Interstitial lung disease associated with Sjögren's disease: Management and prognosis

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 interstitial lung disease in SjD will be reviewed here. The clinical manifestations, classification, evaluation, and diagnosis of Sjögren's disease and its associated interstitial lung diseases are presented separately. (See "Diagnosis and classification of Sjögren’s disease" and "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis" and "Overview of the management and prognosis of Sjögren's disease" and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)

MANAGEMENT — Management strategies for Sjögren-associated lung diseases are empiric, since no controlled studies have been performed. We base the treatment approach on the identified lung pathology, and 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 interstitial lung disease (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. If progressive disease is identified, we typically advise further evaluation to identify the radiologic pattern of the underlying ILD. (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) 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 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 [4]. 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 nonspecific interstitial pneumonia. In a series of five patients with a confirmed diagnosis of NSIP, four improved with prednisone at this dose [4]. (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 continue a low dose for at least six months, monitoring the response with interval clinical evaluations, pulmonary function tests, and HRCT scanning.

●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, immunosuppressive therapy may be beneficial.

•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) [5]. 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 [6]. 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 – The optimal role of rituximab in SjD-associated ILD is not known. A few case reports and case series have described improvement in SjD with rituximab treatment, but as the patients did not undergo lung biopsy, the exact histopathology is not known [7]. 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 [8]. 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 [9]. 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 [10]. The use of rituximab in the management of rheumatic disease is discussed separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" 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 interstitial lung disease due to SjD that is resistant to glucocorticoids [11-13]. These agents carry substantial toxicity. Their use in the management of NSIP is discussed separately. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Cyclophosphamide' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Calcineurin inhibitors'.)

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 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 [14]. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Nintedanib' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Future directions'.)

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. 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 are treated with an oral glucocorticoid at an initial dose equivalent to prednisone 1 mg/kg per day. (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 [13]. 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 [15]. Instead, symptoms, pulmonary function, and HRCT are monitored at 6- to 12-month intervals.

For symptomatic patients with evidence of impairment on PFTs, we usually initiate treatment with an oral glucocorticoid. Successful treatment with oral glucocorticoids at a median initial dose of prednisone 40 mg daily has been described [15]. A series of five SjD patients with severe bronchiolitis reported clinical and functional improvement with inhaled steroid, inhaled bronchodilators, and macrolides [16].

In a case series of patients with pSjD-associated lung disease, a patient who had bronchiolar involvement had a clinical response to rituximab [9]. 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 [17]. In addition, a few case reports and case series of nodular lymphoid hyperplasia not associated with SjD describe stability or regression [18,19]. 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 [20]. We typically monitor patients with a repeat CT scan at six-month intervals for the first year and then annually.

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 [21-23]. (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 diffusing capacity (DLCO) or forced vital capacity (FVC) over four years [24,25], but others describe a mixture of improvement (16 percent), stabilization (43 percent), and deterioration (37 percent) [26]. A separate 10-year follow-up of pulmonary function reported that many patients do not experience progressive lung disease and that diffusing capacity may improve independent of treatment [27].

In a series of 85 patients with primary SjD, the development of interstitial lung disease (ILD) was associated with a trend towards poorer survival compared with those who did not have ILD (hazard ratio for death 2.16, 95% CI 0.99-4.74) [28]. In another study, patients with primary SjD and ILD (n = 33) the overall five-year survival rate was 87 percent [29]. The Norwegian systemic connective tissue disease (CTD) and vasculitis registry (NOSVAR), among 216 pSjD patients, found 59 (27 percent) with ILD, those patients had Physical Functioning subscore (SF-36) significantly reduced (P = 0.03) and a fourfold increased risk of dying after 10 years of disease (n = 10, 17 percent) compared with those without lung involvement (n = 7, 4.5 percent) (P = 0.002) [30].

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, lymphoid interstitial pneumonia, and organizing pneumonia in the setting of SjD is generally favorable [29,31]. Adverse prognostic factors include purpura, decreased levels of C4 complement, mixed monoclonal cryoglobulinemia, pulmonary hypertension, and lymphoma [29,31]. Features associated with usual interstitial pneumonia, such as more extensive reticular changes on high-resolution computed tomography (HRCT) and a greater number of fibroblast foci on histologic examination, are associated with a worse prognosis [29].

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

●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'.)

●For asymptomatic patients with SjD-associated nonspecific interstitial pneumonia (NSIP) with normal or minimally abnormal PFTs, we suggest longitudinal clinical, functional, and radiological evaluation rather than active treatment (Grade 2C). (See 'Nonspecific interstitial pneumonia' above.)

For symptomatic patients with SjD-associated NSIP who have worsening symptoms, PFTs, and radiographic abnormalities, we suggest initiating treatment with oral glucocorticoids (Grade 2C). We typically use prednisone at a dose of 1 mg/kg ideal body weight per day. Subsequent management is based on the response to therapy. (See 'Nonspecific interstitial pneumonia' above.)

●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. (See 'Usual interstitial pneumonia' above and "Treatment of idiopathic pulmonary fibrosis".)

●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'.)

●The treatment of organizing pneumonia associated with SjD follows that for cryptogenic organizing pneumonia and is discussed separately. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.)

●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 steroid, bronchodilator and macrolide (Grade 2C), reserving oral glucocorticoid (prednisone at 40 mg daily) for more severe cases. When follicular bronchiolitis occurs in combination with NSIP, LIP, or OP, the treatment is directed at the ILD. (See 'Follicular bronchiolitis' above.)

●For patients with ILD or follicular bronchiolitis that is unresponsive to glucocorticoids and immunosuppressive agents (eg, azathioprine, mycophenolate), rituximab may be a therapeutic option. (See 'Nonspecific interstitial pneumonia' above and 'Follicular bronchiolitis' above.)

●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).

●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)".)

●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.