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Interstitial lung diseaseassociated with Sjgren'ssyndrome: Clinicalmanifestations, evaluation,and diagnosis

Authors Carlos Roberto Ribeirode Carvalho, MD, PhDDaniel Deheinzelin, MD,PhDRonaldo A Kairalla, MD,PhD

Section Editor Talmadge E King, Jr, MD Deputy Editor

Helen Hollingsworth,MD

Last literature review version 19.1: January 2011 | This topic last updated:February 17, 2011 (More)

INTRODUCTION Sjgren's syndrome (SS) is a chronic inflammatorydisorder characterized by diminished lacrimal and salivary gland function andassociated with lymphocytic infiltration of exocrine glands, especially thelacrimal and salivary glands. In addition to causing dry eyes(keratoconjunctivitis sicca) and dry mouth (xerostomia), SS can affectextraglandular organ systems including the skin, lung, heart, kidney, neural,and hematopoietic systems.

Respiratory complications of SS include airway mucosal dryness (also known

as xerotrachea), a variety of interstitial lung diseases (ILDs), non-Hodgkinlymphomas, pleural thickening or effusion, and, rarely, thromboembolicdisease or pulmonary hypertension.

The clinical manifestations, evaluation, and diagnosis of interstitial lungdisease in SS will be reviewed here. The clinical manifestations, classification,criteria for diagnosis, and pathogenesis of Sjgren's syndrome are presentedseparately. (See "Clinical manifestations of Sjgren's syndrome: Exocrinegland disease" and "Clinical manifestations of Sjgren's syndrome:Extraglandular disease and prognosis" and "Classification and diagnosis of


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Sjgren's syndrome" and "Pathogenesis of Sjgren's syndrome" .)

NOMENCLATURE

American-European criteria The American-European criteria for thediagnosis of Sjgren's syndrome (SS) combine subjective symptoms of dry eyeand dry mouth with objective signs of keratoconjunctivitis sicca andxerostomia ( table 1 ). They were not developed for clinical practice and notevery patient who receives a diagnosis of SS fulfills the proposed criteria.Diseases that can mimic SS and should be considered in the differentialdiagnosis of SS are included in the table ( table 2 ). The diagnosis of SS isdiscussed separately. (See "Classification and diagnosis of Sjgren'ssyndrome", section on 'American-European Classification Criteria' .)

Primary Sjgren's syndrome Primary Sjgren's syndrome (pSS) isdiagnosed only when all other systemic rheumatic diseases are excluded; itpredominantly affects women between 50 and 70 years of age [ 1 ]. (See"Classification and diagnosis of Sjgren's syndrome", section on 'Primary SS' .)

Secondary Sjgren's syndrome Secondary Sjgren's syndrome (sSS)refers to SS that occurs in association with another connective tissue disease,most commonly rheumatoid arthritis, but also including systemic lupuserythematosus, systemic sclerosis, mixed connective tissue disease, andinflammatory myositis [ 1-3 ]. (See "Classification and diagnosis of Sjgren'ssyndrome", section on 'Secondary SS' .)

EPIDEMIOLOGY Interstitial lung disease (ILD) is the most commonpulmonary abnormality in pSS [ 4-11 ]. ILD appears more common amongpatients with pSS than in those with sSS, although it tends to be less severethan the ILD associated with sSS or other connective tissue diseases [ 6,7,12 ].The greater severity of ILD in sSS may be caused by the simultaneous effectsof lung involvement due to SS and the associated connective tissue disorder(eg, rheumatoid arthritis, systemic lupus erythematosus) [ 6 ]. SS-associatedILD is most common in patients who have both glandular and extraglandularmanifestations [ 10 ].

The proportion of patients with SS who develop ILD at some point isestimated to be 25 percent, although reports describe variable frequencies[5,7,13-15 ].

Among 840 patients with pSS identified by computerized chart review,ILD was noted in 104 (12 percent) [ 16 ]

A series of 343 patients found evidence of pulmonary involvement in 9percent based on reported symptoms, chest radiographs, and pulmonaryfunction tests [ 5 ]


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A separate series of 36 patients with pSS found ILD in 25 percent, basedon clinical, laboratory, plain chest radiograph, and functional criteria [ 7 ]

Less commonly, ILD can be the presenting manifestation of SS. Among acohort of patients with various diffuse ILDs, a surprisingly high prevalence of objective xerostomia (17 percent) was reported [ 17 ]. Definite SS wasdiagnosed in 5.4 percent of the cohort, suggesting that undiagnosed SS maybe a more common cause of ILD than previously noted [ 17 ].

CLINICAL FEATURES Lung disease associated with SS is more common inwomen and has a median age of onset of 60 years [ 18 ]. Onset of ILD istypically 5 to 10 years after the onset of SS, although lung disease mayoccasionally precede the diagnosis of SS. The symptoms and signs of SS-associated ILD depend on the type and severity of lung parenchymal andlower airway involvement [ 4-8,13-15,19 ]. In two retrospective studies(combined total of 51 patients), the most common type of pSS-associated ILDwas nonspecific interstitial pneumonia (NSIP) [ 20,21 ]. Additional types of ILDidentified in these series included lymphocytic interstitial pneumonia (LIP),organizing pneumonia, usual interstitial pneumonia (UIP), primary pulmonarylymphoma, and diffuse interstitial amyloidosis.

The pattern of presenting respiratory symptoms was assessed in a series of 20 patients with pSS-associated ILD; 18 presented with at least onepulmonary symptom, such as cough (usually nonproductive), chest pain, ordyspnea [ 20,22 ]. The severity of respiratory symptoms ranges from subclinicallung disease to mild cough or dyspnea to slowly progressive respiratoryinsufficiency, although mild dyspnea on exertion is most common [ 12,20,23 ].

