Pulmonary Manifestations of Sjögren’s Syndrome

Introduction

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and other organs with resultant keratoconjunctivitis sicca, salivary hypofunction, and various extraglandular manifestations (1). It occurs either as a primary disorder or in association with other connective tissue diseases (secondary SS). An estimated 0.4 million to 3.1 million adults in the US had primary SS in 2005 (2).

The prevalence of pulmonary involvement in patients with SS is difficult to estimate. The classification criteria for SS have changed over time and both study design and patient populations have varied. In large series, the estimated prevalence of clinically significant lung involvement is between 9-24% (3–5). On the other hand, evaluation of asymptomatic patients with pulmonary function tests (PFTs), bronchoalveolar lavage, and computed tomography detected abnormalities in up to 75% of patients (6). Pulmonary manifestations in SS typically develop late in the course of disease and are rarely the presenting feature (7). Lesions affecting the small airways, such as follicular bronchiolitis, are among the most common histologic findings in SS patients with pulmonary involvement. Patients with SS-related lung disease report impaired quality of life and impaired physical functioning compared with other SS patients (3). Importantly, pulmonary involvement is associated with a 4-fold increased mortality risk after 10 years of disease (3).

Upper airway disease

Nasal crusting and epistaxis are common symptoms in SS and were reported , respectively, by 18.5% and 31.8% of patients in one series (8). Nearly one half of patients with SS in this series had nasal crusting and dryness on physical examination. Chronic sinusitis was also reported secondary to inspissated secretions.

Hoarseness is reported by approximately one third of SS patients. It is associated with the presence of dryness or thick mucus coating the vocal cords. Rarely, hoarseness may indicate the presence of vocal fold lesions. A bamboo node is a white or yellow transverse submucosal lesion of the vocal folds that has been described in SS (9). Granulomatous and non-granulomatous laryngeal nodules have also been described (10).

Fifty percent of primary SS patients report having a constant dry cough that impairs their quality of life (11)(12). When present as an isolated symptom with an unremarkable radiological and functional evaluation, the term xerotrachea is used. In a study by Mathieu et al, the tracheobronchial mucociliary clearance in SS patients was significantly lower compared to controls, 3.3 ± 1.2 mm/min vs 5.9 ± 1.1 mm/min. Interestingly, patients with xerotrachea had undetectable mucociliary clearance (13). Xerotrachea is classically described in pathology literature as being associated with lymphocytic inflammation and atrophy of the submucosal glands (14); however bronchial gland atrophy was not evident in a morphometric analysis of goblet cells and bronchial glands in SS patients compared to controls (15). This raises the possibility of a functional, rather than structural, glandular defect. Patients with xerotrachea usually have difficulty clearing thickened secretions and are thus predisposed to atelectasis, bronchiectasis, recurrent bouts of bronchitis and bronchopneumonia, as well as peribronchial and peribronchiolar scarring with airway narrowing (14).

Distal airway disease

Follicular bronchiolitis (FB) is one of the most common pulmonary manifestations of SS. FB is a rare type of cellular bronchiolitis characterized by the presence of hyperplastic lymphoid follicles with reactive germinal centers, distributed along the bronchovascular bundles (13). The lymphoid infiltrate is confined to bronchioles and the immediate peribronchiolar interstitium without significant extension into parenchyma. This latter features distinguishes FB from lymphocytic interstitial pneumonia (LIP), in which such parenchymal extension is observed (16). In a study of endobronchial biopsies from non-smoking SS patients and control subjects, the SS patients had an increased number of CD4-positive T cells in the lamina propria outside of the bronchial submucosal glands(17). Peribronchiolar mononuclear cell infiltration may cause airway narrowing due to a ball-valve mechanism, and ultimately lead to bullae formation (18) but this proposed mechanism cannot explain the formation of cysts and bullae in other organs, for example the thymus (19). The profile of the inflammatory infiltrate in the airways of patients with SS is similar to that of atopic asthma, and includes a large number of mast cells and neutrophils in addition to lymphocytes(17). This inflammatory infiltrate causes bronchial hyperreactivity (18) manifested by dry cough, recurrent “bronchitis” and dyspnea (3). The overexpression of IL-12 in the lungs of mice resulted in bronchial and alveolar abnormalities strikingly similar to those found in the lungs of SS patients with lymphocytic infiltrates around the bronchi, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages leading to decreased mucociliary clearance and increased oxidative stress (20). The role played by IL-12 and other cytokines in the evolution of SS lung disease remains to be elucidated. The most common radiographic findings are nodules ranging in size from 1 to 3 mm with a predominant centrilobular distribution, while cystic forms secondary to bronchiolar obstruction are rare (19). PFTs classically show restrictive disease and the diffusing capacity (DL_CO) appears to be the most sensitive test (19). The clinical course and prognosis for most patients with isolated follicular bronchiolitis is relatively good, and progressive lung disease is uncommon (20).

