Pulmonary manifestations of Sjögren's syndrome

Epidemiology of Sjögren's syndrome

Sjögren's syndrome is the second most common autoimmune disease after rheumatoid arthritis. Incidence has recently been estimated at between 3.9 and 5.3 cases per 100 000 person-years in Europe [7]. Population-based and sample-based studies estimate its prevalence at 43 and 282 per 100 000 inhabitants respectively, the former probably being more representative of the actual prevalence [7]. Sjögren's syndrome mostly affects middle-aged women, with a peak at 56 years of age; men are affected less frequently and later in life, mostly after the age of 65 years [7]. There is a clear sex ratio, ranging from 9 to 13 women to one man [8]. Sjögren's syndrome is likely to be associated with other autoimmune diseases such as thyroiditis.

Pathophysiology of Sjögren's syndrome

Like other autoimmune diseases, the aetiopathogenesis of Sjögren's syndrome combines environmental factors such as viruses (cytomegalovirus, HIV, Human T-cell leukaemia virus, and hepatitis C virus) [9] or solvents [10], a genetic predisposition as reported by the large 2013 genome-wide association study [11], and hormonal deregulation, which leads to an initial glandular inflammation called autoimmune epithelitis and a deregulated immune response [12].

Recent studies have sought to characterise the immune response that occurs in Sjögren's syndrome. They confirm that B and T cells play a major role in this immune response, but also highlight the important role of innate immunity. B-cell demethylation [13], activation and proliferation [14] are abnormal, and activated B-cells promote plasma cell secretion of anti-Ro (SSA) and anti-La (SSB) autoantibodies directed to the small cytoplasmic RNP-bound peptides SSA-60kD, SSA-52kD and SSB-48kD [15]. It is noteworthy that anti-Ro52 autoantibodies have only recently been proven to be able to directly cause gland dysfunction in mice [16]. The role of T-cells in Sjögren's syndrome has been extensively studied and reviewed [10] with divergent conclusions, especially regarding the roles of regulatory T-cells and T-helper 17 cells [17], but T-cell activation and cytotoxicity are undeniable. Innate immunity in Sjögren's syndrome is an area of growing interest, with promising results, such as the role of the interferon signature [18]. New findings regarding innate immunity also include apoptotic cell clearance defect [19], the interaction between P2X7 receptors and inflammasome [20], and the role of epithelial cells, like other pro-inflammatory elements, in the immune response [21].

This immune response, combined with local inflammation, gland infiltration and pathogenic anti-Ro52 autoantibodies, could cause the bronchopulmonary damage observed in some Sjögren's syndrome patients.

Extrathoracic involvement

While glandular involvement is by far the most frequent manifestation, with sicca symptoms affecting up to 95% of patients, numerous extra-glandular symptoms have be encountered in up to one-third of patients with Sjögren's syndrome [22].

Sicca symptoms mostly concern the mouth; xerostomia, periodontal disease, caries, angular cheilitis or endobuccal ulcers are frequently encountered. Eyes are the next most involved organ; xerophtalmia is often incapacitating and causes photophobia and impaired night vision, while cornea dryness can be complicated by keratitis, ulcers or even perforations. Other ocular complications such as conjunctivitis, uveitis, scleritis and episcleritis, orbital inflammation, retinal vasculitis or optic neuritis have also been reported [23]. The ear, nose and throat area is also affected, with symptoms such as smell and taste disorders, hoarseness and itching of the external ear canal, while parotitis or salivary gland swelling is also common (30% of patients). Genital sicca can significantly impair quality of life, especially in women [24], with dyspareunia and loss of desire and arousal. Skin involvement includes xeroderma, hypohydrosis, itching, cutaneous shedding, annular erythema, atypical folliculitis and Raynaud's phenomenon. Purpura or leukocytoclastic vasculitis, sometimes mimicking urticaria, can also be encountered, especially in association with cryoglobulinaemia [25].

