Consensus Guidelines for Evaluation and Management of Pulmonary Disease in Sjogrens

in collaboration with the Consensus Expert Panel (CEP) Members* BACKGROUND: Pulmonary disease is a potentially serious yet underdiagnosed complication of Sjogren's syndrome, the second most common autoimmune rheumatic disease. Approximately 16% of patients with Sjogren's demonstrate pulmonary involvement with higher mortality and lower quality of life.RESEARCH QUESTION: Clinical practice guidelines for pulmonary manifestations of Sjogren's were developed by the Sjogren's Foundation after identifying a critical need for early diagnosis and improved quality and consistency of care.STUDY DESIGN AND METHODS: A rigorous and transparent methodology was followed according to American College of Rheumatology guidelines. The Pulmonary Topic Review Group (TRG) developed clinical questions in the PICO (Patient, Intervention, Comparison, Outcome) format and selected literature search parameters. Each article was reviewed by a minimum of two TRG members for eligibility and assessment of quality of evidence and strength of recommendation. Guidelines were then drafted based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale and data extraction tables were submitted to a Consensus Expert Panel for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version.RESULTS:The literature search revealed 1,192 articles, of which 150 qualified for consideration in guideline development. Of the original 85 PICO questions posed by the TRG, 52 recommendations were generated. These were then reviewed by the Consensus Expert Panel and 52 recommendations were finalized, with a mean agreement of 97.71% (range, 79%-100%). The recommendations span topics of evaluating Sjogren's patients for pulmonary manifestations and assessing, managing, and treating upper and lower airway disease, interstitial lung disease, and lymphoproliferative disease.INTERPRETATION: Clinical practice guidelines for pulmonary manifestations in Sjogren's will improve early identification, evaluation, and uniformity of care by primary care physicians, rheumatologists, and pulmonologists. Additionally, opportunities for future research are identified. CHEST 2021; 159(2):683-698 KEY WORDS: guideline; lung; pulmonary; Sjogren; Sjogren's ABBREVIATIONS: ACR = American College of Rheumatology; CEP = Consensus Expert Panel; CTD = connective tissue disease; DLCO = diffusing capacity of the lung for carbon monoxide; EULAR = European League Against Rheumatism; HRCT = high-resolution CT; ILD = interstitial lung disease; MALT = mucosa-associated lymphoid tissue; NYHA = New York Heart Association; PFT = pulmonary function test; PICO = Patient, Intervention, Comparison, Outcome; TRG = Topic Review Group; UIP = usual interstitial pneumonia [ Diffuse Lung Disease Guideline and Consensus Statement ] chestjournal.orgFUNDING/SUPPORT: The Sjogren's Foundation Clinical Practice Guidelines are supported by the Foundation with no industry funding. No compensation was paid for study participation.
Clinical practice guidelines for the diagnosis, management, and treatment of pulmonary manifestations of Sjogren's were developed by the Sjogren's Foundation after identifying a critical need for early diagnosis and improved quality and consistency of care. Pulmonary disease is a potentially serious yet underdiagnosed complication of Sjogren's syndrome, a chronic autoimmune disease with substantial disease morbidity and burden as well as reduced quality of life. 1,2 Sjogren's not occurring with another autoimmune disease has a prevalence second only to rheumatoid arthritis among the inflammatory rheumatic illnesses, [bib_ref] Estimates of the prevalence of arthritis and other rheumatic conditions in the..., Helmick [/bib_ref] and although the disease can be observed in children and men, [bib_ref] The epidemiology of Sjogren's syndrome, Patel [/bib_ref] it is most prevalent in women. [bib_ref] Sex differences in autoimmune disease, Whitacre [/bib_ref] Approximately 10% to 20% of Sjogren's patients demonstrate pulmonary involvement with an associated higher mortality and lower quality of life. [bib_ref] Characterization of systemic disease in primary Sjogren's syndrome: EULAR-SS Task Force recommendations..., Ramos-Casals [/bib_ref] [bib_ref] Lung manifestation in asymptomatic patients with primary Sjogren syndrome: assessment with high..., Uffman [/bib_ref] [bib_ref] Primary Sjogren's syndrome 1976-2005 and associated interstitial lung disease: a population-based study..., Nannini [/bib_ref] [bib_ref] High-resolution CT imaging of the lung for patients with primary Sjogren's syndrome, Lohrmann [/bib_ref] [bib_ref] Prevalence and characterization of non-sicca onset primary Sjogren syndrome with interstitial lung..., Manfredi [/bib_ref] [bib_ref] Respiratory manifestations in primary Sjogren's syndrome. A clinical, functional, and histologic study, Constantopoulos [/bib_ref] In addition, up to 65% of asymptomatic Sjogren's patients will have abnormal pulmonary imaging, 7 emphasizing the need for provider awareness of pulmonary manifestations and education on evaluation, monitoring, and treatment.
Pulmonologists are encouraged to consider the possibility of Sjogren's in patients with pulmonary disease who have not previously been diagnosed as having Sjogren's. As such, pulmonologists can play an important role in Sjogren's diagnosis and ensure that nonpulmonary complications of Sjogren's are addressed by the appropriate specialists.

