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Revue des Maladies Respiratoires
Vol 24, N° 4  - avril 2007
pp. 67-82
Doi : RMR-04-2007-24-4-0761-8425-101019-20064258
Pulmonary involvement in Sjögren’s syndrome
 

B. Crestani [1 et 6], S. Schneider [5], H. Adle-Biassette [2 et 6], MP Debray [3 et 6], M. Bonay [4 et 6], M. Aubier [1 et 6]
[1] Service de Pneumologie A, APHP, Hôpital Bichat, Paris, France.
[2] Laboratoire d’Anatomie Pathologique, APHP, Hôpital Bichat, Paris, France.
[3] Service de Radiologie, APHP, Hôpital Bichat, Paris, France.
[4] Laboratoire d’Explorations fonctionnelles respiratoires, APHP, Hôpital Bichat, Paris, France.
[5] Service de Pneumologie, Centre Hospitalier de Bayonne, France.
[6] Université Paris 7 Denis Diderot, paris France.

Tirés à part : B. Crestani

[7]  Service de Pneumologie A, Groupe Hospitalier Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris.

To cite the present paper, use exclusively the following reference: Crestani B, Schneider S, Adle-Biassette H, Debray MP, Bonay M, Aubier M. Manifestations respiratoires au cours du syndrome de Gougerot-Sjögren (full text in english on cliquez ici). Rev Mal Respir 2007;24:535-51.


Abstract

Sjögren’s syndrome is a common auto-immune disease. The respiratory system is frequently involved with 10% of the patients developing a clinically significant lung disease. Respiratory disease may be the first manifestation of the syndrome. Beside interstitial lung diseases and bronchiolar disorders, cough is a very common symptom affecting about 50% of the patients in some studies, with limited therapeutic opportunities. Lung cysts, amyloid deposits, sometimes associated with lymphoma, have been recently described. Primary pulmonary lymphoma, usually from the MALT, is a very severe complication of the Sjögren’s syndrome.

Keywords: Connective tissue diseases , Lymphoma , Auto-immune disease , Pulmonary fibrosis , Sjögren


Introduction

Sjögren’s syndrome (SS) is an auto-immune disease involving the exocrine glands, typically the salivary glands and lacrimal glands, characterized on histology studies by lymphocytic infiltration of the glands. The disease presents with the classic triad of dry mouth (xerostomia), dry eyes (xerophthalmia) and fatigue. Five to 10% of patients will present significant clinical involvement apart from the lacrimal and salivary gland disorders. The disease most commonly affects the lungs.

Among the connective tissue disorders, SS is relatively frequent, occurring in 0.1% of the general population and 3% of adults [1]. As in many auto-immune disorders, women are more often affected than men (female-to-male ratio of 9:1). There are two incidence peaks for onset of the disease: between the age of 20 and 30 and between 40 and 60. Secondary SS occurs in association with a defined connective tissue disease; primary SS occurs alone.

Lymphoproliferative disorders are a major complication of SS, and approximately 5% of patients with primary SS develop marginal zone B-cell lymphoma [2].

The syndrome was first reported in 1892 by Jan Mikulicz-Radecki, a Polish surgeon, who described a male patient with bilateral swelling of the parotid and lacrimal glands with mononuclear infiltration. In 1926, Henri Gougerot, a Parisian dermatologist, described three female patients who presented severe eye and mouth dryness. One of these patients presented signs of pulmonary involvement that were probably specific [3] with chronic permanent hoarseness related to laryngeal dryness and recurrent bronchitis (text in French accessible on the Paris 5 University website: cliquez ici). In 1933, Henrik Sjögren, the Swedish ophthalmologist, described in his thesis the clinical picture of 19 females presenting mouth and eye dryness and introduced the term “keratoconjunctivitis sicca” or dry eye syndrome.

Pathogenesis
Diathesis

Sjögren’s syndrome occurs in individuals with a genetic predisposition to auto-immune disorders, and is marked by the high prevalence of the HLA B8 and DR3 haplotypes and the high incidence of auto-immune disorders in the relatives of patients with SS (20% to 30%). In individuals with this predisposition, a lesion of the exocrine gland epithelial cells, for example secondary to a viral infection, would cause chronic inflammation characterized by lymphocytic infiltrates composed of T lymphocytes and B lymphocytes, with germinal centres. This inflammation is self- maintained and results in dysfunction then destruction of the gland.

Role of viruses

Various sialotropic viruses (CMV, EBV, Coxsackie) have been suspected as triggers, but none have been demonstrated to play a direct role. Some viruses, such as HIV, HTLV1 and hepatitis C, can cause dry syndromes difficult to differentiate from primary SS [4]. For example, the lymphocyte infiltration of the salivary glands observed during the diffuse infiltrative lymphocytosis syndrome in HIV is composed of CD8 lymphocytes, while in SS, CD4 lymphocytes are mainly involved [5].