Extraglandular, extrathoracic involvement includes psychological manifestations, such as asthenia (70–80%), sleep disorder (15%), anxiety (20%) or depression (40%) [26]. Arthralgia and/or myalgia are estimated to be present in half the cases of Sjögren's syndrome, and symmetrical non-erosive arthritis can be observed. Neurological involvement is common (20%) [27]. The central nervous system can be affected (2%); vasculitis and cranial nerve palsy have been described, as well as transverse myelitis and optic neuritis. The peripheral nervous system is more frequently affected (5–15% of Sjögren's syndrome); sensitive neuropathy, mostly dorsal root ganglionopathy (5%), and painful small-fibre neuropathy (5–10%) are the most common, but sensorimotor polyneuropathy, mononeuritis multiplex, polyradiculoneuropathies, autonomic neuropathies, etc. are also found. Digestive involvement has been reported in Sjögren's syndrome, particularly dysphagia and dyspepsia, probably due to xerostomia (24%). Sjögren's syndrome can also be associated with primary biliary sclerosis [28], autoimmune hepatitis or inflammatory bowel disease [23]. Renal and urological involvement are not unusual; tubulointestitial nephritis, interstitial cystitis, kidney stones and glomerulonephritis have been described, as well as vasculitis and distal renal tubular acidosis [29, 30].

Haematological involvement is amongst the more serious complications of Sjögren's syndrome; even if polyclonal hypergammaglobulinaemia is mostly asymptomatic, it can evolve towards oligoclonal or monoclonal gammapathy. Cryoglobulinaemia (mostly type 2 and 3) can occur and cause vasculitis, which is mostly cutaneous but likely to be responsible for multi-organ involvement. Cryoglobulinaemic vasculitis can also affect peripheral nerves. Lymphadenopathy is also frequently reported, possibly associated with autoimmune cytopenias. Finally, the most serious haematological complication is B-cell mantle lymphoma, with a frequency that is six to 44 times higher in Sjögren's syndrome than in the general population [31].

The SSA/Ro antigen consists of two polypeptide components of 52 and 60 kDa. The clinical associations of anti-SSA60 autoantibodies include Sjögren's syndrome, systemic lupus erythematosus and foetal–maternal autoimmune syndromes. Anti-Ro/SSA52 autoantibodies are the most prevalent extractable nuclear antigen specificity identified. Their specific diagnostic value is mostly based on the simultaneous presence of other autoantibodies whose diagnostic weight is more relevant. Anti-Ro/SSA52 autoantibodies are expressed in systemic lupus erythematosus (53%), myositis (35%), systemic sclerosis (19%), Sjögren's syndrome (63%) and primary biliary cirrhosis (28%) [32]. Finally, babies of mothers with SSA antibodies can develop neonatal lupus, with cutaneous involvement and/or congenital atrioventricular heart block [33].

Classification criteria

The involvement of the lacrimal and salivary glands results in the typical features of dry eyes and salivary dysfunction, which are the most common subjective manifestations of Sjögren's syndrome. Evaluation of this impairment is based on four objective criteria: 1) Shirmer's test <5 mm in 5 min; 2) histopathology of minor salivary glands exhibiting focal lymphocytic sialadenitis with a focus score (the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm² glandular section) of >1; 3) salivary gland involvement (unstimulated whole salivary flow, parotid sialography showing the presence of diffuse sialectasia without evidence of obstruction in the major ducts, or salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer, salivary gland ultrasonography or magnetic resonance imaging is an alternative); and 4) autoantibodies found in the serum with SSA or SSB.

The American College of Rheumatology proposed new classification criteria in 2012 based on at least two of the three following objective features [3]: 1) positive serum anti-SSA/Ro and/or anti-SSB/La (or positive rheumatoid factor and anti-nuclear antibodies at a dilution >1/320); 2) minor salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score >1/4 mm2; and 3) keratoconjunctivitis sicca with ocular staining score >3 (assuming that the individual is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the past 5 years).