Chronic Obstructive Pulmonary Disease (COPD)

In a cohort from Sweden, 37% of primary SS patients fulfilled COPD criteria over 11 years of followup (21). COPD was 5 times more prevalent among ever smokers, but even the prevalence among non-smokers was unexpectedly high. Primary SS patients had significantly decreased VC, TLC, FEV₁, FEV₁/VC and DL_CO while the RV was increased in comparison with expected values. Respiratory symptoms, radiological abnormalities, and inflammatory and serological features of disease had no association with PFT variables, although in previous studies, an association was shown between PFT variables and anti-SSA antibodies (22), focal sialadenitis (22), hypergammaglobulinaemia, and β₂-microglobulin (23).

Interstitial Lung Disease

Interstitial lung disease (ILD) refers to a group of lung diseases affecting the interstitium of the lung: alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues (24). Historically, the predominant form of ILD in primary SS was deemed to be lymphocytic interstitial pneumonitis (LIP). In a case series by Parambil et al (25) only 17% of primary SS patients with ILD had a histologic diagnosis of LIP. This rather dramatic change in prevalence of LIP could be the result of revisions of histopathologic criteria for LIP so that more cases are categorized as nonspecific interstitial pneumonia (NSIP) based on the degree of lymphocytic infiltration. Currently, NSIP is the most common subtype of ILD in SS patients, with a prevalence ranging between 28% (25) and 61% (26). The role of the autoantibody profile in the etiopathogenesis of ILD is unknown, but anti-SSA antibody positivity even in the absence of other SS criteria has been shown to be associated with an NSIP pattern on imaging and more severe lung function impairment (27).

Nonspecific Interstitial Pneumonia (NSIP)

NSIP is characterized histologically by varying proportions of interstitial inflammation and fibrosis that are temporally uniform. The most common presenting complaint is dyspnea for several months, and chest radiographs usually show bilateral interstitial infiltrates. The characteristic findings on high resolution computed tomography (HRCT) include ground-glass opacities with subpleural and basilar predominance, seen in 75% of cases (28). Reticular abnormalities, with or without traction bronchiectasis, are common and appear to correlate with the amount of fibrosis observed histopathologically. Two findings that correlate with the histological diagnosis of NSIP are subpleural sparing and tracking of opacities along lower-zone bronchovascular bundles (28). Honeycombing is rare in NSIP and is often considered an exclusion factor. The prognosis is good and is dependent on the presence or absence of fibrosis. In a case series by Katzenstein et al (29), no deaths occurred in the patients whose biopsies showed pure inflammation without fibrosis, while the mortality rate was 11% for those ILD patients with fibrosis.

