Version July 2025
INTRODUCTION —
Sjögren's disease (SjD) is a chronic inflammatory disorder characterized by diminished lacrimal and salivary gland function and associated with lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands. Respiratory complications of SjD include airway mucosal dryness (also known as xerotrachea), a variety of interstitial lung diseases (ILDs), non-Hodgkin lymphomas, pleural thickening or effusion, and, rarely, thromboembolic disease or pulmonary hypertension [1-3].
The management and prognosis of ILD in SjD will be reviewed here. The clinical manifestations, classification, evaluation, and diagnosis of SjD and its associated ILDs are presented separately. General management of patients with ILD is also covered elsewhere.
●(See "Overview of the management and prognosis of Sjögren's disease".)
●(See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)
●(See "Overview of the management of adults with interstitial lung disease".)
MANAGEMENT —
Management strategies for Sjögren-associated lung diseases are empiric, since no controlled studies have been performed, and should be made on a case-by-case basis [4]. We base the treatment approach on the identified lung pathology, as well as the severity of symptoms, physiologic impairment, and extent of radiographic disease. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Diagnosis'.)
Sjögren-associated ILD without biopsy confirmation — Asymptomatic patients with mild ILD based on high-resolution computed tomography (HRCT) and/or pulmonary function testing (PFTs) may prefer not to pursue a lung biopsy for histopathologic diagnosis. For these patients, we monitor symptoms, HRCT, and PFTs at 6- to 12-month intervals [5]. If progressive disease is identified, we typically advise further evaluation to identify the radiologic pattern of the underlying ILD, which may impact the management. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Evaluation'.)
Nonspecific interstitial pneumonia — For asymptomatic patients with SjD-associated nonspecific interstitial pneumonia (NSIP) pattern with normal or minimally abnormal PFTs, we suggest longitudinal clinical, functional, and radiological evaluation rather than active treatment, as some patients with NSIP can improve or stabilize without therapy. The majority of patients, though, are symptomatic, with abnormalities on PFTs, and require therapy. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Overview of treatment'.)
●Initial therapy – For symptomatic patients with SjD-associated NSIP who have worsening symptoms, PFTs, and radiographic abnormalities, we typically initiate treatment with oral glucocorticoids, although clinical trial data are lacking. Prednisone is usually started at a dose of 0.5 to 1 mg/kg ideal body weight up to a maximum of 60 mg per day [3,6,7]. This treatment is similar to that used for idiopathic NSIP and is supported by the results of reported case series, in which the specific type of ILD was not specified but was most likely NSIP. In a series of five patients with a confirmed diagnosis of NSIP, four improved with prednisone at this dose [6]. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Glucocorticoids'.)
The response to therapy is assessed after four to six weeks with evaluation of symptoms and PFTs. For patients who respond to prednisone, we taper but continue a low dose for at least six months, monitoring the response with interval clinical evaluations, PFTs, and HRCT scanning.
●Long-term use, lack of improvement or intolerance of glucocorticoids – For patients who do not improve with systemic glucocorticoids or who improve, but develop side effects of therapy, or for those who need long-term use, immunosuppressive therapy is required [3,4,7]. The following immunosuppressants may be used at this phase:
•Azathioprine – Azathioprine has been used with limited success in SjD-associated NSIP. As an example, a nonrandomized study found that 11 patients treated with azathioprine showed a significant improvement in forced vital capacity at six months when compared to untreated patients (p <0.05) [8]. We typically follow the treatment approach outlined for using azathioprine in NSIP. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Azathioprine'.)
•Mycophenolate mofetil – Small case series suggest that mycophenolate mofetil (MMF) may be effective in connective tissue disease-associated ILD, although few data exist regarding SjD-ILD. In a series of 125 patients with connective tissue disease of which five had SjD, MMF was well-tolerated and had a glucocorticoid-sparing effect [9]. The use of MMF in the treatment of rheumatic disease is reviewed separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
●Refractory disease – Rituximab and other agents may be used in refractory SjD-ILD, in cases without response to glucocorticoids and to the above immunosuppressants [3,4,7].