Patients with lymphocytic interstitial pneumonia associated with SS are rarelyasymptomatic; cough (71 percent) and dyspnea (61 percent) are the mostcommon symptoms, but weight loss, fevers, and pleuritic chest pain can alsobe present. (See "Lymphocytic interstitial pneumonia in adults", section on'Symptoms' .)

An isolated nonproductive cough without associated dyspnea may reflectxerotrachea, a condition of excessive dryness of the airway due to Sjgreninvolvement of the airway epithelial glands. (See 'Xerotrachea' below.)

Occasionally, patients will report Raynaud phenomenon, arthralgias, fever, orrash. The extrapulmonary symptoms of SS are described separately. (See"Clinical manifestations of Sjgren's syndrome: Extraglandular disease andprognosis" and "Clinical manifestations of Sjgren's syndrome: Exocrine glanddisease", section on 'Exocrine gland involvement' .)

Bibasilar crackles are noted on physical examination in approximately 60percent and a normal chest examination in 28 percent [ 16,21,24 ]. Cutaneousvasculitis occurs in approximately 10 percent of patients with SS and can


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present with urticarial lesions, purpura, or punctate erosions. Theextrapulmonary signs of SS and other ILDs are discussed separately. (See"Clinical manifestations of Sjgren's syndrome: Exocrine gland disease",section on 'Exocrine gland involvement' and "Clinical manifestations of Sjgren's syndrome: Extraglandular disease and prognosis", section on'Extraglandular organ involvement' and "Approach to the adult with interstitiallung disease: Clinical evaluation", section on 'Extrapulmonary findings of systemic disease' .)

DIFFERENTIAL DIAGNOSIS The differential diagnosis of dyspnea andcough in SS includes xerotrachea, pulmonary vascular disease, other ILDs thatmay present with sicca symptoms or salivary gland involvement (eg,sarcoidosis, IgG4-related systemic disease), and ILDs related to theunderlying connective tissue disease in patients with sSS (eg, rheumatoidarthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma),inflammatory muscle disease). The characteristics of ILD associated with theseconnective tissue diseases and the differential diagnosis of ILD in general arereviewed separately. (See "Interstitial lung disease in rheumatoidarthritis" and "Pulmonary manifestations of systemic lupus erythematosus inadults" and "Pulmonary manifestations of systemic lupus erythematosus inadults", section on 'Interstitial lung disease' and "Clinical manifestations of systemic sclerosis (scleroderma) lung disease", section on 'Interstitial lungdisease' and "Interstitial lung disease in dermatomyositis and polymyositis:Clinical manifestations and diagnosis" and "Approach to the adult withinterstitial lung disease: Diagnostic testing", section on 'Differential diagnosis' .)

Xerotrachea Among patients with SS, involvement of the tracheobronchialepithelial glands can lead to excessive dryness of the airway, which usuallypresents with a nonproductive cough. Pulmonary function tests andradiographic imaging are normal. Examination by flexible bronchoscopy revealsa dry, erythematous mucosa [ 25 ].

Pulmonary vascular disease Pulmonary vascular disease (eg,thromboembolic disease, pulmonary arterial hypertension) should beconsidered in the differential of SS complicated by dyspnea.

An increased risk of thromboembolic disease has been described in patients

with SS [ 26 ]. Thromboembolism should be suspected in patients with an acuteonset of dyspnea, particularly when the chest radiograph does not suggestILD. The evaluation and diagnosis of suspected pulmonary embolism isdiscussed separately. (See "Diagnosis of acute pulmonary embolism" .)

Pulmonary arterial hypertension (PAH) should be considered in a patient withmore gradual onset of dyspnea when the degree of dyspnea is notwell-explained by the extent of ILD on high resolution computed tomography(HRCT). PAH has rarely been described in the setting of Sjgren-associated


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ILD, typically in patients with Raynaud phenomenon and cutaneous vasculitis[27 ]. In this review of 28 patients, antinuclear, anti-Ro/SSA, andanti-ribonucleoprotein (RNP) autoantibodies, as well as positive rheumatoidfactor and hypergammaglobulinemia, were often present. The evaluation anddiagnosis of PAH is discussed separately. (See "Treatment of pulmonaryhypertension" .)

Sjgren's syndrome and sarcoidosis Sarcoidosis can present with lacrimaland salivary gland involvement, as well as diffuse parenchymal lung disease.In addition, sarcoidosis can occur concomitantly with SS. In one patient withSS, for example, lung biopsy revealed a chronic noncaseating granulomatousinflammatory reaction with moderate lymphocytic infiltration of the surroundingalveoli, a finding that led to the concurrent diagnosis of sarcoidosis [ 28 ]. Aliterature review of histopathologic changes in the exocrine glands of 53patients with sarcoidosis noted coexistence of sarcoidosis and SS in 28 cases;in the remaining 25 patients, sarcoidosis mimicked SS [ 29 ]. (See "Clinicalmanifestations and diagnosis of sarcoidosis", section on 'Diagnosis' .)

Potential explanations for the simultaneous occurrence of both disordersinclude the following:

The two diseases share a common immunologic abnormalityThe derangement caused by one disorder may result in the otherThe finding is coincidental

Possible support for the first hypothesis comes from a study of lung biopsyspecimens from 10 patients with SS [ 30 ]. There were significant elevations in

CD4 positive lymphocytes in the bronchial mucosa, an abnormality that is alsodescribed in sarcoidosis. In general, sarcoidosis and SS are differentiated bythe preponderance of noncaseating granulomata found on biopsy specimensfrom patients with sarcoidosis. (See "Pathogenesis of sarcoidosis" and"Clinical manifestations and diagnosis of sarcoidosis", section on'Histopathology' .)

IgG4-related systemic disease IgG4-related systemic disease, also knownas IgG4-related sclerosing disease or hyper-IgG4 disease, is felt to be distinctfrom SS. Patients with IgG4-related systemic disease experience relatively

mild xerophthalmia and xerostomia, although marked lacrimal and salivarygland enlargement may occur. Lung involvement in IgG4-related systemicdisease is estimated to occur in 10 percent and pleural involvement in 5percent [ 31 ]. A variety of chest computed tomography (CT) presentationshave been described, including patchy ground glass, nodular andconsolidative opacities, and also honeycombing [ 32 ].