Lymphocytic interstitial pneumonia (LIP)

Carrington and Liebow described the first case of LIP (30). It is characterized histopathologically by diffuse interstitial infiltration of lymphocytes and plasma cells that diffusely expands the alveolar septa and small airways. LIP differs from the pattern of involvement seen in lymphoma, which is nearly always distributed along bronchovascular bundles, pleura, and interlobular septa. Patients nearly always present with respiratory symptoms, including cough and slowly progressive dyspnea, sometimes associated with pleuritic chest pain (31,32). PFTs typically reveal a restrictive pattern with reduced DL_CO (33). Chest radiography usually demonstrates bilateral reticular or reticulonodular opacities that are more prominent in the lower lung zones. The most common CT findings are diffuse ground-glass opacity and consolidation, with occasional thin-walled cysts, presumably due to follicular bronchiolitis (28). Patients with LIP generally respond well to initial corticosteroid therapy, but up to one third may die within several years of diagnosis from progression of disease or infectious complications related to immunosuppressive therapy (16).

Usual Interstitial Pneumonia (UIP)

The histopathology of UIP is one of destructive fibrosis alternating with normal lung. The prevalence of UIP among SS patients with ILD is 17% (25). Patients may be asymptomatic in the initial stages of disease, but most often present with progressive dyspnea and dry cough. Pulmonary function tests reveal evidence of restriction and impaired gas exchange (34). The classic findings on HRCT include bibasilar reticular abnormalities with honeycombing (35). Among all the ILD subtypes associated with CTD, UIP has the worst prognosis and this is true for SS as well. All three patients with UIP in the series by Parambil et al had progressive lung disease with no response to corticosteroid therapy (25).

Organizing Pneumonia (OP)

OP is a relatively rare clinicopathologic entity characterized by intraluminal inflammatory debris composed of masses of fibroblasts and myofibroblasts in the alveolar ducts and airspaces with coexistent chronic inflammation of the surrounding alveoli (36). Clinical findings of progressive dyspnea, low grade fever, constitutional symptoms, and pulmonary infiltrates that are unresponsive to antibiotic therapy should raise the possibility of organizing pneumonia. PFTs most commonly show a mild to moderate restrictive ventilatory defect with a reduced DL_CO (37,38). The typical CT pattern consists of peripheral parenchymal consolidations with air bronchograms and variable associated ground-glass opacities. Corticosteroids are the mainstay of therapy and response is seen within several days to a few weeks. The optimum dose and length of treatment is not known and relapses are common (39).

Cystic Lung Disease

Cystic lung disease is found in up to 10% of primary SS patients (6,26). Besides being a primary finding, cysts can accompany other pulmonary complications of primary SS, including amyloidosis (40–42), malignant lymphoma (26) and lymphocytic interstitial pneumonia (43). The lower lobes are predominantly affected (Figure 1). Pulmonary function tests show a variable mixed restrictive and obstructive pattern. On PFTs, the number of small cysts on HRCT appears to correlate with the severity of obstructive findings and the severity of interstitial inflammation appears to correlate with the restrictive findings (19). Cysts, like fibrosis, are an irreversible manifestation of pulmonary SS and early diagnosis and treatment, especially in cases associated with LIP, may successfully halt the process (44).

Figure 1.

Chest CT scan: Sjogren’s syndrome associated cystic lung disease. A patient with longstanding primary SS underwent evaluation for new onset dyspnea on exertion. The patient was a lifelong non-smoker. Pulmonary function tests showed a mixed restrictive and obstructive pattern. The chest CT scan demonstrates extensive cystic changes. Subsequent surgical lung biopsy revealed follicular bronchiolitis as well as amorphous material that was consistent with lambda light chain deposition.

Pulmonary Lymphoma

Mucosa-associated lymphoid tissue is a general term that includes BALT (bronchus-associated lymphoid tissue) and GALT (gastrointestinal lymphoid tissue). MALT lymphomas originate from the marginal zone B cells that surround the mantle zone and germinal center and are currently classified as a distinct subgroup of non-Hodgkin’s lymphomas under the term extra-nodal marginal zone B-cell lymphoma of MALT-type (45). SS patients have a disproportionate tendency to develop lymphoproliferative disorders with lymphomas arising mainly in mucosal extranodal sites including the salivary and lacrimal glands, stomach and lung. Low-grade marginal zone B-cell lymphomas are the most common (46), but high-grade diffuse large B-cell lymphoma may also occur.

