumatic disease (eg, rheumatoid arthritis, systemic lupus erythematosus) [11]. SjD-ILD is most common in patients who have both glandular and extraglandular manifestations of SjD [18].
The proportion of patients with SjD who develop ILD at some point is estimated to be 10 to 20 percent, although reports describe variable frequencies [10,16,19-21].
●In a large review conducted by the European Alliance of Associations for Rheumatology (EULAR)-SjD task force including 273 articles, comprising 4897 patients of pSjD fulfilling the 2002 American European Consensus Group definition, 16 percent (795) of the patients exhibited pulmonary involvement. Computed tomography (CT) scans available for 526 of these patients disclosed ground-glass appearance or interstitial changes in 50 percent [3].
●Among 840 patients with pSjD identified by computerized chart review, ILD was noted in 104 (12 percent) [22].
●A series of 343 patients found evidence of pulmonary involvement in 9 percent based on reported symptoms, chest radiographs, and pulmonary function tests [10].
●In a longitudinal study of 105 patients with pSjD who were followed at a referral center, ILD developed in 10 percent after one year and in 20 percent after five years [23].
Less commonly, ILD can be the presenting manifestation of SjD. Among a cohort of patients with various diffuse ILDs, a surprisingly high prevalence of objective xerostomia (17 percent) was reported [24]. Definite SjD was diagnosed in 5.4 percent of the cohort, suggesting that undiagnosed SjD may be a more common cause of ILD than previously noted [24].
CLINICAL FEATURES — Onset of ILD is typically 5 to 10 years after the onset of SjD, although lung disease may occasionally precede the diagnosis of SjD [24,25]. The symptoms and signs of SjD-ILD depend on the type and severity of lung parenchymal and lower airway involvement [9-12,16,19-21,26,27].
In a review of 260 reported patients with primary Sjögren's disease (pSjD) and lung involvement, the clinical features included dyspnea (62 percent), cough (54 percent), sputum (14 percent), chest pain (5 percent), and fever (2 percent) [3]. Clubbing is rare [2]. The severity of respiratory symptoms ranges from subclinical lung disease to mild cough or dyspnea to slowly progressive respiratory insufficiency, although mild dyspnea on exertion is most common [1,17,28].
Patients with lymphoid interstitial pneumonia (LIP) associated with SjD are rarely asymptomatic; cough (71 percent) and dyspnea (61 percent) are the most common symptoms, but weight loss, fevers, and pleuritic chest pain can also be present. (See "Lymphoid interstitial pneumonia", section on 'Symptoms'.)
Occasionally, patients with SjD-ILD will report Raynaud phenomenon, arthralgias, fever, or rash. The extrapulmonary symptoms of SjD are described separately. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Clinical manifestations of Sjögren's disease: Exocrine gland disease".)
Bibasilar crackles are noted on physical examination in approximately 60 percent of patients with SjD-ILD [2,22,29]. Cutaneous vasculitis occurs in approximately 10 percent of patients with SjD and can present with urticarial lesions, purpura, or punctate erosions. The extrapulmonary signs of SjD are discussed separately. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Extraglandular organ involvement' and "Clinical manifestations of Sjögren's disease: Exocrine gland disease".)
EVALUATION — The diagnostic approach to suspected ILD in patients with SjD follows the general approach to interstitial lung disease; infectious, drug-induced, inhalational, and cardiovascular causes must be excluded, as with any new diagnosis of ILD. Because of the high frequency of lung involvement in SjD and the potential for sarcoidosis to mimic SjD, we typically obtain a chest radiograph as part of the initial evaluation of a patient with SjD. If ILD is suspected on the basis of cough, dyspnea, audible crackles, or an abnormal chest radiograph, we obtain complete pulmonary function tests and a high-resolution computed tomography (HRCT) scan. Further evaluation is based on the results of these tests and collaboration with the patient’s rheumatic disease specialist. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
Laboratory — When ILD is suspected in a patient with SjD, we usually confirm the original diagnosis of SjD by reviewing or obtaining serologic studies such as the antinuclear antibody, anti-Ro/SSA (preferably as separate components anti-Ro52 and anti-Ro60), anti-La/SSB antibodies, rheumatoid factor, erythrocyte sedimentation rate [ESR], and immunoglobulin quantification. The laboratory evaluation and diagnosis of SjD are discussed separately. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Sjögren's disease' and "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Anti-Ro60 versus anti-Ro52 antibodies' and "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Autoantibodies' and "Diagnosis and classification of Sjögren’s disease", section on 'Serologic and other laboratory testing'.)