# Materials and methods
A rigorous and transparent methodology was followed according to the American College of Rheumatology (ACR) guidelines.The methodology employed for these guidelines was first developed and used by the Foundation for recommendations for rheumatologic management in Sjogren's [bib_ref] Treatment guidelines for rheumatologic manifestations of Sjogren's: use of biologics, management of..., Carsons [/bib_ref] and included direction from the ACR as well as other guidelines methodology consultants. [bib_ref] Innovations in American Society of Clinical Oncology Practice Guideline Development, Somerfield [/bib_ref] The Pulmonary Topic Review Group (TRG) included equal parts rheumatologists and pulmonologists (n 14 4 each) and one hematologist-oncologist as well as participation and oversight by a rheumatologist chair for all Foundation guidelines and a rheumatology/systemic symptoms guidelines chair. The TRG defined systematic review parameters and end points (e-Appendix 1), including MEDLINE/PubMed peer-reviewed articles in English between January 1, 1990, and February 1, 2020, and studies with Sjogren's patients classified or diagnosed by any published set of criteria. Although currently either the 2002 American-European Consensus Group 15 or the 2016 ACR/European League Against Rheumatism (EULAR) [bib_ref] American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjogren's..., Shiboski [/bib_ref] classification criteria for primary Sjogren's are utilized most often, a number of criteria have been used historically.
An outline with clinical questions was developed based on the PICO (Patient, Intervention, Comparison, Outcome) format (e-Appendix 2). For the systematic review, literature search terms were compiled by the TRG, and the searches were executed by a librarian (e-Appendix 1). Each article was reviewed by a minimum of two TRG members for eligibility and assessment of quality of evidence. Full data were extracted into four tables: Study Characteristics, Sample and Disease, Evidence, and Quality (https://www.sjogrens.org/researchersproviders/clinical-practice-guidelines). The Quality table rated the overall quality of each study according to criteria related to study design and the risk of bias used in recommendation development.
Guidelines were drafted based on available evidence using a strength of the evidence rating (e-Appendix 3), the expertise of the TRG and Consensus Expert Panel (CEP) members who reviewed the recommendations, and clinical importance. Each recommendation also was rated for the strength of the recommendation, which was gauged by the TRG based on a combination of available evidence as well as the confidence level that the recommendation offers the best current guidance for practice.
Draft recommendations and strength of the recommendation were submitted to the CEP for consideration and approval, with at least 75% agreement required for inclusion in the manuscript. A clinical rationale for each recommendation and data extraction tables for articles used in developing the recommendations also were provided. The CEP, composed of 68 members (including 40 rheumatologists, 21 pulmonologists, and seven additional members, all of whom were Sjogren's patients or family of patients [e-Appendix 4]), voted on each recommendation using a six-point Likert scale, the strength of the recommendation (rating), and provided commentary for TRG review. If the consensus threshold was not met, the recommendation would be adjusted by the TRG until the consensus threshold was met. The commentary provided by the CEP was considered in the final wording of the recommendations and clinical rationales. Recommendations were again evaluated by the CEP following minor wording changes to better align with standard guideline language.
The formal consensus process was deemed especially critical in view of the lack of high-quality evidence. The guidelines committee utilized principles of the American Society of Clinical Oncology, Grading of Recommendations Assessment, Development and Evaluation, Agency for Health Research and Quality, and the US Preventive Services Task Force to formulate the methodology.