Immunopathology

Sjögren’s syndrome progresses through several successive stages: 1) the initial exocrine gland lesion responsible for gland cell necrosis or apoptosis resulting in abnormal expression of antigenic proteins (Ro/SSA, La/SSB, fodrine) to epithelial cells; 2) cytokine and chimiokine production in the affected gland, by the epithelial cells, the stromal cells (fibroblasts), and the resident macrophages, resulting in endothelial cell activation and recruitment of lymphocytes and dendritic cells; 3) production of anti-SSA antibodies by the B lymphocytes, facilitated by a genetic predisposition to autoantibody production; 4) activation of dendritic cells by antibodies to the SSA/ribonucleoprotein complex [6], [7]; 5) secretion of type 1 interferons (interferon alpha/beta) by the dendritic cells infiltrating the glands, particularly the plasmacytoid dendritic cells [8], [9] resulting in perpetuation of lymphocyte recruitment, plasmocyte differentiation and autoantibody secretion, epithelial cell apoptosis and finally destruction of the gland.

There is considerable B lymphocyte activation in SS, far more than that observed in other autoimmune diseases. This is evidenced by an increase in the blood gammaglobulin levels, the presence of various autoantibodies (rheumatoid factor, anti-SSA, anti-SSB, anti-fodrine) and the particularly frequent development of B-cell lymphomas. Murine models for SS shed light on the important role played by B lymphocytes in the pathophysiology of the disease. Transgenic mice overexpressing BAFF (a B cell activator belonging to the TNF family which is involved in the survival of autoreactive B lymphocytes [10]) develop with age a syndrome similar to SS with lymphocyte infiltration followed by destruction of the salivary glands [11]. These mice also develop B cell lymphomas [12]. BAFF is strongly overexpressed in the accessory salivary glands in patients with SS [11] which suggests involvement of this factor in the pathogenesis of the disease in humans.

Mechanisms causing dryness of the mucosa

Destruction of the glands alone cannot explain the impaired function (dryness) observed in patients. Lymphocyte infiltration is focal, at least at the beginning of the disease, leaving a considerable number of glands intact, and salivary flow is not related to lymphocyte infiltration. Dysfunction of the remaining glands certainly contributes to the discomfort, because of impaired control of lacrimal and salivary secretions by the autonomic nervous system, which could be related in particular to autoantibodies directed against the M3 antimuscarinic receptors [5], [13]. There is also a deficiency in membrane expression of aquaporine-5, a water channel protein in the lacrimal and salivary glands [14] whose expression is modulated by M3 receptors [15]. These pathophysiological data point to interesting treatment perspectives for patients with SS [16]. Aquaporine-5 is also expressed in bronchial and alveolar epithelium, but its expression has not been studied in SS.

Extraglandular manifestations

The pathophysiology of systemic manifestations of SS, in particular lung involvement, remains poorly understood. However, some of the principle signs are probably common to systemic manifestations of the disease: lymphocyte infiltration of exocrine glands and tissues, B lymphocyte activation responsible for development of pulmonary lymphomas, autonomic nervous system dysfunction resulting in reduced secretions and dryness of the airways. Lymphocyte recirculation from the salivary glands towards other organs, in particular to the lung, has already been demonstrated [17].

  • Sjögren’s syndrome occurs in individuals with a genetic predisposition to autoimmune disorders.
  • Certain viruses have been suspected as triggers.
  • There is considerable B lymphocyte activation in SS, with high polyclonal gammaglobulin levels, the presence of autoantibodies and B cell lymphomas.
  • BAFF protein overexpression is noted.
  • The dryness is not explained by gland destruction alone; the autonomic nervous system plays a role and also a deficiency in membrane expression of aquaporine-5.

Diagnostic criteria

In the last 30 years there has been a great deal of confusion concerning the diagnostic criteria for SS, with competition between different more or less restrictive definitions, resulting in great variations in the prevalences reported. Since 2002, the revised version of the European criteria has been widely adopted (table I) [18].

Primary Sjögren’s syndrome

The diagnosis of primary SS requires the presence of symptoms of mouth and eye dryness, and either the presence of lymphocyte infiltration on the salivary gland biopsy or the presence of autoantibodies (anti-SSA or anti-SSB). These criteria have a specificity of 96% and a sensitivity of 94% for the diagnosis of primary SS [18].

Secondary Sjögren’s syndrome

Secondary SS is defined as 1) the presence of another connective tissue disorder, 2) symptoms of eye and mouth dryness, and 3) evidence of eye or salivary gland involvement. The presence of anti-SSA or anti-SSB antibodies is not necessary for the diagnosis of secondary SS. These criteria have a specificity of 97% and a sensitivity of 90% for the diagnosis of secondary SS [18]. Among the connective tissue disorders, rheumatoid arthritis is the most frequently observed in association with secondary SS, but scleroderma, lupus, polymyositis, and primary biliary cirrhosis are also possible. Typically, secondary SS is characterized by less frequent visceral involvement and vasculitis compared with primary SS [19], [20]. However, pulmonary involvement is more frequent and more severe in secondary than in primary SS [19], [20]. Its characteristics seem to vary depending on the associated disorder. Thus, in secondary SS associated with rheumatoid arthritis, the dry syndrome is less severe and anti-SSA and anti-SSB antibodies are found les frequently than in primary SS. But, when secondary SS is associated with lupus or scleroderma, the clinical presentation and serology findings are comparable with those in primary SS [21]. The pathophysiology of secondary SS is different from that of primary SS [5].