Patients with ILD related to primary Sjögren's disease (pSjD) or secondary Sjögren's disease (sSjD) tend to have variable patterns of antibody positivity. As an example, in a series of 14 patients with pSjD-associated ILD documented on lung biopsy, antinuclear antibodies (ANA) were noted in six, anti-Ro/SSA antibody in eight, and anti-La/SSB antibody in two [22]. Similar findings were noted in 13 patients with ILD and SjD (diagnosed by a positive minor salivary gland biopsy): ANA and anti-Ro/SSA antibodies were positive in eight; rheumatoid factor (RF) in three; and anti-La/SSB antibody in two [30]. While no serologic marker has been identified that clearly predicts ILD in SjD, some studies have found an increased risk of ILD associated with anti-Ro52 antibodies [31,32]. Among 68 patients with pSjD, ILD was noted in 42 percent of the anti-Ro52 positive patients compared with 16 percent of the anti-Ro52 negative patients [31].
Limited data are available to assess whether specific antibodies correlate with disease severity [29,32]. A series of 30 patients noted that anti-Ro/SSA antibody positivity correlated with a significantly lower diffusing capacity than anti-Ro/SSA antibody negativity [29].
If IgG4-related disease is suspected as an alternative diagnosis due to lacrimal and salivary gland enlargement, immunoglobulin subclass levels are obtained looking for an elevated level of IgG4. (See 'IgG4-related disease' below and "Clinical manifestations and diagnosis of IgG4-related disease".)
Chest imaging — A chest radiograph is usually part of the initial evaluation of patients with SjD due to the frequency of lung involvement and as sarcoidosis is in the differential diagnosis. If respiratory symptoms develop or worsen, imaging is repeated, usually with HRCT.
Chest radiograph — The chest radiograph in patients with SjD-ILD typically shows a fine reticular or nodular pattern with basilar prominence, but may be normal or less commonly show cysts or pleural abnormalities [4,10,33]. Retrospective series of patients with either pSjD or sSjD have noted abnormalities on chest radiograph in 10 to 20 percent [10,34]; the rate of radiographic abnormalities may be higher in patients with pSjD than sSjD [35].
High-resolution computed tomography — HRCT is more sensitive for identifying interstitial lung disease than a chest radiograph [28,36,37]. In a series of 37 patients with SjD and normal chest radiographs, 25 (64 percent) had abnormalities on HRCT [29]. A separate study found abnormalities suggestive of interstitial lung disease on CT in 34 percent of patients with pSjD, while the chest radiograph was abnormal in only 14 percent [37]. (See "High resolution computed tomography of the lungs".)
A variety of HRCT patterns have been reported in SjD-ILD [3,22,37-40]. In a series of 60 patients with pSjD-associated ILD, HRCT abnormalities included ground-glass attenuation (92 percent), subpleural small nodules (78 percent), nonseptal linear opacities (75 percent), interlobular septal thickening (55 percent), bronchiectasis (38 percent), and cysts (30 percent) [38]. Bronchial wall thickening and pleural irregularities are less frequently noted [28].
The frequency of each pattern depends on the characteristics of the population studied. As an example, among four studies of symptomatic patients with ILD, the frequency of nonspecific interstitial pneumonia patterns ranged from 20 to 60 percent [1,37,41,42]. In two studies of asymptomatic patients, 8 percent had HRCT findings consistent with pulmonary fibrosis (honeycombing) [28,37]. In a separate series, honeycombing was almost four times more common in sSjD as compared with pSjD, likely due to the presence of usual interstitial pneumonia (UIP) in patients with rheumatoid arthritis. (See "Interstitial lung disease in rheumatoid arthritis", section on 'Pathologic patterns'.)
In general, HRCT is as reliable in predicting the histopathology of ILD in rheumatic disease as in the idiopathic ILDs (table 2). HRCT patterns associated with individual types of ILD in SjD include the following:
●Nonspecific interstitial pneumonia (NSIP) – NSIP is associated with patchy ground-glass attenuation and intralobular reticulation with a lower lobe predilection. Traction bronchiectasis may be present and, occasionally, small areas of subpleural honeycombing. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Chest imaging studies'.)