IgG4-related systemic disease is characterized by increased serum levels of IgG4, IgG4-positive plasmacytic infiltration and sclerosis of a wide variety of exocrine glands, most commonly the pancreas. The diagnosis of IgG4-related


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systemic disease is based on the clinical features, a serum concentration of IgG4 2 times the upper limit of normal (140 mg/dL) and the presence of IgG4positive cells on histopathology. (See "Autoimmune pancreatitis", section on'Diagnosis' .)

Other causes of diffuse parenchymal lung disease Other causes of diffuselung disease that are not associated with SS, but are generally in the

differential of ILD include hypersensitivity pneumonia, eosinophilic pneumonia,infection, lymphangitic tumor, and hemorrhage. The evaluation of theseentities is discussed in the appropriate topic reviews. (See "Approach to theadult with interstitial lung disease: Clinical evaluation" .)

EVALUATION AND DIAGNOSIS The diagnostic approach to suspected ILDin patients with SS follows the general approach to interstitial lung disease.Because of the high frequency of lung involvement in SS and the potential forsarcoidosis to mimic SS, we typically obtain a chest radiograph as part of theinitial evaluation of a patient with SS. If ILD is suspected on the basis of

cough, dyspnea, audible crackles, or an abnormal chest radiograph, we obtaincomplete pulmonary function tests and a high resolution computedtomography scan. Further evaluation is based on the results of these tests.(See "Approach to the adult with interstitial lung disease: Clinicalevaluation" and "Approach to the adult with interstitial lung disease:Diagnostic testing" .)

Laboratory When ILD is suspected in a patient with SS, we usually confirmthe original diagnosis of SS by reviewing or obtaining serologic studies suchas the antinuclear antibody, anti-Ro/SSA and anti-La/SSB antibodies,

rheumatoid factor, and serum protein electrophoresis. The laboratoryevaluation and diagnosis of SS are discussed separately. (See "Classificationand diagnosis of Sjgren's syndrome", section on 'Diagnostic tests' and"Clinical significance of anti-Ro/SSA and anti-La/SSB antibodies", section on'Clinical significance in Sjgren's syndrome' and "Clinical manifestations of Sjgren's syndrome: Extraglandular disease and prognosis", section on'Serologic findings' .)

No serologic marker has been identified that predicts the development of ILDin patients with pSS or sSS, and most studies conclude that patients with

interstitial involvement have a similar immunologic profile compared to thosewithout lung disease [ 33,34 ]. In a series of 14 patients with pSS-associatedILD who underwent lung biopsy, antinuclear antibodies (ANA) were noted insix, anti-Ro/SS-A antibody in eight, and anti-La/SS-B antibody in two [ 16 ].Similar findings were noted in a series of 13 patients with ILD and SS(diagnosed by a positive minor salivary gland biopsy): ANA and anti-Ro/SS-Aantibodies were positive in eight; rheumatoid factor (RF) in three; andanti-La/SS-B antibody in two [ 35 ].


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Limited data are available to assess whether specific antibodies correlate withdisease severity. A series of 30 patients noted that anti-Ro/SS-A antibodypositivity correlated with a significantly lower diffusing capacity thananti-Ro/SS-A antibody negativity [ 24 ].

If IgG4-related systemic disease is suspected due to marked lacrimal andsalivary gland enlargement, immunoglobulin subclass levels are obtained

looking for an elevated level of IgG4. (See 'IgG4-related systemicdisease' above and "Autoimmune pancreatitis", section on 'Serologic testingfor IgG4' .)

Chest imaging A chest radiograph is usually obtained as part of the initialevaluation of patients with SS due to the frequency of lung involvement andas sarcoidosis is included in the differential diagnosis. The chest radiograph isrepeated if respiratory symptoms develop or change.

Chest radiograph The chest radiograph in patients with SS-associatedILD typically shows a fine reticular or nodular pattern with basilar prominence,but may be normal. Retrospective series of patients with either pSS or sSShave noted abnormalities on chest radiograph in 10 to 20 percent [ 5,36 ].Based on small case series, the rate of radiographic abnormalities may behigher in patients with pSS than sSS [ 22 ]. The most common findings arereticular or ground glass opacities, although cysts and pleural abnormalitieshave been described [ 5,37 ].

High resolution computed tomography High resolution computedtomography (HRCT) is obtained in patients with SS if respiratory symptoms

develop or if the chest radiograph or pulmonary function tests are abnormal.High resolution computed tomography (HRCT) is more sensitive than the chestradiograph for interstitial lung disease [ 23,38,39 ]. In a series of 37 patientswith SS and normal chest radiographs, 25 (64 percent) had abnormalities onHRCT [ 24 ]. A separate study found abnormalities suggestive of interstitial lungdisease on CT in 34 percent of patients with pSS, while the chest radiographwas abnormal in only 14 percent [ 39 ]. (See "High resolution computedtomography of the lungs" .)

A variety of HRCT patterns have been reported in ILD associated with SS

[16,39-41 ]. As an example, in a series of 60 patients with pSS-associated ILD,HRCT abnormalities included ground-glass attenuation (92 percent),subpleural small nodules (78 percent), non-septal linear opacities (75percent), interlobular septal thickening (55 percent), bronchiectasis (38percent), and cysts (30 percent) [ 40 ]. Bronchial wall thickening and pleuralirregularities are less frequently noted [ 23 ]. The frequency of each patterndepends on the characteristics of the population studied. As an example,among four studies of symptomatic patients with ILD, the frequency of nonspecific interstitial pneumonia patterns ranged from 20 to 60 percent


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[20,39,42,43 ]. In two studies of asymptomatic patients, eight percent hadHRCT findings consistent with pulmonary fibrosis (honeycombing) [ 23,39 ]. In aseparate series, honeycombing was almost four times more common in sSS ascompared with pSS, likely due to the presence of usual interstitial pneumoniain patients with rheumatoid arthritis.