If SS is suspected, an unrelenting search for anti-SSA and anti-SSB antibodies is required; these antibodias are often detected when antinuclear antibodies are present. It should however be noted that anti-SSA antibodies can be present when antinuclear antibodies are absent (up to 50% of cases in a Danish series of patients with primary SS) [22]. Anti-SSB antibodies are the most characteristic of SS. In approximately one case in two they are associated with an anti-SSA antibody. The joint presence of both antibodies is highly suggestive of SS.

According to these criteria, the presence of sarcoidosis excludes the diagnosis of SS, as does the presence of hepatitis C virus infection. However, the coexistence of authentic SS is indisputable in the above contexts [4], [23].

  • Primary SS presents as mouth and eye dryness, and either lymphocyte infiltration of the salivary glands, or the presence of autoantibodies (anti-SSA or anti-SSB).
  • Secondary SS is characterized by the presence of another connective tissue disorder, symptoms of eye and mouth dryness, and evidence of eye or salivary gland involvement.
  • Secondary SS is associated with connective tissue disorders, rheumatoid arthritis, scleroderma, lupus, polymyositis or primary biliary cirrhosis.
  • Suspected SS requires a search for anti-SSA and anti-SSB antibodies.

Prevalence of pulmonary involvement in Sjögren’s syndrome

The exact prevalence of pulmonary involvement in SS is difficult to define, varying between 9% and 90% of patients depending on the studies. These large variations are mainly due to differences in methodology: considerable variation in the population size studied, inclusion of primary and secondary SS (not permitting the separation of elements due to SS and those due to associated connective tissue disorders), presence or not of a control population, use of non-standardized criteria to define lung involvement (physical examination, chest radiograph, lung CT scan, respiratory function tests, bronchoalveolar lavage, etc.).

Nevertheless, clinically significant pulmonary involvement is infrequently observed, affecting 9% of the series of 343 patients studied at the Mayo Clinic [24] and 10% of the most recent series of patients studied by Davidson et al. [25].

Subclinical involvement is far more frequent, as shown below. For the sake of clarity, we limit discussion to pulmonary involvement in primary SS. In secondary SS, it is very difficult to distinguish manifestations of SS from those of the associated connective tissue disorder.

Specific pulmonary involvement in Sjögren’s syndrome
Upper airway involvement

Involvement of the upper airways in SS is frequent but poorly described [26]. The manifestations are nasal dryness and rhinitis with crusting of secretions. Recurrent upper airway infections, impaired sense of smell and taste, epistaxis, nasal septum perforation, chronic sinusitis, and recurrent otitis due to chronic Eustachian tube obstruction can also occur. Hypoacusis, possibly related to modifications of cochlear epithelium autoimmune in origin, can also complicate the ENT picture of the disease. Laryngeal involvement can be prominent in the clinical picture [27].

Lower airway involvement
Histopathological data
Proximal airways

Histology studies of changes in the proximal airways have not been frequent in SS. Papiris et al. performed bronchial and transbronchial biopsies in 13 non-smokers with SS and chest radiograph abnormalities. Submucosal mononuclear infiltrates were observed in the proximal and distal bronchi in 10 of the 13 patients. In a second study, Papiris analyzed bronchial biopsies from 10 consecutive patients presenting primary (n=6) or secondary (n=4) SS and observed extraglandular submucosal CD4+ T lymphocyte infiltration in 6 of the 10 patients [28]. The role of this lymphocyte infiltration in the origin of respiratory symptoms is uncertain. Lymphocyte infiltration is similar in subjects with and without symptoms [28]. Mast cell and neutrophil infiltration associated with changes in bronchial epithelium is also frequently observed [29].

Peripheral airways

Involvement of the bronchioles is rarely prominent in the lung biopsies of patients with SS. It was found in 2 of the 12 cases in the series studied by Deheinzelin [30]. In the study by Ito, bronchiolar involvement was the main abnormality in 4 out of 33 patients, and an associated abnormality in 4 other patients, i.e. 8 of the 33 patients (25%) [31]. Four types of histological lesions are observed in SS, but none are specific to SS:

  • Follicular bronchiolitis: the most frequent in the context of SS. The lumina of the bronchioles are compressed by hyperplastic lymphoid follicles developing in the bronchiolar walls. Lymphocyte infiltration of the bronchiolar wall is frequently observed. Follicular bronchiolitis is sometimes associated with lymphocytic interstitial pneumonia (LIP). Sjögren syndrome is a frequent cause of follicular bronchiolitis (25% of the cases in a series of bronchiolitis associated with connective tissue disorders) [32]. The definitive diagnosis requires a surgical lung biopsy, but transbronchial biopsies can sometimes show peribronchial lymphocyte infiltration suggesting this diagnosis in the appropriate radioclinical context [33].
  • Lymphocytic bronchiolitis: this is characterized by lymphocyte infiltration with follicle formation and is particularly observed in SS [34] [35] [36].
  • Constrictive bronchiolitis (also called bronchiolitis obliterans): there is destruction of the bronchiolar wall with disappearance of the lumen which is sometimes total with the bronchioles being replaced with a fibrous scar. This type of involvement is exceptional in primary SS [37]. The onset of constrictive bronchiolitis in rheumatoid arthritis, possibly associated with secondary SS, is well recognized although very rare.
  • Bronchiolitis obliterans organizing pneumonia. Here, the airways are obstructed by loose connective tissue proliferation from the terminal bronchioles. The clinical, functional and respiratory signs are not those of an airway disease but rather those of a parenchymal disease with alveolar opacities on the radiographs, and restrictive ventilatory disorders on the respiratory function tests. This type of involvement is rare in SS [38], [39].

  • The prevalence of pulmonary involvement in SS is unknown, but clinical pulmonary impairment is relatively rare.
  • Upper airway involvement can affect the entire ENT sphere.
  • Lesions of the lower airways are mainly lymphocyte infiltration, but can also be mast cell or neutrophil infiltration.
  • Bronchiolar involvement is not frequent and is mainly characterized by follicular bronchiolitis.

Respiratory function test abnormalities
Obstructive ventilatory disorders

Many studies have reported the presence of reduced expiratory flows measured at low lung volumes (FEF25 and FEF50) in SS, considering this as an index of small airways disease. However, most of these studies did not have a control group, mixed primary and secondary SS, and were not checked for smokers. In a controlled study of 61 consecutive patients, Papiris [40] observed a reduction in FEF50 and FEF25 below 75% of the theoretical value in 87% and 97% of the patients respectively. These percentages are unusually high as to date percentages between 22% and 46% have been published in the literature [34], [41], [42]. These results contrast with those of Papathanasiou et al. who observed the prevalence of obstructive ventilatory disorders was no higher in the SS population than in the controls [20]. Despite these contradictory data, it seems that small airways involvement rarely results in clinically significant obstructive ventilatory disorders in patients with SS. In fact, only 11% of the patients studied by Papiris presented a reduction in FEV1 to below 80% of the theoretical value [40], a value very close to that reported by Kelly et al. who observed a reduction in FEV1 in 14% of the patients at the time of diagnosis in a series of 100 patients with SS [43]. The evolution with time of these respiratory function abnormalities is poorly understood. In the majority of cases, when obstructive ventilatory disorder is present, it does not seem to worsen [25], [43] [44] [45]. Severe forms of obstructive ventilatory disorder have been described [34].

Bronchial hyperresponsiveness

Bronchial hyperresponsiveness can be detected in approximately 50% of patients with SS with a methacholine test [46]. Contrary to the observation in atopic asthma, bronchial hyperresponsiveness is less marked when tested with adenosine monophosphate (AMP) or with hyperventilation of cold dry air [47]. This high prevalence of bronchial hyperresponsiveness is not usual in connective tissue diseases, being observed only in systemic sclerosis [48], [49]. The precise pathogenesis of bronchial hyperresponsiveness is unknown, as the degree of hyperresponsiveness does not correlate with the severity or the duration of SS, or with the severity of salivary gland lymphocyte infiltration [48]. There is however a strong correlation between bronchial hyperresponsiveness and tracheal dryness [50]. There is an increase in exhaled nitrous oxide in patients with SS which is not correlated with the degree of hyperresponsiveness [51].

Dryness of the mucosa

The presence of dryness of the bronchial mucosa has never been objectively demonstrated in SS. The study of mucociliary clearance has been proposed as a test to investigate bronchial dryness [52]. A reduction in mucociliary clearance (measured with ventilation scintigraphy) was observed in symptomatic patients, with primary or secondary SS, with good correlation between degree of deterioration in clearance and degree of deterioration in secretion of saliva [52]. However, the deficiency in mucociliary clearance is variable (4 patients out of 7 in the study by Becquemin et al.) [53] and is not found by all the studies [54]. In addition, morphometric analysis of bronchial glands and goblet cells in the proximal and distal airways in 6 patients with SS did not show atrophy of the bronchial glands, but on the contrary an increase in the relative surface of the bronchial glands and goblet cells compared with the control subjects [55]. If a deficiency in seromucous gland secretion exists, it seems more related to a functional disorder (regulation abnormality) than to extensive destruction of the glands.