# Results
The TRG originally developed 85 topics/questions in the PICO format that spanned epidemiology, evaluation, diagnostics, and therapeutics of Sjogren's-related pulmonary manifestations, including upper and lower airway disorders, interstitial lung diseases, pulmonary vascular disease, and lymphoproliferative disorders. The number of questions was reduced after TRG members ranked all clinical questions as Primary, Secondary, or Minor in terms of the question's importance for recommendation development, and final selection was determined by TRG leadership when consensus was lacking. Following the literature search, some PICO questions were determined to be irrelevant and/or not suited to recommendations for a pulmonary condition or to be within the scope of this paper.
Medical literature searches utilizing the predefined search terms and search criteria (e-Appendix 1) identified 1,192 articles, of which 178 abstracts were selected and 150 of those deemed qualified for data extraction and use in guideline development. Abstracts identified by the literature search but eliminated by the TRG were excluded for the following reasons: not relevant to guidelines (such as unrelated to Sjogren's and/or pulmonary), article type (commentary, editorial, letter to the editor), case studies that provided no unique information, or were not in English (e-Appendix 1, Quorum Diagram).
The TRG then generated 52 recommendations along with a rating on the strength of each recommendation that was submitted to the CEP. A clinical rationale for each recommendation (e-Appendix 5), and all references with data extracted were provided in support of the recommendations. Consensus agreement on the 102 questions used to form the recommendations and ratings exceeded the required 75% threshold after one round, with a range of agreement between 79% to 100% and an average of nearly 98%. The CEP results are provided in e-Appendix 4. Additionally, commentaries provided by the CEP were reviewed by the TRG and led to rewording 12 recommendations and 13 clinical rationales without altering their substance. Because these recommendations were intended to be wide-reaching and used across multiple specialties, the authors preferred to make firm recommendations and avoided vaguer terms such as "may be considered" when reasonable.

## Evaluation for lung involvement
Consensus recommendations on evaluating Sjogren's patients for potential pulmonary signs and symptoms and the use of imaging, full (complete) pulmonary function tests (PFTs), which includes spirometry, diffusing capacity of the lung for carbon monoxide (DLCO), and lung volumes ideally measured by body plethysmography, and bronchoscopy are listed in [fig_ref] TABLE 1 ]: Recommendations for Evaluating Patients With Sjogren's [/fig_ref] and [fig_ref] Figure 1 -: Respiratory evaluation for Sjogren's patients [/fig_ref]. In addition, we have provided practical clinical guides to assist in the history taking and symptom detection for evaluation purposes in e-Appendix 6. An additional consideration that was borne out of the literature review was that Sjogren's is often diagnosed after a pulmonary disorder is initially recognized. These include patients with airway disorders (eg, refractory cough, small airway disease), indeterminate interstitial lung diseases (ILD), and pulmonary lymphoproliferative disorders (eg, mucosaassociated lymphoid tissue [MALT]-type lymphoma). [fig_ref] TABLE 2 ]: Evaluating for Potential Sjogren's in Patients with Pulmonary Symptoms Do you get... [/fig_ref] provides a list of Sjogren's symptoms for the clinician to consider when the etiology of a patient's pulmonary condition remains undiagnosed.
Since lung involvement is common in Sjogren's, a baseline chest radiograph is recommended. If concern is high for lung involvement, however, a high-resolution CT (HRCT) scan may be preferred due to its higher sensitivity and specificity. [bib_ref] Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practic guideline, Raghu [/bib_ref] [bib_ref] Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper, Lynch [/bib_ref] Full PFTs as described above may additionally identify patients with subclinical Sjogren's lung disease. [bib_ref] Lung function in primary Sjogren's syndrome: a cross sectional and longitudinal study, Kelly [/bib_ref] Although few outcomes data exist, a baseline chest radiograph and full PFTs were chestjournal.org

## Intermediate moderate
1B. In a Sjogren's patient with respiratory symptoms, the interval for repeat HRCT and PFTs must be determined on a case-by-case basis and individualized according to the nature and severity of the underlying pulmonary abnormality and the degree of symptoms and functional impairment.

## Insufficient strong
2. In a Sjogren's patient with dyspnea, an echocardiogram is recommended in the following circumstances: a) In patients with suspected pulmonary hypertension b) In patients with unexplained dyspnea after pulmonary etiologies (asthma, small airway disease, bronchiectasis, ILD) have been excluded c) In patients with suspected cardiac involvement HIGH STRONG 3. In a Sjogren's patient with respiratory symptoms, a CTPA to look for pulmonary embolism must not be performed routinely in all patients but rather dictated by clinical suspicion for pulmonary embolism in individual circumstances. If clinically concerned about a pulmonary embolism, CTPA is the confirmatory test of choice. Ventilation-perfusion scan should only be considered in the following circumstances: a) To rule out chronic thromboembolic pulmonary hypertension in patients with pulmonary hypertension b) When clinical concern for pulmonary embolism exists, and a physician is unable to do a CTPA because of patient allergy to contrast or renal insufficiency LOW STRONG Recommendations: Evaluating for Sjogren's in patients with lung disease 1. In patients who have an uncharacterized ILD, diffuse cystic lung disease, or pulmonary lymphoma, clinical and serologic evaluation for Sjogren's is recommended.