●Usual interstitial pneumonia (UIP) – The characteristic HRCT appearance of UIP is increased reticular markings in a basilar and peripheral distribution and, as the disease progresses, areas of subpleural honeycombing. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Chest imaging'.)
●Lymphoid interstitial pneumonia (LIP) and follicular bronchiolitis – The HRCT findings in LIP include ground-glass attenuation, centrilobular and subpleural nodules, septal thickening, reticular opacities, bronchial/bronchiolar thickening, and thin-walled cysts (image 1 and image 2) [28,41,43]. In some cases, ground-glass attenuation is more prominent (image 3); in other cases, the cystic changes predominate (image 4), such that diffuse cystic lung disease can be a presenting manifestation of SjD [44]. (See "Lymphoid interstitial pneumonia", section on 'Chest imaging'.)
Occasionally, patients have thin-walled cysts in the absence of other lung parenchymal abnormalities [15,44]. In these patients, the cysts tend to be lower lobe predominant and peribronchovascular, and may range in number from 1 to almost 100 [44]. Cystic lung disease is variably associated with anti-Ro-SSA antibodies [15] or anti-La-SSB antibodies [14]. (See 'Laboratory' above.)
●Follicular bronchiolitis – Follicular bronchiolitis can be present alone or in combination with LIP or NSIP. HRCT features include centrilobular and peribronchial nodules 1 to 12 mm in diameter and thickening of the bronchial/bronchiolar walls. (See "Overview of bronchiolar disorders in adults", section on 'Follicular bronchiolitis'.)
●Organizing pneumonia (OP) – The HRCT findings of SjD-associated OP include consolidative and ground-glass opacities, in addition to centrilobular nodules and tree-in-bud opacities [2,45-47]. (See "Cryptogenic organizing pneumonia", section on 'Computed tomographic (CT) scanning'.)
●Nodular lymphoid hyperplasia – Pulmonary nodular lymphoid hyperplasia typically presents with a solitary mass or nodule, but can present with multiple nodules or as an area of ground-glass opacity or parenchymal consolidation with an air bronchogram [7,26,48]. The nodules are often subpleural, but can be peribronchial [8]. Mediastinal and hilar lymphadenopathy and pleural effusions are typically absent. (See 'Nodular lymphoid hyperplasia' below.)
●Pulmonary nodular amyloidosis – In the rare patients with SjD-associated amyloidosis, HRCT findings include diffuse nodules, cystic lesions, focal consolidation, and diffuse septal thickening [49,50]. (See 'Pulmonary nodular amyloidosis' below and "Pleuropulmonary manifestations of amyloidosis", section on 'Nodular pulmonary amyloidosis'.)
Positron emission tomography — Fluorodeoxyglucose-positron emission tomography (FDG-PET) may demonstrate increased lung uptake in certain types of SjD-associated lung disease. In a study that included 10 patients with SjD-associated lung disease, FDG-PET revealed increased lung uptake of FDG in seven patients [51]. Among those with increased FDG uptake, the SUVmax was less than 3 except in one patient with lymphoid interstitial pneumonia who had areas of consolidation with a SUVmax of 8. Two patients had nodular consolidations in the lungs with a higher SUVmax (6.5 and 12) than that associated with ILD; these lesions were found to be mucosa-associated lymphoid tissue (MALT) lymphoma.
Pulmonary function tests — Pulmonary function tests (PFTs) are obtained to evaluate respiratory symptoms, crackles on chest examination, or an abnormal chest radiograph. The main role of PFTs is to confirm the presence of abnormalities consistent with ILD and to assess the severity of respiratory impairment.
Patients with SjD and diffuse parenchymal opacities on chest radiographs typically have a restrictive pattern on PFTs with a low diffusing capacity [1,11,18,20,52-55]. In one study of 20 patients with pSjD, significant reductions in forced expiratory volume in one second (FEV1), vital capacity, and diffusing capacity (transfer factor for carbon monoxide or diffusing capacity of carbon monoxide [DLCO]) were noted in 14, 12, and 10 patients, respectively [17]. The combination of a restrictive defect and a low DLCO appears to be more common in pSjD than in sSjD [11,18].
Evidence of airways disease has been reported patients with pSjD [11,28,43,55], but the frequency is variable [18]. Based on one series, an obstructive pattern may be more common in sSjD [18].