HRCT findings in lymphocytic interstitial pneumonia (LIP) include thin-walled

cysts, ground-glass attenuation, centrilobular and subpleural nodules, septalthickening, reticular opacities, and bronchial/bronchiolar thickening ( figure 1 )[23,42,44 ]. Cyst formation is more common in patients with lymphocyticinterstitial pneumonia and those with anti-SSB/La antibodies [ 18 ].Bronchial/bronchiolar thickening may be due to associated follicularbronchiolitis. (See "Lymphocytic interstitial pneumonia in adults", section on'Chest imaging' and 'Follicular bronchiolitis' below.)

Pulmonary nodular lymphoid hyperplasia typically presents with a solitarymass or nodule, but can present with multiple nodules or as an area of

parenchymal consolidation with an air bronchogram [ 19,45 ].In the rare patients with SS-associated amyloidosis, HRCT findings includediffuse nodules, focal consolidation, and diffuse septal thickening [ 46 ].

Pulmonary function tests Pulmonary function tests (PFTs) are obtained toevaluate respiratory symptoms, crackles on chest examination, or anabnormal chest radiograph. The main role of PFTs is to confirm the presence of abnormalities consistent with ILD and to assess the severity of respiratoryimpairment.

Patients with SS and diffuse parenchymal opacities on chest radiographstypically have a restrictive pattern on PFTs with a low diffusing capacity[6,10,14,20,47-49 ]. In one study of 20 patients with pSS, significantreductions in FEV1, vital capacity, and diffusing capacity (transfer factor forcarbon monoxide or DLCO) were noted in 14, 12, and 10 patients, respectively[12 ]. The combination of a restrictive defect and a low DLCO appears to bemore common in pSS than in sSS [ 6,10 ].

An isolated obstructive pattern is unusual in pSS; this pattern is more commonin sSS or with rheumatoid arthritis alone [ 6,10 ]. (See "Overview of lungdisease associated with rheumatoid arthritis" and "Interstitial lung disease inrheumatoid arthritis" .)

Evidence of small airway airflow obstruction is common in nonsmoking patientswith pSS [ 23,44 ]. This pattern is frequently associated with asymptomaticdisease [ 23 ].

Minor salivary gland biopsy Occasionally, ILD is the presentingmanifestation of pSS and the presence of sicca symptoms is elicited during theevaluation of ILD [ 35 ]. In these patients, a minor salivary gland biopsy may


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lead to a more precise diagnosis of the underlying connective tissue disease.(See "Classification and diagnosis of Sjgren's syndrome", section on 'Salivarygland biopsy' .)

Bronchoalveolar lavage Bronchoalveolar lavage (BAL) cell count patterns inSS are nonspecific, so the main role of BAL in a patient who is suspected of having SS-associated ILD is to exclude other causes of diffuse parenchymal

lung disease, such as eosinophilic pneumonia, infection, lymphangitic tumor,and hemorrhage. Thus, BAL is usually performed in patients with SS and ILDwhen respiratory symptoms have an acute onset or are accompanied by afever, hemoptysis, or peripheral eosinophilia. BAL results would not besufficient to differentiate sarcoidosis from SS-associated ILD. The technique of BAL and the role of BAL in the diagnosis of interstitial lung disease arediscussed separately. (See "Basic principles and technique of bronchoalveolarlavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lungdisease" .)

Increased numbers of BAL lymphocytes or neutrophils are common amongpatients with pSS. However, the data are conflicting about whether thedegree of lymphocytosis or neutrophilia predicts the presence or severity of ILD. Among 13 patients with symptomatic pSS-associated ILD, BAL revealedeither lymphocytosis or an increased number of polymorphonuclear cells [ 22 ].

In a study of 23 patients with pSS, those patients whose BAL containedgreater than 15 percent lymphocytes, were more likely to have pulmonarysymptoms (cough and dyspnea), radiographic evidence of interstitial lungdisease, and decreased pulmonary function than those whose BAL had less

than 15 percent lymphocytes [ 33 ].On the other hand, elevated numbers of lymphocytes or neutrophils can beseen in the BAL of patients without clinical or radiographic evidence of pulmonary disease [ 28 ]. Among 29 patients with pSS who did not havepulmonary symptoms or chest radiograph abnormalities, elevated BALlymphocytes or neutrophils were noted in 55 percent [ 28 ]. It is unknownwhether patients with subclinical disease based on BAL results will developsymptomatic pulmonary disease.

The prognostic value of BAL cell counts in SS-associated ILD is also unclear.Among 18 patients with pSS and an initial lymphocytic or mixedlymphocytic/neutrophilic BAL, chest radiographs and pulmonary function werevirtually unchanged over two years [ 43 ]. Of 14 patients with an initiallymphocytic BAL (>15 percent lymphocytes), the BAL differential normalized insix. BAL neutrophilia was associated with a greater rate of reduction in thediffusing capacity of carbon monoxide (DLCO), than BAL lymphocytosis. Incontrast, a longer study (12 years) found that only those patients withgreater than 15 percent lymphocytosis in their BAL died [ 50 ].


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Lung biopsy Lung biopsy is not always necessary when evaluating patientswith SS and radiographic and/or physiologic evidence of ILD. The usualindications for lung biopsy are a suspicion of malignancy or a combination of increasing respiratory symptoms, deteriorating pulmonary function studies,atypical HRCT pattern, and worsening radiographic abnormalities.Circumscribed or nodular areas of consolidation that are persistent and notattributable to infection generally require histopathologic evaluation. (See"Role of lung biopsy in the diagnosis of interstitial lung disease", section on'Indications' .)