## High strong
Recommendations: Use of bronchoscopy 1. In a Sjogren's patient with respiratory symptoms, bronchoscopy with BAL must not be performed routinely but determined on a case-by-case basis and limited to special circumstances, such as the need to: a) Rule out infectious etiologies, especially in patients on immune suppression b) Rule out endobronchial abnormalities such as amyloidosis in patients with chronic cough not otherwise responsive to treatment c) Distinguish between other etiologies of sicca symptoms such as sarcoidosis LOW STRONG 2. In a Sjogren's patient with respiratory symptoms, use of bronchoscopy with endobronchial biopsies and transbronchial lung biopsy are not recommended for routine use.

## Insufficient strong
CTPA 14 CT pulmonary angiogram; ILD 14 interstitial lung diseases; PFTs 14 pulmonary function tests.
recommended by the TRG and the CEP when weighing the risks and benefits, as these tests are likely to aid in identifying subclinical disease, in future comparisons when symptoms develop, and in guiding the timing of any specific interventions.
In general, all symptomatic patients should have serial clinical and PFT monitoring. However, monitoring strategy depends on the clinician's consideration of the specific condition, its severity, the patient's symptoms and functional status, and the pace of clinical deterioration. While no specific guidance regarding intervals for repeat testing can be given, the majority of TRG members repeat PFTs at least every 6 to 12 months to better understand longitudinal disease trajectory. Typically, spirometry is performed as the main Symptoms should prompt the physician to engage in further serologic evaluation and/or rheumatology consultation.
chestjournal.org monitoring test at each interval, with complete PFTs, which include lung volumes and DLCO performed at longer intervals.