Minor salivary gland biopsy — Occasionally, ILD is the presenting manifestation of pSjD and the presence of sicca symptoms is elicited during the evaluation of ILD [30]. If serologic testing (anti-SSA/Ro and anti-SSB antibodies, ANA by an immunofluorescence assay, and rheumatoid factor) is nondiagnostic, a minor salivary gland biopsy may lead to a more precise diagnosis underlying SjD. (See "Diagnosis and classification of Sjögren’s disease", section on 'Salivary gland biopsy'.)
Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) cell count patterns in SjD are nonspecific, so the main role of BAL in a patient who is suspected of having SjD-ILD is to exclude other causes of diffuse parenchymal lung disease, such as eosinophilic pneumonia, infection, lymphangitic tumor, and hemorrhage. Thus, BAL is usually performed in patients with SjD and ILD when respiratory symptoms have an acute onset or are accompanied by a fever, hemoptysis, or peripheral eosinophilia. BAL results are not sufficient to differentiate SjD-ILD from sarcoidosis. The technique of BAL and the role of BAL in the diagnosis of interstitial lung disease are discussed separately. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
Increased numbers of BAL lymphocytes or neutrophils are common among patients with pSjD [35,56]. However, data are conflicting about whether the degree of lymphocytosis or neutrophilia predicts the presence or severity of ILD. In a study of 23 patients with pSjD, those patients whose BAL contained greater than 15 percent lymphocytes were more likely to have pulmonary symptoms (cough and dyspnea), radiographic evidence of interstitial lung disease, and decreased pulmonary function than those whose BAL had less than 15 percent lymphocytes [56].
BAL cell counts do not appear to have prognostic value in SjD-ILD, and it is unknown whether patients with subclinical disease based on BAL results will develop symptomatic pulmonary disease.
●Among 18 patients with pSjD and an initial lymphocytic or mixed lymphocytic/neutrophilic BAL, chest radiographs and pulmonary function were virtually unchanged over two years [42]. Of 14 patients with an initial lymphocytic BAL (>15 percent lymphocytes), the BAL differential normalized in six. BAL neutrophilia was associated with a greater rate of reduction in the DLCO, than BAL lymphocytosis.
●In contrast, a longer study (12 years) of 22 patients with pSjD found that only those patients with greater than 15 percent lymphocytosis in their BAL died [57].
●Among 29 patients with pSjD who did not have pulmonary symptoms or chest radiograph abnormalities, elevated BAL lymphocytes or neutrophils were noted in 55 percent [58].
Lung biopsy — Lung biopsy is generally not necessary when evaluating patients with SjD and radiographic and/or physiologic evidence of ILD. The usual indications for lung biopsy are a suspicion of malignancy or an atypical HRCT pattern and worsening clinical and radiographic abnormalities. Circumscribed or nodular areas of consolidation that are persistent and not attributable to infection generally require histopathologic evaluation. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Overview'.)
Depending on the location of the abnormality and local expertise, transbronchial or cryobiopsy, video-assisted thoracoscopic, or surgical lung biopsy may be performed. Transbronchial lung biopsy is helpful in the positive diagnosis of sarcoidosis or lymphangitic carcinomatosis, whereas a larger biopsy from video-assisted thoracoscopic or open thoracotomy is needed to differentiate the various types of ILD. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)
Histopathology — The histopathology of the interstitial pneumonias commonly associated with SjD mirror the idiopathic interstitial pneumonias [27], which are described separately. (See "Idiopathic interstitial pneumonias: Classification and pathology".)
In a review of 146 published cases with histopathology, 45 percent were NSIP, 16 percent were UIP, 15 percent were LIP, 7 percent OP, and the remaining 17 percent other pathologies [3]. The features described in patients with SjD include the following:
●Nonspecific interstitial pneumonia (NSIP) – NSIP is characterized by expansion of alveolar septa by a variably dense infiltrate of predominantly mononuclear inflammatory cells with or without associated fibrosis. Within the category of NSIP, three subsets have been described: a cellular pattern with a greater degree of interstitial inflammation, a more fibrotic pattern, and a mixed pattern (table 3 and picture 1 and picture 2). The significance of these subsets is not entirely clear, although the more fibrotic pattern appears to be more common in pSjD [59]. In a series of 20 patients with NSIP associated with pSjD, the fibrotic pattern of NSIP was noted in 19 and the cellular pattern in 1 [1]. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Histopathology and interpretation'.)