Depending on the location of the abnormality and local expertise,transbronchial, video-assisted thoracoscopic, or open lung biopsy may beperformed. Transbronchial lung biopsy is helpful in the positive diagnosis of sarcoidosis or lymphangitic carcinomatosis, whereas a larger biopsy fromvideo-assisted thoracoscopic or open thoracotomy is needed to differentiatethe various types of ILD. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Types of lung biopsy' .)

Histopathology A wide spectrum of histopathologic findings have beenreported in patients with SS, most commonly those that mirror the main typesof idiopathic interstitial pneumonia (eg, nonspecific interstitial pneumonia,lymphocytic interstitial pneumonia, end-stage fibrosis with honeycombing,organizing pneumonia) [ 16,20-22,35,51 ]. Lymphocytic infiltration is acharacteristic of SS manifestations throughout the body and several patternsof lymphocytic lung involvement have been described: lymphocytic interstitialpneumonia, follicular bronchiolitis, nodular lymphoid hyperplasia, andlymphoma. It is not clear whether there is an evolution from one lymphocyticpattern to another. (See "Idiopathic interstitial pneumonias: Clinicalmanifestations and pathology" .)

Nonspecific interstitial pneumonia Nonspecific interstitial pneumonia(NSIP) is the most common form of lung inflammation found in patients with SS[20,21 ]. The NSIP pattern is also recognized as the most common pattern inseveral other connective tissue diseases, including systemic sclerosis,polymyositis/dermatomyositis, rheumatoid arthritis and systemic lupuserythematosus. (See "Nonspecific interstitial pneumonia" .)

Within the category of NSIP, three subsets have been described: a cellularpattern with a greater degree of interstitial inflammation, a more fibroticpattern, and a mixed pattern ( table 3 and figure 2 and figure 3 ). Thesignificance of these subsets is not entirely clear, although the more fibroticpattern appears to have a worse prognosis. In a series of 20 patients withNSIP associated with primary SS, the fibrotic pattern of NSIP was noted in 19and the cellular pattern in one [ 20 ]. (See "Nonspecific interstitial pneumonia",section on 'Pathology' .)


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Lymphocytic interstitial pneumonia Lymphocytic interstitial pneumonia(LIP) is characterized by an extensive proliferation of lymphoid cells (T and B)and varying numbers of plasma cells along the alveolar septae, oftenassociated with follicular bronchiolitis ( table 4 and picture 1 and figure 4 ).Germinal centers and multinucleated giant cells with occasional noncaseatinggranulomas are also described ( picture 2 and picture 3 and picture 4 ). Withadvanced disease, fibrotic changes with cyst formation or honeycombing areseen. (See "Lymphocytic interstitial pneumonia in adults", section on'Pathologic findings' and 'Follicular bronchiolitis' below.)

Usual interstitial pneumonia The histologic hallmark and chief diagnostic criterion of usual interstitial pneumonia (UIP) is a heterogeneousappearance with alternating areas of normal lung, interstitial inflammation,fibroblast foci, and honeycomb change. The histopathologic pattern of UIP ismore commonly seen in patients with sSS associated with rheumatoid arthritisor systemic sclerosis, than in pSS. Among 42 patients with pSS and interstitiallung disease, none had UIP on biopsy, although UIP had been suspectedbased on high resolution computed tomography (HRCT) in four [ 20 ]. (See"Idiopathic interstitial pneumonias: Clinical manifestations and pathology",section on 'Pathology' .)

Organizing pneumonia The characteristic histopathologic lesions of organizing pneumonia include excessive proliferation of granulation tissuewithin small airways (proliferative bronchiolitis) and alveolar ducts, associatedwith chronic inflammation in the surrounding alveoli. Foci of organizingpneumonia can be seen in association with NSIP. Organizing pneumonia is anuncommon complication of pSS [ 21,52,53 ]. (See 'Nonspecific interstitialpneumonia' above and "Cryptogenic organizing pneumonia", section on'Pathological changes' .)

Follicular bronchiolitis Follicular bronchiolitis is characterized bylymphoid hyperplasia of mucosa-associated lymphoid tissue (MALT), alsoknown as bronchus-associated lymphoid tissue (BALT) when it refers toperibronchial tissue. Hyperplastic lymphoid follicles with reactive germinalcenters are distributed along the bronchioles and can cause compression of the airway lumen ( picture 3 ). The lymphoid proliferation is generally limited tothe peribronchiolar area, but may extend into the surrounding alveolar septa[30,44 ]. In SS, follicular bronchiolitis is seen alone and in association with NSIPor LIP [ 16 ]. (See "Bronchiolitis in adults", section on 'Follicular bronchiolitis' .)

Nodular lymphoid hyperplasia (pseudolymphoma) Nodular lymphoidhyperplasia (also known as follicular lymphoid hyperplasia or the nowoutdated term pseudolymphoma) is characterized by mixed infiltrates of mature lymphocytes and plasma cells with numerous germinal centers ( picture5A-C ). Nodular lymphoid hyperplasia has been described in the lung, salivaryglands, skin, and kidney of patients with SS and is more common in patients


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with pSS than other connective tissue diseases [ 30,45,54-56 ]. It may regress,remain stable, or progress to frank lymphoma [ 30 ].

Nodular lymphoid hyperplasia has certain key features that are used todifferentiate it from marginal zone B-cell lymphoma of mucosa-associatedlymphoid tissue (MALT), including a well-circumscribed lesion, minimallymphangitic spread, presence of polyclonal lymphocytes, absence of

intranuclear inclusions, and absence of immunoglobulin heavy chainrearrangements [ 30 ]. (See "Clinical manifestations, pathologic features, anddiagnosis of extranodal (MALT) and nodal marginal zone lymphomas" .)