•Rituximab – The optimal role of rituximab in SjD-associated ILD is not completely known. A few case reports and case series have described improvement in SjD-ILD with rituximab treatment, but as the patients did not undergo lung biopsy, the exact histopathology is not known [10]. In one report, a patient with refractory pulmonary opacities, pleural effusion, and other systemic manifestations of primary Sjögren's disease (pSjD) responded to rituximab treatment with clearing of the lung manifestations [11]. In a review of the efficacy of rituximab in pSjD from a French Registry, among 78 pSjD patients, 9 had pSjD-related pulmonary involvement: one bronchiolar and eight ILD [12]. Six of the eight ILD patients responded to the first cycle of rituximab, as did the patient with bronchial involvement. Larger clinical trials are needed before rituximab is considered for routine use in SjD-associated ILD [13]. The use of rituximab in the management of rheumatic disease is discussed separately. (See "Rituximab: Principles of use and adverse effects in rheumatologic disease" and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Rituximab'.)
•Other agents – Cyclophosphamide and cyclosporine have been employed in limited numbers of patients with SjD-ILD that is resistant to glucocorticoids [14-16]. These agents carry potential toxicity. Their use in the management of NSIP is discussed separately. Nintedanib, an antifibrotic agent, may be reasonable for patients with progressive fibrotic phenotype [17]. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Cyclophosphamide' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Calcineurin inhibitors' and "Overview of the management of adults with interstitial lung disease", section on 'Patients with progressive fibrotic changes or worsening restriction'.)
Progressive fibrosing ILD and usual interstitial pneumonia — The usual interstitial pneumonia (UIP) pattern is uncommon in patients with SjD, and formal study of treatment options is lacking. For patients with progressive fibrosing ILD or UIP who are unimproved after a trial of the above therapies, antifibrotic therapy, such as nintedanib (used in idiopathic pulmonary fibrosis [IPF]), may slow disease progression, based on results in other progressive fibrosing ILDs [7,17]. (See "Overview of the management of adults with interstitial lung disease", section on 'Patients with progressive fibrotic changes or worsening restriction' and "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Nintedanib'.)
Lymphoid interstitial pneumonia — Most patients with lymphoid interstitial pneumonia (LIP) associated with SjD are symptomatic and have evidence of physiologic impairment. No clinical trials have been performed, but our experience suggests that such patients respond well to oral glucocorticoids, although some require the addition of an alternate immunosuppressive agent, such as azathioprine or MMF. The management of LIP is discussed separately. (See "Lymphoid interstitial pneumonia" and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Cardiopulmonary manifestations'.)
Organizing pneumonia — The treatment of organizing pneumonia associated with SjD follows that of cryptogenic organizing pneumonia and is discussed separately. The majority of patients, especially those symptomatic and with abnormalities on PFTs, are treated with an oral glucocorticoid at an initial dose equivalent to prednisone 0.5 to 1 mg/kg per day [3]. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.)
Follicular bronchiolitis — The optimal treatment of follicular bronchiolitis complicating SjD is not known. Often, follicular bronchiolitis is found in association with NSIP, LIP, or organizing pneumonia in which case the treatment typically follows that of the associated ILD [16]. When follicular bronchiolitis complicates rheumatoid arthritis, treatment is aimed at the underlying rheumatoid arthritis. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Overview of treatment' and "Lymphoid interstitial pneumonia", section on 'Treatment' and "General principles and overview of management of rheumatoid arthritis in adults" and "Cryptogenic organizing pneumonia", section on 'Treatment'.)
For patients with minimal or no symptoms and no associated ILD, treatment is not indicated, as progressive disease is uncommon [18]. Instead, symptoms, PFTs, and HRCT are monitored at 6- to 12-month intervals.
For symptomatic patients with evidence of obstruction on PFTs, a short-course of systemic steroids for two to four weeks may be tried and may be prolonged if there is a good response [3,18]. Inhaled glucocorticoids, inhaled bronchodilators, and macrolides can be used for persistent and symptomatic bronchiolitis [3,19].