●Lymphoid interstitial pneumonia (LIP) – LIP is characterized by an extensive proliferation of lymphoid cells (T and B) and varying numbers of plasma cells along the alveolar septae, often associated with follicular bronchiolitis (table 4 and picture 3 and picture 4). Germinal centers and multinucleated giant cells with occasional noncaseating granulomas are also described (picture 4 and picture 5 and picture 6).
Lymphocytic infiltration is a characteristic of SjD manifestations throughout the body. In addition to LIP, several patterns of lymphocytic lung involvement have been described: LIP, follicular bronchiolitis, nodular lymphoid hyperplasia, and lymphoma. It is not clear whether there is an evolution from one lymphocytic pattern to another.
●Usual interstitial pneumonia (UIP) – The histologic hallmark and chief diagnostic criterion for UIP is a heterogeneous appearance with alternating areas of normal lung, patchy interstitial inflammation, fibroblast foci, and honeycomb change. In patients with SjD and UIP, a greater degree of lymphocytic infiltration may be noted compared with idiopathic cases. The histopathologic pattern of UIP is more commonly seen in patients with sSjD associated with rheumatoid arthritis or systemic sclerosis, than in pSjD. Among 42 patients with pSjD and ILD, none had UIP on biopsy, although UIP had been suspected based on HRCT in four [1]. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology'.)
●Organizing pneumonia (OP) – The characteristic histopathologic lesions of organizing pneumonia include excessive proliferation of granulation tissue within small airways (proliferative bronchiolitis) and alveolar ducts, associated with chronic inflammation in the surrounding alveoli. Foci of organizing pneumonia can be seen in association with NSIP. (See "Cryptogenic organizing pneumonia", section on 'Histopathologic diagnosis of organizing pneumonia'.)
●Follicular bronchiolitis – In follicular bronchiolitis, hyperplastic lymphoid follicles with reactive germinal centers are distributed along the bronchioles and can cause compression of the airway lumen (picture 4). The lymphoid proliferation is generally limited to the peribronchiolar area, but may extend into the surrounding alveolar septa [43,60].
●Nodular lymphoid hyperplasia – Nodular lymphoid hyperplasia (also known as follicular lymphoid hyperplasia and the outdated term pseudolymphoma) is characterized by mixed infiltrates of mature T and B lymphocytes and plasma cells with numerous germinal centers (picture 7A-C). It has certain key features that are used to differentiate it from marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, including a well-circumscribed lesion, minimal lymphangitic spread, presence of polyclonal lymphocytes, absence of intranuclear inclusions, and absence of immunoglobulin heavy chain rearrangements [60]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)
DIAGNOSIS — For patients with known SjD and suspected ILD, the first step is to exclude infectious, drug-induced, and cardiovascular causes, as with any new diagnosis of ILD (see 'Evaluation' above). The next step is to review the high-resolution computed tomography (HRCT), keeping in mind that SjD-ILD usually mirrors the main types of idiopathic interstitial pneumonia (eg, nonspecific interstitial pneumonia [NSIP], usual interstitial pneumonia [UIP], lymphoid interstitial pneumonia [LIP], organizing pneumonia [OP]) and the HRCT pattern will often guide further evaluation [1,2,22,30,35,61]. (See 'Types of interstitial lung disease' above.)
Interstitial pneumonias — For patients with an HRCT pattern suggestive of NSIP or UIP, a presumptive diagnosis can often be made based on the symptom pattern (eg, gradually progressive cough and dyspnea), basilar crackles, and HRCT findings (eg, increased reticular markings, patchy ground-glass opacities, lower lobe predominance) (table 2) [1,2,62]. Atypical features, such as fever, rapidly progressive disease, hemoptysis, or a nodular or mass-like HRCT appearance, typically require further evaluation. (See 'High-resolution computed tomography' above and "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia".)
While not typical, OP can mimic NSIP with patchy ground-glass opacities and increased reticular markings. As the treatment of ILD in SjD is dictated more by the disease extent, respiratory impairment, rate of progression, and extrapulmonary disease, a precise diagnosis for these overlapping radiographic presentations is usually not necessary.