CT scan data (table II)

Systematic performance of thoracic CT scans has confirmed the high frequency of bronchial abnormalities in SS. Systematic study of patients, without prior selection, shows bronchial thickening in 8% to 22% of patients, bronchiectasis in 6% to 38%, and bronchiolar nodules in 6% to 23% of patients [40], [56] [57] [58]. These very different proportions probably indicate different recruitment methods in the centres where the studies were performed as shown by the high frequency of abnormalities observed in a series of patients with respiratory symptoms: bronchial wall thickening: 68%, bronchiectasis: 42%, bronchiolar nodules: 29% [59].

All these data demonstrate the high frequency of airway involvement in SS when precise detection methods are used. However, in the majority of cases, these abnormalities have little impact on the respiratory function tests.

Radioclinical presentation

Airways involvement is very frequent, from both the functional and imaging viewpoints, but the most often the abnormalities have little or no clinical impact. However, sometimes clinically significant involvement can be observed, in isolation or associated with another specific or nonspecific respiratory disorder.

Cough

Chronic cough can affect 10% to 50% of patients [19], [20], [40], [44]. This is a dry cough, which can precede by several years the diagnosis of SS. Usually attributed to dryness of the bronchial mucosa, its mechanisms are poorly understood. A diagnostic approach in search of an alternative cause must be systematic, in particular oriented towards the search for gastroesophageal reflux, which is particularly frequent in SS (65% of patients in a recent series [60]). The treatment of cough in SS has not been codified. Some physicians prescribe aerosols with normal saline, inhaled corticosteroids (despite the absence of effect on bronchial hyperresponsiveness), or pilocarpine (as for the other symptoms of dryness). Pilocarpine has been shown to be effective for reducing mouth, eye, and vaginal dryness, and to improve expectoration [61] but its effectiveness in coughing has never been formally evaluated. Even though pilocarpine is a cholinergic agonist, it does not seem to pose problems with tolerance in asthmatic subjects. Another cholinergic agonist, cevimeline, is apparently also effective for dryness but is not available in Europe [62].

Recurrent respiratory tract infections

Recurrent respiratory tract infections are a frequent complication of SS; 10% to 35% of patients with SS present repeated episodes of bronchitis or pulmonary infections [24], [44], [54]. This is specific to the respiratory tract, as SS is not associated with a higher frequency of infections outside the ENT sphere. These infections are usually attributed to tracheobronchial dryness but no specific studies have been performed and abnormalities of local immunity are probably involved. As with a cough, a diagnostic approach in search of a specific cause other than SS must be systematic,focusing particularly on gastroesophageal reflux, dental infection (periodontal disease contributed to by mouth dryness) or ENT infections.

Bronchiectasis

Bronchiectasis is frequently detected on CT scans in SS (table II). The frequency of symptomatic bronchiectasis is not well known and seems to be less than in rheumatoid arthritis. In an English series of 150 patients with bronchiectasis [63], there were no cases of SS whereas there were three cases of rheumatoid arthritis. In our opinion, screening for SS should be performed in the etiological workup for diffuse bronchiectasis.

Bronchiolar involvement

Bronchiolar involvement can reveal SS. There are three cases in the literature of diffuse bronchiolitis occurring in patients with primary SS. The association with a thymoma was unusual in these patients [64]. We recently described the radioclinical picture of 6 patients with predominantly bronchiolar disease, revealing SS in 5 of the 6 cases, characterized by recurrent ENT and respiratory infections, sometimes severe obstructive ventilatory disorder, hypoxaemia and profuse bronchiolar nodules on the CT scan accompanied by bronchiectasis and bronchial wall thickening [65]. Three of these 6 patients were treated with macrolides for periods of between 6 months and 2 years, with complete regression of the disease in one case (fig. 1) and stabilization in another. Hayakawa et al. described a similar clinical pattern in 15 patients with rheumatoid arthritis and bronchiolar lesions (variously associated with follicular bronchiolitis or constrictive bronchiolitis) [66]. All patients presenting with chronic bronchiolar disease should be systematically investigated for SS. The treatment of bronchiolitis in SS is not well established. In some cases, corticosteroids and immunosuppressants have been prescribed [30], [31] with success.

  • Clinically significant obstructive ventilatory disorders are relatively rare in SS.
  • Bronchial hyperresponsiveness is found; it is not correlated with the severity or the duration of SS, or with the severity of lymphocyte infiltration of the salivary glands.
  • Dryness of the bronchial mucosa has not been demonstrated in SS.
  • Thoracic CT scans confirm the high frequency of bronchial abnormalities in SS.
  • Clinical involvement is rare in SS, but the following manifestations can be found: cough, recurrent respiratory infections, bronchiectasis, and bronchiolar involvement.
  • All patients presenting with chronic bronchiolar disease should be systematically investigated for SS.