## Upper and lower airway disorders
Upper and lower airway disease reported in association with or as a result of Sjogren's includes xerotrachea, dysphagia, laryngopharyngeal reflux, vocal cord cystic lesions ("bamboo nodules"), OSA, bronchiectasis, bronchiolitis, obstructive lung disease, and reactive airway disease. Approximately 38% of Sjogren's patients have chronic cough. [bib_ref] Chronic non-productive cough in patients with primary Sjogren's syndrome, Do Gru [/bib_ref] Interestingly, among patients without an initial Sjogren's diagnosis, an unexplained cough associated with dry eyes led to confirmation of Sjogren's in 36%. [bib_ref] Unexplained cough: it is time to rule out Sjogren's syndrome, Koslow [/bib_ref] An evaluation is warranted in a Sjogren's patient with chronic cough (> 8 weeks), starting with an assessment for common causes (eg, asthma, gastroesophageal reflux disease, upper airway cough syndrome, non-asthmatic eosinophilic bronchitis), [bib_ref] CHEST Expert Cough Panel. Classification of cough as a symptom in adults..., Irwin [/bib_ref] followed by evaluation for pulmonary complications of Sjogren's, including xerotrachea, ILD, bronchiolitis, bronchiectasis, and pulmonary lymphoma. Small airway disease in the setting of Sjogren's may represent histopathologic follicular or constrictive bronchiolitis. [bib_ref] Small airway disease associated with Sjogren's syndrome: clinico-pathological correlations, Nakanishi [/bib_ref] Although there is often overlap on imaging and physiology, these distinctive histologic findings have variable types of inflammation (neutrophilic, lymphocytic, eosinophilic, fibroblast) and bronchiolocentric fibrosis. Bronchiectasis is characterized radiographically by the atypical dilation of the airways larger than the accompanying bronchial artery, or visible to 1 cm of the costal pleural margin. Inhaled corticosteroids, while possibly increasing the risk for candidiasis, have been recommended for inflammatory airway disease by the 2020 EULAR recommendations for managing Sjogren's. [bib_ref] EULAR recommendations for the management of Sjogren's syndrome with topical and systemic..., Ramos-Casals [/bib_ref] Bronchodilators may be tried empirically. And, while no broadly accepted criteria exist for xerotrachea, following exclusion of other causes of cough, empirical humidification in all Sjogren's patients with chronic cough is recommended along with consideration of an empiric trial of a secretagogue and/or guaifenesin. Most of these and other recommendations as listed in [fig_ref] TABLE 3 ]: Recommendations for Assessment and Management of Upper and Lower Airway Disease in... [/fig_ref] largely draw upon experience from related airway disorders outside of the specific context of Sjogren's. [fig_ref] Figure 2 -: Evaluation and management of patients with Sjogren's who exhibit symptoms and/or physical... [/fig_ref] is a suggested clinical pathway based on these recommendations. [bib_ref] Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice..., Qaseem [/bib_ref] Interstitial Lung Disease
Most Sjogren's patients who have ILD exhibit pulmonary symptoms such as shortness of breath, cough, sputum production, or chest pain. [bib_ref] Characterization of systemic disease in primary Sjogren's syndrome: EULAR-SS Task Force recommendations..., Ramos-Casals [/bib_ref] Symptom severity varies from asymptomatic to minimal dyspnea on exertion to severe. The onset of ILD increases over time, with one study showing a prevalence of 10% within the first year of diagnosis and 20% after 5 years. [bib_ref] Primary Sjogren's syndrome 1976-2005 and associated interstitial lung disease: a population-based study..., Nannini [/bib_ref] Among Sjogren's patients with ILD, specific subtypes that have been reported include: nonspecific interstitial pneumonia 45%, respiratory bronchiolitis 25%, usual interstitial pneumonia (UIP) 16%, lymphoid interstitial pneumonia 15%, organizing pneumonia 7%, amyloid 6%, and lymphoma 4%. [bib_ref] Characterization of systemic disease in primary Sjogren's syndrome: EULAR-SS Task Force recommendations..., Ramos-Casals [/bib_ref] Cystic lung disease is found more commonly in Sjogren's compared with the other connective tissue diseases (CTDs). Martinez-Balzano et al [bib_ref] Cystic lung disease among patients with Sjogren syndrome: frequency, natural history, and..., Martinez-Balzano [/bib_ref] reported that cystic lung disease was associated with older age, a diagnosis of secondary Sjogren's, and elevated anti-SSA (or Ro) antibody, whereas Lechtman et al [bib_ref] Cystic lung disease in Sjogren's syndrome: an observational study, Lechtman [/bib_ref] reported a higher frequency of anti-SSB (or La) antibody. Pulmonary function testing was nonspecific, and no significant radiographic progression was noted (n 14 12) after a median follow-up of 4 years. Two patients had secondary infections complicating the cysts, but pneumothoraces appeared to be an uncommon presentation of cystic lung disease. The prognosis of cystic lung disease in Sjogren's depends on the specific histopathologic findings. Cystic lung disease in Sjogren's is most commonly secondary to lymphoid interstitial pneumonia/follicular bronchiolitis but might also suggest the presence of amyloid or MALT lymphoma, especially if associated with concomitant nodules. [bib_ref] Amyloid-associated cystic lung disease in primary Sjogren's syndrome, Baqir [/bib_ref] A large proportion of the ILDs in Sjogren's tend to follow an indolent course. However, ILD with a UIP pattern in Sjogren's can be progressive and portend a worse prognosis. [bib_ref] Interstitial lung disease in primary Sjogren syndrome, Parambil [/bib_ref] [bib_ref] Characteristics of patients with primary Sjogren's syndrome associated interstitial lung disease and..., Zhang [/bib_ref] Acute exacerbations of nonspecific interstitial pneumonia and UIP have been reported and can precipitate respiratory failure and death. Most cases do not require biopsy confirmation, as the diagnosis usually can be made based on HRCT and PFTs, and treatment is not always necessary. [bib_ref] Interstitial lung disease in primary Sjogren syndrome, Parambil [/bib_ref] Ito et al 32 reported that mortality is associated with decreased baseline PaO 2 and presence of microscopic honeycombing. A large retrospective cohort from Taiwan 33 of 4,954 Sjogren's patients reported that the incidence of respiratory failure was higher than in non-Sjogren's patients, regardless of sex, age, and comorbidities. Respiratory failure in primary Sjogren's was most commonly attributed to ILD (25%), followed by small airway disease (22%), desiccation of upper respiratory tract (17%), and large airway obstruction (8%).
When obtaining baseline PFTs, it should be noted that discordance between PFT abnormalities, degree of symptoms, and HRCT findings can occur. [bib_ref] Lung manifestation in asymptomatic patients with primary Sjogren syndrome: assessment with high..., Uffman [/bib_ref] LOW MODERATE 6. Rapidly progressive or exacerbating ILD-IV steroids: In Sjogren's patients with ILD who are rapidly progressive or present with acute respiratory failure, a trial of high-dose corticosteroids (such as IV methylprednisolone) is recommended.
Alternative etiologies, such as infections or lymphoproliferative disorders, must be considered.