Organizing pneumonia — For patients with consolidative or mass-like opacities on HRCT, a diagnosis of OP typically requires a lung biopsy [2,45,46,63]. Particularly in patients with SjD, it is important to exclude lymphoma, nodular lymphoid hyperplasia, and other lymphoproliferative processes. Due to the small sample size of transbronchial biopsies, a video-assisted transthoracic or surgical approach is preferred. (See "Cryptogenic organizing pneumonia", section on 'Diagnosis'.)
Lymphoid interstitial pneumonia — LIP is well-described in patients with SjD and a clinical diagnosis can often be made based on a combination of thin-walled, perivascular cysts associated with ground-glass opacities or poorly defined centrilobular or subpleural nodules [44]. However, when LIP presents with consolidative nodular opacities, a biopsy is required to exclude lymphoma and other causes of lung nodules. (See "Lymphoid interstitial pneumonia", section on 'Pathologic findings' and 'Follicular bronchiolitis' below.)
When thin-walled air cysts raise the possibility of LIP, it is important to consider the possibility of other causes or mimics of cystic lung disease, such as pulmonary Langerhans histiocytosis or combined pulmonary fibrosis and emphysema, especially in current or former cigarette smokers. (See "Diagnostic approach to the adult with cystic lung disease", section on 'Parenchymal lucencies that may mimic cysts'.)
Follicular bronchiolitis — The diagnosis of follicular bronchiolitis may be suspected in a patient with SjD on the basis of dyspnea and associated HRCT findings of centrilobular and peribronchial nodules, sometimes with a tree-in-bud pattern, or follicular bronchiolitis may be identified as an associated finding in a patient with NSIP or LIP [22]. Follicular bronchiolitis is characterized by lymphoid hyperplasia of mucosa-associated lymphoid tissue (MALT), as described above. (See 'Diagnosis' above and "Overview of bronchiolar disorders in adults", section on 'Follicular bronchiolitis'.)
Nodular lymphoid hyperplasia — Nodular lymphoid hyperplasia (NLH; also known as follicular lymphoid hyperplasia or the outdated term "pseudolymphoma") is more common among patients with primary SjD than other rheumatic diseases and requires a lung biopsy for diagnosis [7,8,60,64-66]. The HRCT appearance of one or more nodular or mass-like consolidation with or without air bronchogram does not allow differentiation from organizing pneumonia, lymphoma, or other consolidative processes [8]. NLH may regress, remain stable, or progress to frank lymphoma [60]. (See "Cutaneous T cell pseudolymphomas".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ILD in SjD includes ILDs that present with sicca symptoms or salivary gland involvement (eg, sarcoidosis, IgG4-related systemic disease), ILDs related to the underlying rheumatic disease in patients with secondary Sjögren's disease (sSjD; eg, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis [scleroderma], inflammatory muscle disease), drug-induced pneumonitis, and unrelated ILDs (eg, hypersensitivity pneumonitis, eosinophilic pneumonia). The characteristics of ILD associated with these rheumatic diseases and the differential diagnosis of ILD in general are reviewed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Interstitial lung disease in rheumatoid arthritis" and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Interstitial lung disease' and "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis" and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)".)
Sjögren's disease and sarcoidosis — Sarcoidosis can present with lacrimal and salivary gland involvement, as well as diffuse parenchymal lung disease. In addition, sarcoidosis can occur concomitantly with SjD. In one patient with SjD, for example, lung biopsy revealed a chronic noncaseating granulomatous inflammatory reaction with moderate lymphocytic infiltration of the surrounding alveoli, a finding that led to the concurrent diagnosis of sarcoidosis [58]. A literature review of histopathologic changes in the exocrine glands of 53 patients with sarcoidosis noted coexistence of sarcoidosis and SjD in 28 cases; in the remaining 25 patients, sarcoidosis mimicked SjD [67]. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Diagnostic approach'.)
Potential explanations for the simultaneous occurrence of both disorders include the following:
●The two diseases share a common immunologic abnormality
●The derangement caused by one disorder may result in the other
●The finding is coincidental
Possible support for the first hypothesis comes from a study of lung biopsy specimens from 10 patients with SjD [60]. There were significant elevations in CD4 positive lymphocytes in the bronchial mucosa, an abnormality that is also described in sarcoidosis. In general, sarcoidosis and SjD are differentiated by the preponderance of noncaseating granulomata found on biopsy specimens from patients with sarcoidosis. (See "Pathology and pathogenesis of sarcoidosis" and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Histopathology' and "Clinical manifestations and diagnosis of sarcoidosis".)