Diffuse infiltrative lung disease
Histopathological data

Infiltrative lung disease is particularly frequent in SS. Little histopathological data is available, one of the reasons being that surgical lung biopsies are not routinely performed in most centres caring for patients with SS. Deheinzelin et al. reported a large variety of lesions in the lung biopsies of patients with SS who presented with diffuse infiltrating lung disease: follicular bronchiolitis, lymphocytic interstitial pneumonia, pulmonary fibrosis with honeycomb cysts [30]. The presence of epithelioid and giant cell granulomas was also reported in nearly 10% of patients [30]. More recent series using modern classifications of idiopathic interstitial pneumonias [67], [68] have been published. These are surgical series, thus subject to bias concerning the indication, and included a limited number of patients. The information available is thus not robust and requires confirmation. The largest series studied 33 Japanese and Korean patients with primary SS and infiltrative lung disease [31]. Analysis of the pulmonary specimens (lung biopsy for 31 patients, autopsy in 2 cases) revealed different types of pathological lesions: nonspecific interstitial pneumonia (20 cases, 61%), mainly the fibrotic form (19 cases) and more rarely the cellular form (1 case), bronchiolitis (4 cases), primary pulmonary lymphoma (4 cases, of which 3 also presented amyloidosis), amyloidosis (2 cases), fibrosis without specific features (3 cases). In another Japanese series of 9 patients, 6 presented usual interstitial pneumonia, and 3 mixed (cellular and fibrotic) nonspecific interstitial pneumonia [69]. None of the Far Eastern series found lymphocytic interstitial pneumonia, a surprising result that raises the issue of their representativeness as Sjögren’s syndrome is the autoimmune disorder the most frequently associated with LIP [70] [71] [72]. A recent American study [73] described the presence of LIP in 3 of the 18 patients.

The other types of pathological patterns described in idiopathic interstitial pneumonia are observed in SS: organizing pneumonia [39], diffuse alveolar damage [74], [75], and desquamative interstitial pneumonia [76], [77].

With the data currently available we cannot establish the prognostic value of the underlying pathology, in particular nonspecific interstitial pneumonia and usual interstitial pneumonia.

CT scan data (table III)

Systematic CT scans reveal the high frequency of parenchymal lung abnormalities in patients with SS. The prognostic value of the abnormalities has not been established. The presence of cystic lesions had not been recognized in older series. They now appear to be particularly frequent. As with the previously described bronchial abnormalities, the prevalence of lung abnormalities is higher when the population studied presents respiratory symptoms.

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) is abnormal in 50% of patients with SS, often in the absence of clinical, radiological or lung function test abnormalities [78]. An increase in BAL lymphocytosis is observed in 50% of patients [79]; it is associated with more symptomatic involvement [80]. This lymphocytosis is mainly composed of T lymphocytes (70-90%), B lymphocytes (2-4%) and natural killer cells (10%) [78] with an increase in some cytokines (IL2, gamma- interferon, IL2-receptor) and immunoglobulins. The CD4/CD8 ratio is variable, close to 2 [78]. An isolated increase in polymorphonuclear neutrophils is also possible. The importance of this increase in lymphocytes is not clear; it could indicate lymphocyte infiltration of the bronchi or lymphocytic alveolitis. In a 2-year longitudinal study, Salaffi observed regression of lymphocytosis in BAL in 6 out of 18 patients [78], which had already been observed by Wallaert et al. [81]. In the long term, the presence of alveolar lymphocytosis indicates poor prognosis, with a higher mortality rate [82].

Radioclinical presentation

As in other connective tissue diseases, various radioclinical presentations are possible, and can be classified according to the chronology of involvement.

Acute or subacute infiltrating pneumonia, developing over several days or a few weeks may be due to organizing pneumonia [74] (fig. 2), acute NSIP, eosinophilic pneumonia [83] or sometimes an exacerbation of a previously unrecognized diffuse infiltrative pneumonia (fig. 3) [75]. This may be the first presentation of Sjögren’s syndrome. In this setting, alveolar haemorrhage is very rare and requires the search for cryoglobulinaemia [84] or an associated connective tissue disease, mainly systemic lupus erythematosus.

Chronic interstitial lung disease, developing over several weeks or several months

This type of involvement can reveal SS. The radiographic appearance can suggest NSIP with ground glass opacities, mainly subpleural and posterior, with signs of fibrosis variable in extent (subpleural reticulations, sometimes honeycomb cysts). Disease progression is often very slow, over many years (fig. 4). It is often difficult to differentiate from LIP in the absence of a surgical lung biopsy. In some cases, imaging is suggestive of usual interstitial pneumonia with honeycomb cysts peripheral and subpleural in distribution.