## Intermediate strong
7A. Symptomatic/refractory, rapidly progressive, or exacerbating ILD-cyclophosphamide: In a Sjogren's patient with ILD who has acute or subacute hypoxic respiratory failure requiring hospitalization, despite initial therapies, rituximab or cyclophosphamide should be considered in addition to high-dose corticosteroids.

## Low moderate
7B. Cautions for cyclophosphamide: In Sjogren's with ILD when cyclophosphamide is considered, the significant risks must be assessed a and Pneumocystis jirovecii prophylaxis provided. Risk of bladder cancer can be greatly reduced with IV vs oral route.

## Intermediate strong
8. Drug-induced lung disease: Clinicians and patients must be aware of pulmonary complications associated with medications used in Sjogren's and related CTDs, particularly when patients are progressive or refractory to therapies. Complications may include infections, malignancies, bronchospasm, and drug-induced ILD, and may require bronchoscopy, biopsy, and/or withdrawal of the medication. In addition to medication withdrawal, corticosteroids may be used if significant symptoms and respiratory impairment are present. While the risk is low for most agents (approximately 1%), health-care providers should keep in mind that medications used to treat Sjogren's have been associated with drug-induced ILD, including:
[formula] - TNF-alpha inhibitors - Sulfasalazine - Cyclophosphamide - Rituximab - Leflunomide - Methotrexate - Sulfonamides [/formula]

## Intermediate strong
CTDs 14 connective tissue diseases; HRCT 14 high-resolution CT; ILD 14 interstitial lung diseases; MMF 14 mycophenolate mofetil; NHL 14 non-Hodgkin lymphoma; PFTs 14 pulmonary function tests; TNF 14 tumor necrosis factor. a Refer to the US Food and Drug Administration label for additional information.
b
The antifibrotic, nintedanib, was US Food and Drug Administration-approved for progressive fibrotic ILD just as these recommendations went to consensus. This factor, in addition to the authors' awareness of minimal experience with antifibrotics in autoimmune disease, precluded inclusion of a Recommendation listing cautions for antifibrotics. Please consult the Physicians' Desk Reference for potential risks and side effects.
history of disease progression. While evidence is unavailable on the frequency or duration of PFTs in Sjogren's-ILD, TRG members typically perform full PFTs at the time of the initial evaluation followed by repeat assessment every 3 to 6 months, especially in the first 1 to 2 years. The frequency of subsequent testing is dictated by an individual patient's pace of disease progression.
Many of the pharmacological interventions are based on the severity of the Sjogren's-ILD. While no standard definition exists for staging, the panel bases severity on the pulmonary domain disease activity defined by EULAR Sjogren's Syndrome Disease Activity Index, which uses symptoms defined by the New York Heart Association (NYHA) Functional Classification, imaging, and PFT results. [bib_ref] EULAR Sjogren's syndrome disease activity index (ESSDAI): a user guide, Seror [/bib_ref] In general, moderate and severe/high disease activity is gauged as follows:
Moderate: shortness of breath on exercise (NYHA II) or PFTs restricted to FVC between 60% and 80% predicted or DLCO between 40% and 70% predicted.
Severe/high: shortness of breath at rest (NYHA III, IV) or PFTs with FVC < 60% predicted or DLCO < 40% predicted.
Close follow-up is required for all pharmacological treatments. Additionally, the TRG and CEP recognized the paucity of specific clinical trials dedicated to Sjogren's-ILD as a significant and high priority research gap. The recommendations [fig_ref] TABLE 4 ]: Recommendations for ILD in Sjogren's PatientsRecommendations [/fig_ref] and the clinical pathway [fig_ref] Figure 3 -: Evaluation and management of patients with Sjogren's who exhibit symptoms and/or physical... [/fig_ref] are based on extrapolation of current guidelines and literature on non-Sjogren's ILD, including important recent clinical trials on the potential role of antifibrotic therapies (eg, nintedanib) in CTD-ILD. [bib_ref] Nintedanib in progressive fibrosing interstitial lung diseases, Flaherty [/bib_ref] Therapies reported for Sjogren's-ILD along with their mechanism of action, common side effects, and level and strength of recommendation are summarized in e-Appendix 7. Nintedanib, an antifibrotic, was recently approved for "progressive" fibrotic ILD phenotypes, which may also include those associated with Sjogren's and other CTDs. Common side effects include diarrhea or loose stools and GI upset, the former commonly The panel proposes a dose not to exceed 60 mg daily of prednisone with a slow taper over weeks-months. In rapidly progressive ILD, or acute respiratory failure, consider pulse dose IV corticosteroids or high-dose oral corticosteroids up to 60 mg daily of prednisone. b In patients who are not able to successfully taper off corticosteroids, or experience unfavorable adverse effects, or in patients where the length of corticosteroid therapy is predicted to be long-term, steroid-sparing agents should be initiated as maintenance therapy. c Condition rapidly deteriorates and requires hospitalization. d Nintedanib is approved by the US Food and Drug Administration for progressive fibrotic lung disease phenotype. e Calcineurin inhibitors can be considered in patients who are intolerant to the initial maintenance therapy; no evidence to support the superiority in patients who fail the first-line therapy. AZA 14 azathioprine; CYP 14 cyclophosphamide; HRCT 14 high-resolution CT; ILD 14 interstitial lung disease; MMF 14 mycophenolate mofetil; PFTs 14 pulmonary function tests; PH 14 pulmonary hypertension; RTX 14 rituximab.
chestjournal.org treated with loperamide. Medication monitoring involves assessing for drug-induced liver injury with baseline and serial evaluation of transaminases and total bilirubin.