IgG4-related disease — IgG4-related disease, also known as IgG4-related sclerosing disease or hyper-IgG4 disease, is distinct from SjD. Patients with IgG4-related systemic disease experience relatively mild xerophthalmia and xerostomia, although marked lacrimal and salivary gland enlargement may occur.
Lung involvement in IgG4-related systemic disease is estimated to occur in 10 percent and pleural involvement in 5 percent [68]. A variety of chest CT presentations have been described, including patchy ground-glass, nodular, and consolidative opacities, and also honeycombing [69].
The diagnosis of IgG4-related disease is based on the clinical features, a serum concentration of IgG4 ≥2 times the upper limit of normal (140 mg/dL), and the presence of IgG4 positive cells on histopathology (table 5). (See "Clinical manifestations and diagnosis of IgG4-related disease".)
Other causes of diffuse parenchymal lung disease — Other causes of diffuse lung disease that are not associated with SjD, but are generally in the differential diagnosis of ILD, include drug-induced lung disease, hypersensitivity pneumonia, eosinophilic pneumonia, infection, lymphangitic tumor, and hemorrhage. The evaluation of these entities is discussed in the appropriate topic reviews. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
OTHER PULMONARY MANIFESTATIONS OF SJÖGREN'S DISEASE — Patients with SjD can develop other respiratory complications that present with dyspnea, cough, or abnormal imaging, such as xerotrachea, pulmonary nodular amyloidosis, pulmonary lymphoma, thromboembolic disease, pulmonary arterial hypertension, and pleural disease.
Xerotrachea — Among patients with SjD, involvement of the tracheobronchial submucosal glands can lead to excessive dryness of the airway, which usually presents with a nonproductive cough. Pulmonary function tests and radiographic imaging are normal. Examination by flexible bronchoscopy reveals a dry, erythematous mucosa [70].
Pulmonary nodular amyloidosis — Pulmonary nodular amyloidosis is occasionally described in association with SjD (usually primary Sjögren's disease [pSjD]) [1,49,71,72]. Pulmonary nodular amyloidosis can present with isolated pulmonary nodules, multiple nodules with or without calcification, and sometimes concomitant lung cysts [6,49,50,71,73-76]. Most cases of amyloid associated with SjD are related to the nodular pattern of amyloidosis [49].
A lung biopsy with Congo red staining is typically needed to secure a diagnosis of pulmonary nodular amyloidosis. Further study is needed to determine the type of amyloid deposition. Nodules containing lymphocytes, plasma cells and amyloid deposits (identified by Congo red staining showing green birefringence under polarized light) are reported, sometimes adjacent to or in the wall of lung cysts [71]. In a case report and literature review, deposition of AL (lambda or kappa light chain) or AA amyloid occurs in the absence of systemic amyloidosis [49]. Association with lymphoproliferative disease, such as MALT lymphoma, is often noted and confirmed by the presence of monotypic lymphoid cells on immunohistochemical analysis [71,77-79]. (See "Overview of amyloidosis", section on 'Pulmonary disease' and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Tissue biopsy'.)
Lymphoma — The lung malignancies most frequently associated with SjD are the non-Hodgkin lymphomas, and among these, the most common is pulmonary marginal zone lymphoma (MZL; also known as MALT lymphoma or BALT lymphoma) [1]. Involvement of the lung by lymphoma occurs in approximately 20 percent of patients with SjD-associated lymphoma [80]. A spectrum of low- to high-grade lymphomas is reported [80]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)
Pulmonary vascular disease — Pulmonary vascular disease (eg, thromboembolic disease, pulmonary arterial hypertension) should be considered in the differential of SjD complicated by dyspnea.