In a case series of patients with pSjD-associated lung disease, a patient who had bronchiolar involvement had a clinical response to rituximab [12]. The use of rituximab in the management of SjD is discussed separately. (See 'Nonspecific interstitial pneumonia' above and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Rituximab'.)
Nodular lymphoid hyperplasia — No specific treatment has been established for pulmonary nodular lymphoid hyperplasia in patients with SjD, and at least one patient has remained stable without specific therapy [20]. In addition, a few case reports and case series of nodular lymphoid hyperplasia not associated with SjD describe stability or regression [21,22]. However, others warn that lymphoma may develop in some patients thought to have nodular lymphoid hyperplasia either due to evolution of the process or the emergence of a small focus of lymphoma that was initially missed [23]. We typically monitor patients with a repeat CT scan at six-month intervals for the first year and then annually, especially to surveil for the occurrence of lymphoma.
Lymphoma — The evaluation and management of marginal zone lymphoma is discussed separately. (See "Treatment of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)
Pulmonary nodular amyloidosis — There are insufficient data to advise a particular management strategy for pulmonary nodular amyloidosis occurring in the absence of lymphoma, as only a few cases have been reported. Pulmonary nodular amyloidosis appears to remain stable or progress slowly without specific therapy; gradual enlargement of nodules and occasional cavitation are reported [24-26]. (See "Pleuropulmonary manifestations of amyloidosis" and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)
PROGNOSIS —
The natural history of the various lung diseases associated with SjD is not well established. Some studies report a progressive reduction in lung diffusing capacity for carbon monoxide or forced vital capacity over four years [27,28], but others describe a mixture of improvement (16 percent), stabilization (43 percent), and deterioration (37 percent) [29]. A separate 10-year follow-up of PFTs reported that many patients do not experience progressive lung disease and that lung diffusing capacity for carbon monoxide may improve independent of treatment [30]. In a retrospective study from Taiwan with pSjD-ILD, the prevalence of progressive fibrosing disease was 50 percent, and those with the progressive phenotype had lower albumin serum levels in the follow-up [31]. In a series from South Korea with patients with pSjD-ILD, the prevalence of progression was also approximately 50 percent [32].
The reported survival of patients with SjD-ILD is variable. In a series of 85 patients with pSjD, the development of ILD was associated with a likely poorer survival compared with those who did not have ILD (hazard ratio for death 2.16, 95% CI 0.99-4.74) [33]. In another study, for patients with pSjD and ILD (n = 33), the overall five-year survival rate was 87 percent [34]. In the study from Taiwan, the three-year overall survival in pSjD-ILD was 91 percent and was lower in patients with progressive fibrosing disease compared with those without the progressive form (82 versus 100 percent) [31]. In a study from Saudi Arabia of those with pSjD-ILD, the three- and five-year survival rates were 70 and 56 percent, respectively [35]. In the Norwegian systemic connective tissue disease and vasculitis registry (NOSVAR), 27 percent of SJD patients (59 of 216) had concomitant ILD; those patients had a significantly reduced Physical Functioning subscore (SF-36) and a four-fold increased risk of dying after 10 years of disease (17 versus 4.5 percent) [36].
Variances in the clinical course may reflect the type of lung disease and the severity of the underlying connective tissue disease. When looking individually at the types of ILD, the prognosis of nonspecific interstitial pneumonia (NSIP) pattern, lymphoid interstitial pneumonia (LIP), and organizing pneumonia (OP) in the setting of SjD is generally favorable [34,37]. Adverse prognostic factors include male sex, usual interstitial pneumonia (UIP) pattern, purpura, decreased levels of C4 complement, mixed monoclonal cryoglobulinemia, reduced forced vital capacity, pulmonary hypertension, and lymphoma [34,37,38]. Features associated with UIP, such as more extensive reticular opacities on high-resolution computed tomography (HRCT) and a greater number of fibroblast foci on histologic examination, are also associated with a worse prognosis [34,38]. Acute exacerbations may occur in SjD-ILD and may lead to hospitalization and death [3,35]
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sjögren's disease" and "Society guideline links: Interstitial lung disease".)