## Lymphoproliferative disease
Six recommendations were developed on lymphoproliferative disease in Sjogren's [fig_ref] TABLE 5 ]: Recommendations for Lymphoproliferative Disease in Sjogren's Patients Diagnosis, Evaluation, and Management for... [/fig_ref]. Concerns for lymphoma development in Sjogren's, which ranges from 5% to 18%, are delineated in numerous papers. [bib_ref] Lymphoma and other malignancies in primary Sjogren's syndrome: a cohort study on..., Theander [/bib_ref] [bib_ref] Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within..., Smedby [/bib_ref] [bib_ref] Prognosis and outcome of non-Hodgkin lymphoma in primary Sjogren syndrome, Voulgarelis [/bib_ref] [bib_ref] Characterization and risk estimate of cancer in patients with primary Sjogren syndrome, Brito-Zeron [/bib_ref] [bib_ref] Comparison of patients with and without pre-existing lymphoma at diagnosis of primary..., Vasaitis [/bib_ref] Lymphoproliferative involvement of the lungs can present as non-resolving consolidations, focal nodules (particularly in the presence of parotitis), lymphadenopathy, and cystic lesions accompanied by adjacent nodules and may be asymptomatic.
Examination findings of importance include lymphadenopathy and parotitis, particularly when PETavid parotitis (standardized uptake value $ 4.7) is accompanied by lung nodules. [bib_ref] Usefulness of 18 F-labeled fluorodeoxyglucose-positron emission tomography for the diagnosis of lymphoma..., Keraen [/bib_ref] [bib_ref] Predicting the risk for lymphoma development in Sjogren syndrome: an easy tool..., Fragkioudaki [/bib_ref] Focal lung nodules and consolidations are present in approximately onethird of Sjogren's patients with pulmonary lymphoma vs 3% without lymphoma. [bib_ref] Usefulness of 18 F-labeled fluorodeoxyglucose-positron emission tomography for the diagnosis of lymphoma..., Keraen [/bib_ref] Multiple sub-centimeter lung nodules accompanied by adjacent cystic lesions (typically < 1 cm in size in peribronchovascular and subpleural distributions) may further indicate a MALT lymphoma with focal amyloidosis. [bib_ref] Amyloid-associated cystic lung disease, Zamora [/bib_ref] Presence of ILD does not appear to indicate a higher risk for lymphoma. [bib_ref] Usefulness of 18 F-labeled fluorodeoxyglucose-positron emission tomography for the diagnosis of lymphoma..., Keraen [/bib_ref] Sjogren's patients are at a higher risk for both nonneoplastic (eg, nodular lymphoid hyperplasia, follicular bronchiolitis, lymphoid interstitial pneumonia) and neoplastic monoclonal lymphoproliferative disorders. Approximately 6% of Sjogren's-associated lymphomas may directly involve the lungs and are most commonly of the MALT type, manifesting as focal nodules, consolidations, and/or masses. [bib_ref] Pulmonary manifestations of primary Sjogren's syndrome: a clinical, radiologic, and pathologic study, Ito [/bib_ref] [bib_ref] Usefulness of 18 F-labeled fluorodeoxyglucose-positron emission tomography for the diagnosis of lymphoma..., Keraen [/bib_ref] [bib_ref] Malignant lymphoma in primary Sjogren's syndrome: a multicenter, retrospective, clinical study by..., Voulgarelis [/bib_ref] Cystic lesions in the lungs due to amyloid involvement can be associated with Sjogren's, as well as MALT lymphomas and are highly suggestive of Sjogren's. [bib_ref] Amyloid-associated cystic lung disease, Zamora [/bib_ref] Given the prevalence and increased risk for lymphoproliferative disorders, active clinical surveillance for pulmonary lymphoproliferative complications in Sjogren's is recommended, especially for Sjogren's patients who are at high risk for lymphoma. Known risk factors include persistent salivary gland swelling, vasculitis and palpable purpura, lymphadenopathy, laboratory findings of low complements (C3 or C4), monoclonal gammopathy, cryoglobulins, anti-SSA (or Ro) and/or anti-SSB (or La), rheumatoid factor, anemia, leukopenia, lymphopenia, neutropenia, thrombocytopenia, elevated serum beta 2microglobulin, and/or B-cell activating factor. [bib_ref] Characterization and risk estimate of cancer in patients with primary Sjogren syndrome, Brito-Zeron [/bib_ref] HRCT and PET scan abnormalities are common in Sjogren's with or without lymphomatous complications. [bib_ref] Lung manifestation in asymptomatic patients with primary Sjogren syndrome: assessment with high..., Uffman [/bib_ref] [bib_ref] Usefulness of 18 F-labeled fluorodeoxyglucose-positron emission tomography for the diagnosis of lymphoma..., Keraen [/bib_ref] Multidisciplinary review with oncology can aid in diagnosis and management. MALT lymphomas as well as cystic lung disease associated with Sjogren's often have an indolent course and can be managed conservatively. [bib_ref] Cystic lung disease among patients with Sjogren syndrome: frequency, natural history, and..., Martinez-Balzano [/bib_ref] [bib_ref] Cystic lung disease in Sjogren's syndrome: an observational study, Lechtman [/bib_ref] [bib_ref] Primary pulmonary non-Hodgkin's lymphoma, Kim [/bib_ref] Frequency of HRCT monitoring will be variable based on cyst size/appearance and clinical presentation. Accessibility to PET, costs, and insurance coverage should be considered. Many US clinicians may have difficulty obtaining payor authorization for a PET scan if it is not ordered by an oncologist or if malignancy is not yet diagnosed by histopathologic confirmation.