The European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI) is a clinical score that measures disease activity in Sjögren's syndrome, including evaluation of pulmonary involvement. It is used as a measure of disease activity in clinical studies or as a primary outcome measure in clinical trials [34].

Prevalence of lung disease in Sjögren's syndrome

The pulmonary manifestations of primary Sjögren's syndrome include airway abnormalities, interstitial pneumonia and lymphoproliferative disorders (table 1). Interstitial pneumonia and airway abnormalities often coexist. Infections and drug-induced pneumonia should always be considered and ruled out first. Pulmonary involvement could already be present before diagnosis but it can sometimes begin at the same time as other extrathoracic signs indicative of Sjögren's syndrome (10% of cases) [8]. The respiratory manifestations of Sjögren's syndrome are polymorphic and vary in severity, explaining the wide variability of prevalence reported in different studies. The prevalence of clinically significant lung disease in Sjögren's syndrome is 9–20% [35] with a female predominance [36]. When investigated systematically, prevalence increases to between 43% and 75% [37]. Computed tomography (CT) scan abnormalities are found in 34–50% of patients [38]. The annual incidence of respiratory manifestations is estimated at 10% (±3%) 1 year after diagnosis of Sjögren's syndrome and increases to 20% (±4%) by 5 years [6].

Clinical and biological profile of patients with pulmonary involvement

Studies suggest that the main risk factors of lung involvement are being male, smoking, late onset and long evolution of disease [8, 39–41]. Patients with pulmonary involvement in Sjögren's syndrome have a lower health-related quality of life [42]. A lower physical functioning score and a higher risk of death are found in Sjögren's syndrome patients with lung disease [40].

Pulmonary involvement is mostly associated with systemic manifestations, hypergammaglobulinaemia and anti-SSA and anti-SSB antibodies [37, 39, 43, 44]. Other biological markers proposed as risk factors for pulmonary involvement include the presence of anti-nuclear antibodies or rheumatoid factors [39, 45].

Pulmonary function test in Sjögren's syndrome

Pulmonary function test (PFT) results appear to reflect impairment of either the lung (restrictive syndrome) or airways (obstructive syndrome) [46]. The majority of Sjögren's syndrome patients have preserved lung function [37, 40, 47]. When it is abnormal, the PFT generally shows a restrictive rather than an obstructive pattern. However, Sjögren's syndrome patients with lung involvement revealed by CT scan generally have abnormal PFT results [36]. Reduced diffusing capacity of the lung for carbon monoxide (D_LCO) seems to be the most common abnormality [40, 43, 48–51]. Nevertheless, authors have suggested that D_LCO is a relatively insensitive technique for detecting subclinical pulmonary disease [44]. Changes in PFT results vary between studies. Davidson et al. [44] reported that D_LCO in Sjögren's syndrome patients decreased during the first 4 years and then remained stable for 6 years.

Cough

Cough is observed in 41–61% of Sjögren's syndrome patients [47]. Dry cough may precede Sjögren's syndrome diagnosis by several years and affects quality of life in 50% of Sjögren's syndrome patients [63]. Several hypotheses have been put forward to explain coughing, including airway dryness, abnormal mucociliary clearance [64, 65], bronchial or bronchiolar inflammation, bronchial hyperresponsiveness, and gastro-oesophageal reflux. Cough severity could be correlated with tracheal dryness (local sicca syndrome) [66]. There is no codified treatment protocol, but secretagogues (pilocarpine) or nebulised saline solution may be required.

Bronchial hyperresponsiveness

In contrast to other systemic diseases (except systemic scleroderma), bronchial hyperresponsiveness is frequently reported in Sjögren's syndrome (42–60% of patients) [66–69]. Clinically, patients report increased coughing after exposure to airway irritants (tobacco, pollution, etc.). Sjögren's syndrome patients show greater bronchial reactivity on the methacholine challenge test, but a lower response to adenosine monophosphate, cold and hyperventilation [70]. The mechanisms involved are unknown. Unlike asthma, eosinophils do not seem to act on hyperresponsiveness in Sjögren's syndrome. The intensity of hyperresponsiveness is not correlated with salivary gland infiltration [69] or with exhaled nitric oxide level [71]. No difference in bronchial gland atrophy was observed between Sjögren's syndrome patients and controls [72]. Tracheobronchial dryness has been indirectly measured by mucociliary clearance [65]. These data suggest that local sicca syndrome is a consequence of a functional secretion defect rather than glandular destruction. Bronchial hyperresponsiveness seems to be insensitive to inhaled corticosteroids in 40–60% of cases [66].