Lymphoma The lung malignancies most frequently associated with SSare the non-Hodgkin lymphomas, and among these, the most common ispulmonary marginal zone lymphoma (MZL, also known as mucosa-associatedlymphoid tissue [MALT] lymphoma or bronchial-associated lymphoid tissue[BALT] lymphoma) [ 20 ]. Involvement of the lung by lymphoma occurs inapproximately 20 percent of patients with SS-associated lymphoma [ 57 ]. A

spectrum of low- to high-grade lymphomas is reported [ 57 ]. (See "Clinicalpresentation and diagnosis of non-Hodgkin lymphoma" and "Clinicalmanifestations, pathologic features, and diagnosis of extranodal (MALT) andnodal marginal zone lymphomas", section on 'Extranodal (MALT) MZL' .)

Pulmonary nodular amyloidosis Pulmonary nodular amyloidosis isoccasionally described in association with SS (usually pSS) [ 20,46,58,59 ].Nodules containing lymphocytes, plasma cells and amyloid deposits (identifiedby Congo red staining showing green birefringence under polarized light) arereported, sometimes adjacent to or in the wall of lung cysts [ 58 ]. In a case

report and review, deposition of AL (lambda or kappa light chain) or AAamyloid occurred in the absence of systemic amyloidosis [ 46 ]. Most cases of amyloid associated with SS are related to the nodular pattern of amyloidosis[46 ]. Association with lymphoproliferative disease, such as mucosa-associatedlymphoid tissue (MALT) lymphoma, has also been described [ 58,60 ]. (See "Anoverview of amyloidosis", section on 'Pulmonary disease' and "Diagnosis of primary (AL) amyloidosis", section on 'Tissue biopsy' .)

SUMMARY AND RECOMMENDATIONS

Sjgren's syndrome (SS) is characterized by a particular form of dry eyes(keratoconjunctivitis sicca) and dry mouth (xerostomia). SS can exist as aprimary disorder or as a condition in association with anotherwell-defined autoimmune process such as rheumatoid arthritis, systemiclupus erythematosus (SLE), scleroderma, or inflammatory myositis. (See'Introduction' above and 'Nomenclature' above.)

The proportion of patients with SS who develop ILD at some point isestimated to be 25 percent. Interstitial lung disease (ILD) is more


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common among patients with primary SS than in those with secondarySS, although it tends to be more severe in secondary SS. (See'Epidemiology' above and "Classification and diagnosis of Sjgren'ssyndrome" .)

The differential diagnosis of dyspnea and cough in SS includesxerotrachea, pulmonary vascular disease, other ILDs that may present

with sicca symptoms or salivary gland involvement (eg, sarcoidosis,IgG4-related systemic disease), and ILDs related to the underlyingconnective tissue disease in patients with sSS (eg, rheumatoid arthritis,systemic lupus erythematosus, systemic sclerosis (scleroderma),inflammatory muscle disease). (See 'Differential diagnosis' above.)

We typically obtain a chest radiograph as part of the initial evaluation of a patient with SS. If ILD is suspected on the basis of cough, dyspnea,audible crackles, or an abnormal chest radiograph, we obtain pulmonaryfunction tests and a high resolution computed tomography scan. (See'Evaluation and diagnosis' above.)

If not already performed, we obtain laboratory tests to confirm thediagnosis of SS, including an antinuclear antibody, anti-Ro/SSA andanti-La/SSB antibodies, rheumatoid factor, and serum proteinelectrophoresis. (See 'Laboratory' above.)

For patients with sicca symptoms and evidence of ILD, but without a firmdiagnosis of SS, we typically obtain a minor salivary gland biopsy inaddition to the laboratory testing noted above. (See 'Minor salivary gland

biopsy' above.)

High resolution computed tomography (HRCT) findings include bronchialwall thickening, bronchiectasis, centrilobular nodules, irregularinterlobular thickening, ground-glass attenuation, subpleuralhoneycombing, thin-walled cysts, and branching linear hyperattenuatingareas. Ground glass attenuation is most common. (See 'Chestimaging' above.)

Bronchoalveolar lavage (BAL) most commonly shows a predominance of

lymphocytes in patients with SS-associated ILD, but may occasionallyshow a predominance of neutrophils. The main role of bronchoalveolarlavage (BAL) in a patient with SS and radiographic evidence of ILD is toexclude other causes of interstitial opacities, such as eosinophilicpneumonia, infection, lymphangitic tumor, and hemorrhage. (See'Bronchoalveolar lavage' above.)

Lung biopsy is generally not necessary when evaluating patients with SSand radiographic and/or physiologic evidence of ILD, when the clinical and


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physiologic impairments are mild and stable. The usual indications forlung biopsy are a suspicion of malignancy (especially if associated with anodular pattern or masses) or a combination of increasing respiratorysymptoms, deteriorating pulmonary function studies, and worseningradiographic abnormalities. (See 'Lung biopsy' above.)

Common histopathologic patterns include nonspecific interstitial

pneumonia (NSIP), usual interstitial pneumonia (UIP), organizingpneumonia, and lymphocytic interstitial pneumonia (LIP). Follicularbronchiolitis nodular lymphoid hyperplasia, lymphoma, and pulmonarynodular amyloidosis are seen less commonly. (See'Histopathology' above.)

The management of the ILDs associated with SS is discussed separately.(See "Interstitial lung disease associated with Sjgren's syndrome:Management and prognosis", section on 'Management' .)

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REFERENCES

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Sjgren's syndrome used by the contributors to the First InternationalSeminar on Sjgren's syndrome--1986. Scand J Rheumatol Suppl 1986;61:17.

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Freemer MM, King TE Jr. Connective tissue disease. In: Interstitial LungDisease, King TE Jr, Schwarz MI (Eds), BC Decker, Hamilton, Ontario2003. p.535.

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Vitali C, Tavoni A, Viegi G, et al. Lung involvement in Sjgren's syndrome:a comparison between patients with primary and with secondarysyndrome. Ann Rheum Dis 1985; 44:455.