An increased risk of thromboembolic disease has been described in patients with SjD and appears greatest in the first year after diagnosis [81,82]. Venous thromboembolism should be suspected in patients with an acute onset of dyspnea, particularly when the chest radiograph does not suggest ILD. The evaluation and diagnosis of suspected pulmonary embolism is discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
Pulmonary arterial hypertension (PAH) should be considered in a patient with more gradual onset of dyspnea when the degree of dyspnea is not well-explained by the extent of ILD on high-resolution computed tomography (HRCT). PAH rarely occurs in the setting of SjD-ILD, typically in patients with Raynaud phenomenon and cutaneous vasculitis [83]. In a review of 28 patients, antinuclear, anti-Ro/SSA, and anti-ribonucleoprotein (RNP) autoantibodies, as well as positive rheumatoid factor and hypergammaglobulinemia, were often present. The evaluation and diagnosis of PAH is discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
Pleural disease — Unilateral and bilateral pleural effusions are rarely reported in patients with SjD [84-87]. Pleuroparenchymal fibroelastosis (PPFE), a form of upper lobe pleural and subpleural lung parenchymal fibrosis that can be associated with usual interstitial pneumonia, has been reported in patients with pSjD [88]. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Differential diagnosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sjögren's disease" and "Society guideline links: Interstitial lung disease".)
SUMMARY AND RECOMMENDATIONS
●Sjögren's disease (SjD) can be classified as primary Sjögren's disease (pSjD), in the absence of an associated rheumatic disease or as secondary Sjögren's disease (SjD) when criteria for SjD are met in addition to criteria for an associated rheumatic disease (eg, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or inflammatory myositis). (See 'Introduction' above and 'Nomenclature' above.)
●Both primary and secondary SjD are associated with a variety of interstitial lung diseases (ILDs). The types of SjD-associated ILD (SjD-ILD) largely mirror the idiopathic interstitial pneumonias: nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), lymphoid interstitial pneumonia (LIP), cryptogenic organizing pneumonia (COP). (See 'Introduction' above.)
●The proportion of patients with SjD who develop ILD at some point is estimated to be 10 to 20 percent, although asymptomatic changes on CT are more common. (See 'Epidemiology' above.)
●The onset of SjD-ILD is typically 5 to 10 years after the onset of SjD, although lung disease may occasionally precede the diagnosis of SjD. (See 'Clinical features' above.)
●The presenting manifestations of SjD-ILD include cough (usually nonproductive), chest pain, and dyspnea. Constitutional symptoms may be present; patients may also report Raynaud phenomenon, arthralgias, or rash. (See 'Clinical features' above.)
●A chest radiograph is typically obtained as part of the initial evaluation of SjD. If ILD is suspected on the basis of cough, dyspnea, audible crackles, or an abnormal chest radiograph, we obtain pulmonary function tests and a high-resolution computed tomography (HRCT) scan. (See 'Evaluation' above.)
●If not already performed, we obtain laboratory tests to confirm the diagnosis of SjD, including an antinuclear antibody, anti-Ro/SSA and anti-La/SSB antibodies, rheumatoid factor, and immunoglobulin quantification. (See 'Laboratory' above.)
●HRCT findings depend on the type of ILD; ground-glass opacities are most common. Other findings may include bronchial wall thickening, bronchiectasis, centrilobular nodules, irregular interlobular thickening, subpleural honeycombing, and thin-walled cysts. (See 'Chest imaging' above.)
●The main role of bronchoalveolar lavage (BAL) in a patient with SjD and radiographic evidence of ILD is to exclude other causes of interstitial opacities, such as eosinophilic pneumonia, infection, lymphangitic tumor, and hemorrhage. In SjD-ILD, BAL most commonly shows a predominance of lymphocytes, but may show a predominance of neutrophils. (See 'Bronchoalveolar lavage' above.)
●For patients with known SjD and suspected ILD, the HRCT scan can often guide the need for further diagnostic steps. When the HRCT suggests NSIP or UIP or concomitant air cysts suggest LIP, a clinical diagnosis can often be made. When the HRCT pattern is more nodular or consolidative, a lung biopsy is typically indicated. (See 'Diagnosis' above.)
●The differential diagnosis of ILD in SjD includes ILDs that present with sicca symptoms or salivary gland involvement (eg, sarcoidosis, IgG4-related systemic disease), ILDs related to the underlying rheumatic disease (eg, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis), drug-induced pneumonitis, and unrelated ILDs (eg, hypersensitivity pneumonitis). (See 'Differential diagnosis' above.)
●Other respiratory complications of SjD include xerotrachea, pulmonary nodular amyloidosis, pulmonary lymphoma, thromboembolic disease, pulmonary arterial hypertension, and pleural disease. (See 'Other pulmonary manifestations of Sjögren's disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Deheinzelin, MD, who contributed to earlier versions of this topic review.
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