Lymphocytic interstitial pneumonia (LIP)

With follicular bronchiolitis and BAL lymphocytosis, LIP is one of the pulmonary lymphoproliferative disorders associated with SS. LIP is a rare infiltrating pulmonary disorder. The definitive diagnosis requires a lung biopsy showing lymphoplasmocytic infiltration of the interstitial tissue and the alveolar septa, associated with lymphoid follicles and sometimes germinal centres [70]. Epithelioid and giant cell granulomas, and limited areas of organizing pneumonia, can be observed [70]. A coexistence with follicular bronchiolitis is possible; the final histopathological diagnosis will depend on the dominant component of the lesion. Histological diagnosis of LIP is sometimes difficult [70]. LIP must be differentiated from other lymphoid pulmonary infiltrations, mainly MALT (Mucosa Associated Lymphoid Tissue) lymphoma; this requires the use of immunohistochemical techniques (lymphocyte immunophenotyping) and molecular biology techniques (study of immunoglobulin gene rearrangements) to identify a clonal lymphocyte population. Other pulmonary disorders can be mistaken for LIP, in particular hypersensitivity pneumonitis or cellular NSIP. Sjögren’s syndrome must be sought systematically, as SS is the cause of LIP in 25 to 50% of cases [70] [71] [72].

The CT scan occasionally suggests the diagnosis when it shows centrilobular and subpleural nodules associated with ground glass opacities, and thickening of peribronchovascular tissues and the interlobular septa. Parenchymal cysts are present in more than one in two cases, and enlarged mediastinal lymph nodes variable in size are present in one case in two [71]. Limited areas of pulmonary consolidation are possible [71]. Few data are available concerning the evolution of LIP. In a study of 14 patients followed-up for 13 months, 9 patients improved, and one was stable, while 4 patients worsened and developed fibrotic lesions with honeycombing [85]. In another series, progression to respiratory failure was observed in 3 of the 15 patients studied (20%) despite treatment [72]. The issue of a possible evolution of LIP to lymphoma has not been entirely settled. Some observations in the literature could correspond to undiagnosed MALT lymphomas.

The treatment of LIP is not well established. Corticosteroids are usually administered, sometimes associated with immunosuppressants (methotrexate, cyclophosphamide, azathioprine, ciclosporin) [72]. New treatments targeting B lymphocytes (rituximab) require further evaluation.

Cystic lung disease (fig. 5)

The presence of pulmonary cysts was associated with LIP by Ichikawa et al. in 1994 [86] but cysts are also observed in SS without LIP. The cysts are single or multiple, variable in size (from 5 mm to over 10 cm), with a thin or indiscernible wall. Their distribution is random, but they are often situated within the parenchyma. They sometimes include calcifications. With time, their size can reduce, remain stable, or increase. In rare cases, the cysts can become giant and cause chronic terminal respiratory failure [87]. The mechanism causing cyst formation is poorly understood. They could possibly develop proximal to bronchiolar stenoses caused by follicular bronchiolitis [85]. The cysts are sometimes associated with lymphoid infiltration of the pulmonary parenchyma structures which present as multiple nodules [88], [89]. In this context, the presence of nodules should also prompt a search for pulmonary lymphoma [89]. There is no specific treatment for cystic lung disease associated with SS, but lung transplantation has been performed in some cases.

Pulmonary amyloidosis

Sjögren’s syndrome can be complicated by pulmonary amyloid deposits, composed of amyloid light chains or AA protein, the most often localized in the lung, with or without associated lymphoma [89], and exceptionally associated with systemic amyloidosis [90]. The most frequent radiographic appearance is multiple pulmonary nodules, often associated with cystic lesions such as those described in the previous paragraph.

Pulmonary lymphoma

B-cell lymphomas may affect 5% of patients with Sjögren’s syndrome during their life. In their great majority, these are marginal zone B-cell lymphomas (60%), and MALT lymphomas outside the lymph nodes (75%), low-grade malignancies but which can develop into high-grade malignancy lymphomas. In 60% of cases, they are located in the salivary glands. Their evolution is usually slow with a 90% survival rate at 5 years. Pulmonary localizations, primary or secondary, are observed in 20% of cases. Rare observations have demonstrated selection by successive mutations during development of a malignant B-cell clone among the polyclonal B-cell population infiltrating the salivary glands [17]. Lymphoma can exceptionally reveal SS. The radiographic appearance is not specific. In a series of 10 patients, there were unique or multiple alveolar opacities, predominantly basal, with peribronchovascular extension in 5 cases, and multiple nodules or masses in 4 cases; the ground glass appearance was constant but more or less extensive [91]. Bronchiectasis was observed in 2 cases [91]. Enlarged mediastinal or hilar lymph nodes were rare. Excavation is possible. Bilateral involvement is particularly frequent in MALT lymphomas associated with SS [91]. Molecular biology analysis of BAL fluid can suggest the diagnosis by showing the presence of B lymphocytes in excess, the presence of atypical lymphocytes, and the presence of a dominant B-cell clone. However, the presence of a dominant B-cell clone in the BAL can be observed in benign inflammatory pulmonary disorders and is not sufficient to affirm the diagnosis of lymphoma [92]. Histopathological confirmation is indispensable. The diagnosis is usually obtained with a surgical lung biopsy, more rarely transbronchial or CT scan-guided biopsy, and requires frozen samples to perform molecular biology studies in search of a clonal subpopulation. The diagnostic value of the detection of translocations associated with MALT lymphomas has not be established [93]. There is no standard treatment for pulmonary lymphomas in Sjögren’s syndrome. Surgery is curative in localized disease. The effectiveness of rituximab is variable [91], [94], [95]. Single-agent chemotherapy (e.g. chlorambucil) can be sufficient to control the disease. Combination chemotherapy is indicated in the more extensive forms or those presenting high-grade malignancy.