Bronchiolitis

Bronchiolitis is the most frequent airway disease in Sjögren's syndrome patients. It may be isolated or associated with interstitial pneumonitis [46]. Lung biopsy reveals bronchiolitis in 12% of Sjögren's syndrome patients. Frequency increases to 24% when based on new anatomical and radiological criteria [46]. Lung biopsy reveals different types of bronchiolitis, mainly follicular bronchiolitis (29%) [51]. Follicular bronchiolitis is characterised by the presence of hyperplastic lymphoid follicles with reactive germinal centres distributed along bronchovascular bundles (figure 1d) [73, 74]. Less frequently, other bronchiolitis types have been found, including chronic bronchiolitis [51], obliterative bronchiolitis [51], lymphocytic bronchiolitis [75, 76], constrictive bronchiolitis associated with bronchiolar destruction [77], and panbronchiolitis [78].

The course of bronchiolitis in Sjögren's syndrome is typically described as being fairly mild. However, cases of severe bronchiolitis have been described [62]. Few studies have described treatment for bronchiolitis in Sjögren's syndrome: follicular bronchiolitis could be treated with steroids [41, 46], rituximab [79–82], or macrolides [62] though with a low level of scientific evidence.

Bronchiectasis

The frequency of bronchiectasis in Sjögren's syndrome patients, as assessed by CT, varies from 7% to 54% [43, 49, 56, 59, 83, 84]. In most cases, it concerns cylindrical bronchiectasis. Sjögren's syndrome patients with bronchiectasis are older at the time of diagnosis, are more likely to have hiatal hernia, have a higher frequency of anti-smooth muscle antibody and a lower frequency of anti-SSA antibody than those without bronchiectasis [85].

Pulmonary infections

Recurrent pulmonary infections (particularly pneumonia) are reported in 10–35% of Sjögren's syndrome patients [45, 64, 75]. Suspected mechanisms areabnormalities of mucociliary clearance [65], abnormal sputum, deficit of local immunity, gastro-oesophageal reflux, bronchiectasis, parodontopathy [85] and use of immunosuppressive drugs.

Nonspecific interstitial pneumonia

NSIP is the most common subtype of ILD observed in Sjögren's syndrome patients (45% of patients) [89]. The histological features of the NSIP pattern consist of varying amounts of interstitial inflammation and fibrosis with a uniform appearance (figure 3c). Lung architecture is frequently preserved. Honeycombing is rarely seen, but areas of interstitial fibrosis with enlarged air spaces may induce traction bronchiectasis. This fibrosing stage is the most common NSIP variant in Sjögren's syndrome patients [98]. These histological abnormalities result in a particular CT pattern: bibasal and symmetrically predominant reticular abnormalities with traction bronchiectasis, peri-bronchovascular extension (frequently associated with ground-glass attenuation) and uncommon features including sub-pleural sparing and pulmonary consolidations (figure 3a and b) [92]. These CT abnormalities help distinguish NSIP from UIP.

The outcome of NSIP in Sjögren's syndrome is unpredictable, it can be: 1) reversible with a risk of progression; 2) stable with residual disease; 3) progressive and irreversible with potential stabilisation; or 4) irreversible without respite, despite therapy [99]. The 5-year survival rate of patients with NSIP is 83% [46].