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Constantopoulos SH, Drosos AA, Maddison PJ, Moutsopoulos HM.Xerotrachea and interstitial lung disease in primary Sjogren's syndrome.Respiration 1984; 46:310.

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Launay D, Hachulla E, Hatron PY, et al. Pulmonary arterial hypertension:a rare complication of primary Sjgren syndrome: report of 9 new casesand review of the literature. Medicine (Baltimore) 2007; 86:299.

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Hatron PY, Wallaert B, Gosset D, et al. Subclinical lung inflammation inprimary Sjgren's syndrome. Relationship between bronchoalveolarlavage cellular analysis findings and characteristics of the disease.Arthritis Rheum 1987; 30:1226.

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Ramos-Casals M, Brito-Zern P, Garca-Carrasco M, Font J. Sarcoidosis orSjgren syndrome? Clues to defining mimicry or coexistence in 59 cases.Medicine (Baltimore) 2004; 83:85.

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Travis WD, Galvin JR. Non-neoplastic pulmonary lymphoid lesions. Thorax2001; 56:964.

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Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114cases. Am J Surg Pathol 2010; 34:1812.

32. Kobayashi H, Shimokawaji T, Kanoh S, et al. IgG4-positive pulmonarydisease. J Thorac Imaging 2007; 22:360.33.

Dalavanga YA, Constantopoulos SH, Galanopoulou V, et al. Alveolitiscorrelates with clinical pulmonary involvement in primary Sjgren'ssyndrome. Chest 1991; 99:1394.

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Barranquero-Beltrn A, Meyer O, Haim T, et al. [Comparative profile of antinuclear antibodies in Gougerot-Sjgren syndrome with and withoutdiffuse interstitial pulmonary fibrosis]. Rev Rhum Mal Osteoartic 1986;53:615.

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Fischer A, Swigris JJ, du Bois RM, et al. Minor salivary gland biopsy todetect primary Sjogren syndrome in patients with interstitial lungdisease. Chest 2009; 136:1072.

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Matsuyama N, Ashizawa K, Okimoto T, et al. Pulmonary lesionsassociated with Sjgren's syndrome: radiographic and CT findings. Br JRadiol 2003; 76:880.

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38. Gardiner P, Ward C, Allison A, et al. Pleuropulmonary abnormalities inprimary Sjgren's syndrome. J Rheumatol 1993; 20:831.

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Franquet T, Gimnez A, Monill JM, et al. Primary Sjgren's syndrome andassociated lung disease: CT findings in 50 patients. AJR Am J Roentgenol1997; 169:655.

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Papiris SA, Maniati M, Constantopoulos SH, et al. Lung involvement inprimary Sjgren's syndrome is mainly related to the small airwaydisease. Ann Rheum Dis 1999; 58:61.

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Song MK, Seol YM, Park YE, et al. Pulmonary nodular lymphoidhyperplasia associated with Sjgren's syndrome. Korean J Intern Med2007; 22:192.

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Kelly C, Gardiner P, Pal B, Griffiths I. Lung function in primary Sjgren'ssyndrome: a cross sectional and longitudinal study. Thorax 1991;46:180.

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Brune, J, Emonot, A, Wiesendanger, T, et al. Syndrome de

Gougerot-Sjgren et fibrose parito-alvolare diffuse. A propos de cinqobservations. Rev Fr Mal Resp 1976; 4:560.

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Ziza JM, Kaplan G, Salomon C, Kahn MF. [Severe pulmonary fibrosisdisclosing primary Gougerot-Sjgren syndrome. Apropos of 5 cases, 2 of which were fatal]. Ann Med Interne (Paris) 1986; 137:46.

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Dalavanga YA, Voulgari PV, Georgiadis AN, et al. Lymphocytic alveolitis: Asurprising index of poor prognosis in patients with primary Sjogren'ssyndrome. Rheumatol Int 2006; 26:799.


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Lymphocytic interstitial pneumonia

Prone HRCT shows diffuse ground glass attenuation with multiple lungcysts.

Nonspecific interstitial pneumonia, cellular pattern


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The interstitium is infiltrated by a moderate chronic inflammatoryinfiltrate; fibrosis is absent. The infiltrate consists of lymphocytes andplasma cells.

Nonspecific interstitial pneumonia, fibrosing pattern

The alveolar walls show diffuse thickening by fibrosis and mild interstitial

inflammation. No fibroblastic foci are present. The alveolar walls arethickened by dense collagen and a few lymphocytes and plasma cells.


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Histopathology of LIP with lymphoid hyperplasia. A marked interstitial

infiltrate of mononuclear cells and a germinal center are shown.Courtesy of Talmadge E King, Jr, MD.


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Lymphocytic interstitial pneumonitis

Low power photomicrograph shows the cellular infiltrate tracking alongvessels and bronchovascular bundles.From Colby, TV, Koss, MN, Travis, WD. Tumors of the Lower Respiratory Tract. Armed Forces Institute of Pathology, Washington, DC.

Lymphocytic interstitial pneumonitis

Low power photomicrograph shows an interstitial infiltrate of lymphocytes, plasma cells, and histiocytes and the presence of germinalcenters.From Colby, TV, Koss, MN, Travis, WD. Tumors of the Lower


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Respiratory Tract. Armed Forces Institute of Pathology, Washington, DC.


Histopathology of LIP with lymphoid hyperplasia. A marked interstitialinfiltrate of mononuclear cells and a germinal center are shown.Courtesy of Talmadge E King, Jr, MD.


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Histopathology of LIP with diffuse nodular inflammation of the pulmonaryinterstitium.Courtesy of Talmadge E King, Jr, MD.


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Nodular lymphoid hyperplasia in Sjgren's syndrome

Low power photomicrograph shows extensive polyclonal lymphoidinfiltration of the lung.From: Colby TV, Koss MN, Travis WD. Tumors of the Lower Respiratory Tract. Armed Forces Institute of Pathology, Washington, DC.