Primary pulmonary lymphomas are uncommon, representing less than 1% of lung cancers (47), and fewer than 1% of malignant lymphomas (46). Clinically, more than 80% of patients present at an asymptomatic stage and the lymphoma is usually diagnosed incidentally on imaging (48). Given the indolent clinical course and relatively benign histologic features, BALT lymphomas have frequently been described as “pseudolymphoma” (49–51). In a series of 13 patients with BALT lymphoma, 2 were found to have underlying SS (48). The radiographic presentation of BALT lymphomas in this series was variable, with either lung nodules (62%) or airspace consolidation with or without air bronchograms (39%) and with bilateral disease in more than half of the patients. Lymphadenopathy is characteristically absent. MALT lymphomas have a good prognosis at the time of diagnosis, and the prognosis is similar regardless of the involved organs. A study of 22 patients reported greater than 80% survival at 5 years (52).

Pulmonary amyloidosis

Amyloid is an amorphous, eosinophilic material with a typical apple green birefringence under polarized light after Congo red staining. Amyloid is composed of insoluble, non-branching linear fibrils of protein which deposit in tissues, often causing organ impairment (53).

In the lungs, four general clinical syndromes of amyloidosis are recognized: systemic (generalized), localized, diffuse, and pleural (54). All forms of pulmonary amyloidosis are most commonly of the AL type, which is a protein of immunoglobulin origin (55,56).

AL amyloidosis is a well-recognized complication of SS, most often associated with nodular pulmonary amyloidosis but also with systemic amyloidosis in rare cases.

Nodular pulmonary amyloidosis is almost always localized and is usually an incidental finding on chest radiography. Amyloid nodules are commonly peripheral and subpleural in location, usually affect the lower lobes, may be bilateral, and may reach a diameter of 15 cm. The prognosis of nodular amyloidosis is usually excellent (57,58).

Systemic AL amyloidosis has only rarely been described in association with SS and there are only two case reports described so far in the literature (59,60).

Pleural involvement

Pleural effusion is a rare manifestation of SS. There have only been nine previous reports in the literature of pleural effusion occurring as a specific complication of primary SS (61–67)(68). Pleural fluid in these cases was characterized by lymphocytosis, elevated levels of SS-A/SS-B antibodies, and low complement levels. Pleural effusions in SS are so rare that their occurrence should always bring up the possibility of a second underlying autoimmune disorder, such as systemic lupus erythematosus or rheumatoid arthritis.

Pleural thickening is another rare manifestation of SS. In a series of 37 SS patients who had normal chest radiographs, only one had pleural thickening on HRCT (6).

Pulmonary hypertension

The diagnosis of pulmonary arterial hypertension (PAH) requires right-heart catheterization, demonstrating an elevated mean pulmonary artery pressure (mPAP) >25 mm Hg at rest or >30 mm Hg during exercise with a normal pulmonary capillary wedge pressure (<15 mm Hg) in order to exclude significant left heart disease (69). It is a rare complication of primary SS and less than 50 cases have been described in the literature. Dyspnea in SS patients is commonly attributed to underlying ILD and a diagnostic workup for pulmonary hypertension is usually delayed. In a series by Launay (70), half of the patients had right heart failure at the time of diagnosis, with more than 80% of patients presenting with NYHA functional class III or IV. The severity of PAH in this series was attributed to the late diagnosis. Standard PAH therapy with or without immunosuppression can improve SS-associated PAH, although the best treatment strategy is yet to be defined (70).

Conclusions

SS is associated with multiple pulmonary manifestations extending from the upper airway to the alveolar space. Pulmonary involvement results in both increased morbidity and mortality. Cough and dyspnea are common symptoms and may portend a number of pulmonary manifestations. While clinical pulmonary involvement is relatively rare, pathologic evidence of lung injury is common. Therefore, pulmonary complaints should trigger appropriate evaluation including clinical exam, radiographic imaging and pulmonary function testing. On some occasions, surgical lung biopsy may be necessary for definitive diagnosis. Early identification and treatment is associated with improved outcome.