14.2.4Pulmonary Function Tests in pSS-Associated Airway Disease

Pulmonary function tests in most patients with lung involvement in pSS reveal small airway involvement, with maximal mid-expiratory flows (MMEF) markedly reduced compared to controls. Concomitant impairment in diffusing capacity for carbon monoxide (DLCO) has also been reported [3, 6]. Although the extent of air trapping on expiratory CT scans was found to be increased in non-smoking pSS patients compared to healthy controls, correlation with pulmonary function parameters was found in some but not all studies [19, 24].

Bronchial hyperresponsiveness (BHR) to inhaled aerosolised methacholine was described by a study in a substantial portion (60%) of patients with pSS, in contrast to only 10% of the control population [25]. In the same study, BHR was highly prevalent in patients with small airway disease on spirometry and correlated strongly with subjective symptoms of xerotracheitis. Although the mechanism underlying BHR in pSS is unknown, it may be associated with increased osmolarity in the bronchial mucosa secondary to dryness in the airways or with bronchial or tracheal inflammation [25]. The latter possibility is supported by findings of increased levels of nitric oxide in the exhaled air of patients with pSS, similar to that described in asthma [26]. However, the BHR in pSS, unlike BHR associated with asthma, appears to be resistant to inhaled corticosteroids and sodium cromoglycate [27].

14.3Interstitial Lung Disease

14.3.1Overview

Over the last decade, ILD and especially nonspecific interstitial pneumonia has been recognized as an important subset of ILD associated with CTD. In some cases, clinically evident pulmonary disease precedes the diagnosis of CTD [28, 29]. Initial and retrospective studies have suggested a predominance of ILD in pSS patients [3, 4], but subsequent studies disclosed with larger numbers of pSS patients disclosed a much lower prevalence (<5%) [reviewed in 28]. Primary SS patients occasionally present with radiological and pulmonary function abnormalities suggestive of ILD, but without prominent self-reported sicca symptoms [28, 30]. Careful questioning for sicca symptoms is essential and if pSS is suspected on this basis, minor salivary gland biopsy and serological testing for specific autoantibodies including anti-SSA/Ro and anti-SSB/La should be performed. One study of minor salivary gland biopsy in a cohort of 38 ILD reported positive findings (defined as focus score >1) in 8% of patients [30].

Early studies showed that ILD was more prevalent in pSS patients with extraglandular features [31]. In addition, patients with ILD were more likely to have

Table 14.2 Frequency (n, %) of various histopathological patterns in primary Sjogren’s syndrome related lung involvement

NSIP non specific interstitial pneumonia, LIP lymphocytic interstitial pneumonia, UIP usual interstitial pneumonia, COP cryptogenic organizing pneumonia”

aTwo patients had associated amyloidosis

bInclude non caseating granulomas, amyloidosis, pleural thickening, pseudolymphoma, follicular bronchiolitis, chronic bronciolitis and constrictive bronchiolitis (isolated or in association with other histological patterns)

rheumatoid factor (RF), anti-Ro/SSA and anti-La/SSB antibodies, and lymphopenia [32]. However, the presence of these autoantibodies was associated with the “intensity” of alveolitis, as graded by cellularity in the bronchoalvelolar lavage (BAL) [33].

14.3.2Pathology

Video-assisted thoracoscopic (VATS) lung biopsy is the preferred method for obtaining multiple lung tissue samples for histopathological analysis. The small size of transbronchial biopsies limits the specific pathological diagnosis of ILD and also may miss small airway abnormalities [34]. The main histopathological patterns detected in lung biopsies from pSS patients with ILD include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonitis (UIP), follicular bronchiolitis, lymphocytic interstitial pneumonia (LIP), and cryptogenic organizing pneumonia (COP) [34–37] (details in Table 14.2).

14.3.3Non-Specific Interstitial Pneumonia

NSIP is characterized histopathologically by a uniform interstitial involvement of varying degrees of chronic inflammation or fibrosis [38, 39]. On high-resolution computed tomography (HRCT) studies, the most frequent finding is ground-glass opacities with reticulation, traction bronchiectasis, and little or no honeycombing. In addition to collagen vascular diseases, NSIP may be idiopathic or seen in other settings such as hypersensitivity pneumonitis, drug-induced lung disease, infection, or immunodeficiency [39].

Fig. 14.1 HRCT appearance in a patient with primary Sjögren’s syndrome and interstitial lung disease. Note the fibrotic abnormalities at both bases

NSIP was the most common histological pattern, found in 60% of patients with pSS and ILD reported by Ito et al. [35]. NSIP, followed by UIP and LIP, was also the predominant histopathological type in another study involving 18 patients with pSS and ILD [36]. According to the findings of Ito et al., the NSIP pattern on HRCT had a high positive predictive value for the histological diagnosis of NSIP [35].

14.3.4Usual Interstitial Pneumonia

UIP is characterized histopathologically by a variable distribution of patchy interstitial fibrosis, inflammation, honeycombing, and normal lung. The presence of small aggregates of fibroblasts and myofibroblasts, termed fibroblast foci, is necessary for the diagnosis [38]. UIP in the setting of pSS is rather rare. In the series of 343 patients reported by Strimlan et al., including cases of both pSS and secondary SS, UIP was histopathologically diagnosed in only two patients [4]. Since then most reports of UIP have been found in patients with SS associated with another CTD. Reporting on 18 pSS patients with ILD and available histopathological findings,

Fig. 14.2 Representative HRCT lung findings in a patient with primary Sjögren’s syndrome and a biopsy-proven lymphocytic interstitial pneumonia. Note the bilateral symmetric diffuse micronodular pattern, with a predominantly centrilobular distribution

Parambil et al. described three patients with UIP and demonstrated signs of progression [36]. UIP cases have also been reported in the studies of Deheinzelin and Yamadori by surgical biopsies [37, 40]. In the latter, UIP histology was detected in 6 out of 9 patients tested [40] (Fig. 14.1).

14.3.5Follicular Bronchiolitis

Follicular bronchiolitis is characterized by proliferation of peribronchial lymphoid follicles leading to obliteration of the airway lumen, which in turn through a valve phenomenon can lead to bullae formation. It may present either alone or most commonly in the context of another autoimmune disease such as rheumatoid arthritis or a viral infection, including HIV. Follicular bronchitis usually coexists with LIP in the context of pSS [41, 42].

14.3.6Lymphocytic Interstitial Pneumonia

LIP, first described by Liebow and Carrington [43], is characterized by a diffuse, polyclonal lymphoid cell infiltrate surrounding airways and expanding into the lung interstitium (Fig. 14.2). LIP has been classically associated with underlying autoimmune disorders, including systemic lupus erythematosus and pSS [44].

Early studies suggested that LIP and primary pulmonary lymphoma were the most common forms of parenchymal lung disease in pSS. In the initial report of Strimlan et al., among 13 patients in whom histopathological findings were