High power photomicrograph shows heterogenous foci of lymphocytesand plasma cells.From: Colby TV, Koss MN, Travis WD. Tumors of the Lower Respiratory


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Tract. Armed Forces Institute of Pathology, Washington, DC.


High power photomicrograph shows a focus of small lymphocytes, whichproved polyclonal by immunostaining.From: Colby TV, Koss MN, Travis WD. Tumors of the Lower Respiratory Tract. Armed Forces Institute of Pathology, Washington, DC.

Revised international classification criteria for Sjgren'ssyndrome

I. Ocular symptoms: a positive response to at least one of the followingquestions:

1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?

2. Do you have a recurrent sensation of sand or gravel in the eyes?

3. Do you use tear substitutes more than 3 times a day?

II. Oral symptoms: a positive response to at least one of the following

questions:1. Have you had a daily feeling of dry mouth for more than 3 months?

2. Have you had recurrently or persistently swollen salivary glands as an adult?

3. Do you frequently drink liquids to aid in swallowing dry food?

III. Ocular signs-that is, objective evidence of ocular involvement definedas a positive result for at least one of the following two tests:


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1. Schirmer's test, performed without anaesthesia (5 mm in 5 minutes)

2. Rose bengal score or other ocular dye score (4 according to van Bijsterveld's

scoring system)

IV. Histopathology: In minor salivary glands (obtained throughnormal-appearing mucosa) focal lymphocytic sialoadenitis, evaluated by an

expert histopathologist, with a focus score 1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing mucous acini andcontain more than 50 lymphocytes) per 4 square mm of glandular tissue

V. Salivary gland involvement: objective evidence of salivary glandinvolvement defined by a positive result for at least one of the followingdiagnostic tests:

1. Unstimulated whole salivary flow (1.5 ml in 15 min)

2. Parotid sialography showing the presence of diffuse sialectasias (punctate,

cavitary or destructive pattern), without evidence of obstruction in the major ducts

3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or

delayed excretion of tracer

VI. Autoantibodies: presence in the serum of the following autoantibodies:

1. Antibodies to Ro(SSA) or La(SSB) antigens, or both

Reproduced with permission from: Vitali, C, Bombardieri, S, Jonsson, R,

et al. Classification criteria for Sjgren's syndrome: a revised version of the European criteria proposed by the American-European ConsensusGroup. Ann Rheum Dis 2002; 61:664-558. Copyright 2002 BMJ Publishing Group.

Differential diagnosis of the manifestations of Sjgren'ssyndrome

Examples

Dry eyes

Aqueous teardeficiency

Keratoconjunctivitis sicca (Sjgren's syndrome)


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Mucindeficiency

Hypovitaminosis A

Ocular pemphigoid

Chemical burns

Stevens-Johnson syndrome

Ocular lipidabnormalities

Blepharitis

Cornealepitheliopathy

Cranial nerve V dysfunction

Contact lens use

Impaired lidfunction

Dry mouth

Drugs

Antidepressants

Antihistamines

Anticholinergics

DiureticsNeuroleptics

Psychogenic Anxiety

Systemicdiseases

Sjgren's syndrome

Amyloidosis

SarcoidosisHIV infection

Uncontrolled diabetes mellitus

Dehydration

Salivary gland enlargement


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Uusuallyunilateral

Bacterial infection

Chronic sialadenitis

Obstruction

Primary neoplasm (adenoma, adenocarcinoma,

lymphoma, mixed salivary gland tumors)

Usuallybilateral

Viral infection (EBV, mumps, CMV, coxsackie A)

Sjgren's syndrome

Amyloidosis

Granulomatous diseases (sarcoidosis, TB)

HIV infectionHyperlipidemia

Cirrhosis and alcoholism

Acromegaly

Anorexia

Histologic features of nonspecific interstitial pneumonia

Key histologic features

Cellular pattern*

Mild to moderate interstitial chronic inflammation.

Type II pneumocyte hyperplasia in areas of inflammation.

Fibrosing pattern*

Dense or loose interstitial fibrosis lacking the temporalheterogeneity pattern and/or patchy features of UIP.

Lung architecture may appear lost on examination of H&E-stainedsection, but is relatively preserved with elastin stains.

Interstitial chronic inflammation - mild or moderate.


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Pertinent negative findings

Cellular pattern

Dense interstitial fibrosis: absent.

Organizing pneumonia is not a prominent feature.

Lack of diffuse severe alveolar septal inflammation.

Fibrosing pattern

Temporal heterogeneity pattern: fibroblastic foci with dense fibrosisare inconspicuous or absent - this is especially important in caseswith patchy involvement and subpleural or paraseptal distribution.

Both patterns

Acute lung injury pattern, especially hyaline membranes: absent.

Eosinophils: inconspicuous or absent.

Granulomas: inconspicuous or absent.

Lack of viral inclusions and organisms on special stains fororganisms.

* There is a spectrum from cellular to fibrosing patterns, with somecases showing a combination of cellular and fibrosing features.

Histologic features of lymphoid interstitial pneumonia

Key histologic features

Diffuse interstitial infiltration of involved areas.

Predominantly alveolar septal distribution.

Infiltrates compromised mostly of T and/or B lymphocytes, plasma cells,and macrophages.

Lymphoid hyperplasia (mucosa-associated lymphoid tissue (MALT)hyperplasia) - frequent.

Pertinent negative findings


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Lack of tracking along lymphatic routes (bronchovascular bundles, pleura,and interlobular septa), characteristic of lymphomas.

Organizing pneumonia, inconspicuous or absent.

Lack of Dutcher bodies (ie, intranuclear vacuoles containing IgMmonoclonal protein seen in Waldenstrom's macroglobulinemia).

Lack of monoclonal light chain staining pattern of plasma cells (polyclonalpattern present).

Lack of extensive pleural involvement or lymph node involvement.

Lack of necrotizing granulomas.

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