Corticosteroids (ranging 0.5–1 mg·kg⁻¹·day⁻¹ with azathioprine or cyclophosphamide) are usually prescribed for NSIP patients, but with no evidence of efficacy [26, 100]. In a cohort of 18 Sjögren's syndrome-ILD patients, Parambil et al. [36] described five patients with NSIP treated with corticosteroids associated with other drugs (hydroxychloroquine, azathioprine or cyclophosphamide). Three of these patients showed significant improvements in forced vital capacity (FVC) and/or D_LCO. However, the PFT results of one patient worsened (<10% increase in FVC or <15% increase in D_LCO) [36]. Although these therapies have been shown to be effective in case studies, clinical trials are needed.

Studies of rituximab have not distinguished between different forms of ILD in Sjögren's syndrome. A French review reported nine Sjögren's syndrome patients with pulmonary involvement treated by rituximab. Eight patients had ILD (with no distinction between different forms), of whom six improved after beginning treatment with rituximab, and two were persistent responders 30 months after a single cycle of rituximab [79]. Rituximab appears to be well tolerated, but a recent randomised, blinded, parallel-group trial found a significant increase in adverse events (mainly respiratory infections) for patients with a respiratory disorder treated with rituximab [101].

Usual interstitial pneumonia

UIP appears on CT scans as bilateral areas of intralobular reticular attenuation accompanied by traction bronchiectasis and small cystic changes, with both basal and peripheral predominance and temporal heterogeneity [99]. Honeycombing visible on CT scans (figure 2a) or in lung biopsies is characteristic of UIP. Other histopathological features of UIP are: 1) a patchy pattern of interstitial fibrosis mixed with normal parenchyma (abrupt shifts between fibrotic and normal parenchyma); 2) lesions that are worse directly under the pleura and in the periphery of the lobule; 3) scattered fibroblast foci; and 4) minimal interstitial inflammation.

In a study of 343 Sjögren's syndrome patients, Strimlan et al. [45] reported two cases with a histological diagnosis of UIP. UIP represents ∼16% of cases of ILD in Sjögren's syndrome [89]. It is regarded as an irreversible lung disease with a high risk of progression, despite therapy. The prognosis could be worse than NSIP.

Sjögren's syndrome patients with UIP are generally older and are more often women compared to those with idiopathic pulmonary fibrosis. In addition to the pathological pattern of UIP, Sjögren's syndrome patients have more interstitial inflammation, lymphoid follicles with germinal centres and cysts [102]. In that study, Sjögren's syndrome patients with UIP were younger with higher FVC at diagnosis and had a better prognosis than those with idiopathic pulmonary fibrosis [102]. Four out of ten Sjögren's syndrome–UIP patients died during the follow-up period (4–157 months). Immunosuppressive drugs do not seem to benefit Sjögren's syndrome patients with UIP [36]. However, no clinical trial has yet been performed to confirm this observation.

Lymphocytic interstitial pneumonitis

LIP is a benign lymphoproliferative disorder in Sjögren's syndrome. Probably, a continuum exits between LIP and follicular bronchiolitis. It is characterised by diffuse proliferation of polyclonal lymphocytes and plasma cells in the pulmonary parenchymal interstitium, with lymphoid follicles and germinal centres (figure 2d). Liebow and Carrington [86] found that in a cohort of patients with LIP, 28% had Sjögren's syndrome. LIP seems to account for 15% of cases of Sjögren's syndrome patients with ILD [89]. Most patients have respiratory symptoms (particularly dyspnoea and cough), and bilateral inspiratory crackles” may be heard [103]. Classically, PFT shows a restrictive syndrome depending on the progression of the disease [86]. The most frequent abnormalities shown on CT scans are thickened bronchovascular bundles (evoking association with follicular bronchiolitis), nodules and ground-glass opacities, and thickening of interlobular septa (figure 2b) [103, 104]. Studies have reported cysts in 68–82% of patients with LIP (figure 4b) [93, 103, 105]. Surgical lung biopsy and assessment of clonality are essential to exclude the diagnosis of lymphoma.