Pseudolymphoma is an old term that should no longer be used. It included authentic lymphomas whose clonal nature could not be demonstrated, and non-clonal lymphoproliferations such as LIP and follicular bronchiolitis.

  • Infiltrative lung disease is particularly frequent in SS.
  • Organizing pneumonia, diffuse alveolar damage, and desquamative interstitial pneumonia are also found.
  • BAL is abnormal in 50% of patients with SS, with increased alveolar lymphocytosis.
  • Clinically, infiltrating pneumonia presents as acute infiltrating pneumonia, subacute pneumonia, lymphocytic interstitial pneumonia, pulmonary cysts, and pulmonary amyloidosis.

When should lymphoma be suspected in the presence of pulmonary parenchyma involvement in SS?

In the context of SS, the diagnosis of pulmonary lymphoma should be considered when imaging studies show 1) alveolar opacities or persistent areas of consolidation, 2) the presence of nodules (single or multiple), 3) pleural effusion, or 4) enlarged mediastinal lymph nodes. BAL with immunophenotyping and study of gene rearrangements coding for immunoglobulins is indispensable.

Coexistence of sarcoidosis and Sjögren’s syndrome

The revised classification criteria for SS exclude patients with sarcoidosis [18]. However, cases of SS coexisting with sarcoidosis have been described and clinically well recognized [96]. A recent review regrouped 59 observations from the literature reporting the coexistence of these two diseases in the same patient [23]. The frequency of sarcoidosis during primary SS has been estimated at 1% [96] [23], which is far higher than the prevalence of sarcoidosis in the general population [97] and argues in favour of a pathophysiological connection between the two diseases, both characterized by considerable lymphocyte activation and a high prevalence of HLA-DR3. The diagnosis is made on the presence of antinuclear antibodies with anti-SSA or anti-SSB antibodies and non-granulomatous lymphocytic sialoadenitis in a patient with sarcoidosis [23]. The patients are the most often women (83%). Mean age is 50. Both diseases are diagnosed at the same time in 60% of cases. In 20% of cases, the diagnosis of SS precedes that of sarcoidosis by 4 years on average. In 20% of cases, the sarcoidosis is diagnosed on average 8 years before the SS [23].

The other occurrences of pulmonary involvement in Sjögren’s syndrome are more isolated:

  • Severe pulmonary hypertension (PAH) seems to be very rare [98], [99] but could be underestimated. In a recent series, PAH was detected on echocardiography in 8 patients out of 13 (62%) who presented interstitial pneumonia during SS [100]. This rare feature of the disease has been recently reviewed. Estimated survival rates were low (73% and 66% at 1 and 3 years, respectively). Compared with SS patients without PAH, patients with SS-associated PAH had Raynaud phenomenon, cutaneous vasculitis, and interstitial lung disease significantly more frequently. They also more frequently had antinuclear, anti-Ro/SSA, and anti-RNP autoantibodies, as well as positive rheumatoid factor and hypergammaglobulinemia. These data suggest that systemic vasculopathy, B-cell activation, and autoimmunity could play a role in the pathophysiology of SS-associated PAH. The best therapeutic regimen remains to be defined but should include standard PAH therapy and/or immunosuppressants.
  • pleural thickening, and pleural effusion with or without pericarditis, can also be observed [33];
  • despite the frequency of myositis, which could affect at varying degrees up to 50% of patients, and despite the frequency of neuropathies, respiratory muscle dysfunction seems to be very rare in primary SS [101], [102]. However, there have been several observations of acute respiratory failure secondary to muscle paralysis related to hypokalaemia caused by distal renal tubular acidosis, presenting the clinical picture of hypokalaemic periodic paralysis [103], [104].

As in other connective tissue diseases, the respiratory disorders may not be directly related to Sjögren’s syndrome but can complicate the treatments administered (drug-induced pneumopathy, opportunistic infection) or be secondary to another localization of the disease, e.g. left ventricular dysfunction.

Conclusions

Pulmonary involvement in SS is particularly frequent and its diagnosis places chest physicians in a great variety of contexts including diagnosis of a chronic cough, investigation of diffuse infiltrating pneumonia, and recurrent respiratory tract infections. The tools required to make the diagnosis are very simple: a high degree of clinical suspicion, a thorough search for eye and mouth dryness, testing for anti-SSA and anti-SSB autoantibodies, and performance of accessory salivary gland biopsies.

Establishing the diagnosis is critical for the patient as surveillance will be directed towards investigation of possible lymphoid neoplasm which is one of the major complications of SS.

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