SUMMARY AND RECOMMENDATIONS
●Approach – The management of Sjögren's disease (SjD)-associated interstitial lung disease (ILD) typically depends on the radiographic/histopathologic pattern of disease, the severity of symptoms, and the degree of pulmonary function impairment. (See 'Introduction' above.)
●Asymptomatic ILD – For asymptomatic patients with Sjögren's disease (SjD)-associated interstitial lung disease (ILD) without a specific histopathologic diagnosis, we monitor symptoms, high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) at 6- to 12-month intervals. (See 'Sjögren-associated ILD without biopsy confirmation' above and "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Lung biopsy'.)
●Patients with NSIP pattern (radiographic or histopathologic) – For asymptomatic patients with SjD-ILD and a nonspecific interstitial pneumonia (NSIP) pattern and normal or minimally abnormal PFTs, we suggest longitudinal clinical, functional, and radiologic evaluation rather than active treatment (Grade 2C). (See 'Nonspecific interstitial pneumonia' above.)
For symptomatic patients with SjD-ILD and an NSIP pattern who have worsening symptoms, PFTs, and radiographic abnormalities, we suggest initiating treatment with oral glucocorticoids (Grade 2C). We typically use prednisone at an initial dose of 0.5 to 1 mg/kg ideal body weight per day. Subsequent management is based on response. Mycophenolate mofetil and azathioprine are typical first-line options for glucocorticoid-sparing therapy. (See 'Nonspecific interstitial pneumonia' above.)
●Patients with UIP pattern – The usual interstitial pneumonia (UIP) pattern is uncommon in patients with SjD. The role of antifibrotic therapies, such as those used in idiopathic pulmonary fibrosis (IPF), remains unclear, but treatment is reasonable for those with progressive fibrosing disease. (See 'Progressive fibrosing ILD and usual interstitial pneumonia' above and "Overview of the management of adults with interstitial lung disease", section on 'Patients with progressive fibrotic changes or worsening restriction'.)
●Lymphoid interstitial pneumonia – The management of SjD-associated lymphoid interstitial pneumonia (LIP) follows that for cryptogenic LIP and is discussed separately. (See "Lymphoid interstitial pneumonia", section on 'Treatment'.)
●Organizing pneumonia – The treatment of organizing pneumonia (OP) associated with SjD follows that for cryptogenic organizing pneumonia and is discussed separately. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.)
●Follicular bronchiolitis – The optimal treatment of follicular bronchiolitis is not known. For patients with minimal or no symptoms and no associated ILD, we suggest observation rather than active therapy (Grade 2C). For symptomatic patients with evidence of impairment on PFTs, we suggest initiating treatment with an inhaled glucocorticoid, bronchodilator, and macrolide rather than observation or systemic immunosuppression (Grade 2C). Oral glucocorticoid therapy (typically prednisone at 40 mg daily) is appropriate for severe impairment or progressive disease despite treatment. When follicular bronchiolitis occurs in combination with NSIP, LIP, or OP, the treatment is directed at the ILD. (See 'Follicular bronchiolitis' above.)
●Patients with suboptimal response to immunosuppressive therapy – For patients with NSIP pattern or follicular bronchiolitis that is unresponsive to glucocorticoids and immunosuppressive agents (eg, azathioprine, mycophenolate mofetil), rituximab may be a reasonable third-line therapeutic option. (See 'Nonspecific interstitial pneumonia' above and 'Follicular bronchiolitis' above.)
●Nodular lymphoid hyperplasia – For patients with pulmonary nodular lymphoid hyperplasia, we suggest observation with interval HRCTs to assess for development of lymphoma without specific treatment of the hyperplasia (Grade 2C). (See 'Nodular lymphoid hyperplasia' above.)
●Lymphoma – The evaluation and management of marginal zone lymphoma is discussed separately. (See "Treatment of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)
●Pulmonary amyloidosis – No specific therapy has been described for pulmonary nodular amyloidosis; the nodules appear to remain stable or enlarge slowly without specific therapy. (See 'Pulmonary nodular amyloidosis' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Daniel Deheinzelin, MD, who contributed to earlier versions of this topic review.