LIP seems to be a reversible lung disease with a potential risk of progression [99]. The majority of patients treated with corticosteroids remain clinically stable or show improvement [86, 103]. LIP can worsen with the development of honeycombing [106]. Other immunosuppressive agents (azathioprine, cyclophosphamide and chlorambucil) have been used but with variable response [107, 108]. Rituximab has been described as effective in one patient [82].

Organising pneumonitis

Histological diagnosis of organising pneumonia has been reported in 11% of Sjögren's syndrome patients [36, 46, 89]. Organising pneumonia could even reveal Sjögren's syndrome [109–112]. Clinical presentation is similar to other organising pneumonia aetiologies. CT scans show multiple patchy areas of consolidation with a subpleural or peribronchovascular distribution, often bilateral, accompanied by areas of ground-glass attenuation or fine centrilobular nodules (figure 3d). Histological analyses frequently reveal a pattern of NSIP overlapping with organising pneumonia [51]. Ito et al. [46] reported a good initial response to corticosteroid therapy, but all patients relapsed and developed an NSIP pattern.

Corticosteroids are the reference therapy for organising pneumonitis. In refractory organising pneumonia, immunosuppressive agents such as azathioprine, cyclosporine, infliximab and rituximab have been used [113]. Recently, one case of refractory organising pneumonia was treated by tocilizumab with good efficacy [114].

Uncommon causes of interstitial pneumonia in Sjögren's syndrome

Other causes of interstitial pneumonia in Sjögren's syndrome patients include: Langerhans’ histiocytosis [115], cavitary lung disease and granulomatosis with polyangiitis [116], and combined pulmonary fibrosis and emphysema syndrome (figure 2b) [117]. Alveolar haemorrhage has been reported in two cases, but in association with cryoglobulinaemia and with rapidly progressive pulmonary fibrosis [118, 119].

Pulmonary amyloidosis

Pulmonary amyloidosis associated with Sjögren's syndrome is rare. A review of the literature reported 37 cases; 96.5% of patients were women presenting with cough, dyspnoea, weakness, haemoptysis and pleuritic chest pain. Radiographically, nodules with or without calcification were the most common abnormalities (78.8%). It can be associated with LIP and cystic lesions. Transbronchial biopsy could lead to a high risk of haemoptysis. Surgical lung biopsy is usually required to establish the diagnosis and to rule out lymphoma [120]. No specific therapy has been reported, but corticosteroids could be used for some patients.

Pulmonary lymphoma

Sjögren's syndrome is associated with a 16- to 44-fold increased risk of non-Hodgkin lymphoma [121]. Marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue are the most common subtypes. The prevalence of primary pulmonary lymphoma is 1–2% in patients with primary Sjögren's syndrome, with pulmonary localisation in 20% of cases [122]. It is rarely associated with an infectious agent (human herpesvirus-6 or Epstein–Barr virus). Non-Hodgkin lymphoma is associated with parotidomegaly, hypocomplementemia, type II cryoglobulinaemia, cutaneous vasculitis, CD4 cytopenia and a low CD4/CD8 ratio [123]. Radiological abnormalities are solitary or multiple nodules or masses (figure 4a), with areas of airspace consolidation or ground-glass attenuation, mediastinal lymphadenopathy and pleural effusions. The average 5-year survival rate is 65–90% [31, 122–125]. Lymphomas require specific haematological treatment.

Pulmonary embolism and pulmonary hypertension

A case series combined with a review of the literature described 28 cases of pulmonary hypertension in Sjögren's syndrome patients associated with a mean pulmonary artery pressure of 44 mmHg and a worsened prognosis with low survival rates (73% and 66% at 1 and 3 years, respectively) [126]. Clinical trials are needed to evaluate immunosuppressive drugs and pulmonary antihypertensive in Sjögren's syndrome patients with pulmonary hypertension.

There is an increased risk of thromboembolism in systemic autoimmune diseases. Some studies have found that the risk of venous thrombosis or pulmonary embolism in Sjögren's syndrome patients is significantly greater than in the general population [127, 128].