# Conclusions
Pulmonary involvement due to Sjogren's is common and frequently involves upper and lower airway disease, parenchymal or interstitial lung disease, and associated lymphoproliferative disease. A common theme for all of these recommendations, and endorsed by the TRG, is the need for a multidisciplinary approach in the care of Sjogren's patients with suspected or confirmed pulmonary complications, including a rheumatologist, primary care physician, pulmonologist, pathologist, radiologist, and, when appropriate, an oncologist.
While most of the evidence would be considered of low quality due to the lack of randomized, placebo-controlled clinical trials, our recommendations and strength of the recommendations incorporate Sjogren's-specific expertise in pulmonology, rheumatology, and hematology/oncology. Thirty-five recommendations were rated as strong, indicating the extent of agreement that these recommendations reflect best practice, while 11 were rated as moderate and six as weak. The lowest level of agreement for any recommendation was 79% for the weak recommendation to consider performing PFTs to detect underlying pulmonary manifestations in asymptomatic Sjogren's patients. CEP comments primarily cited the burden and expense of obtaining PFTs as well as an improbability of non-pulmonologists ordering such tests due to inadequate awareness of and appreciation for pulmonary manifestations in Sjogren's. Overall, the CEP provided a high level of agreement for the recommendations and strength of the recommendations, with 76 of the 102 questions provided for voting receiving higher than 98% agreement.
Clinical practice guidelines for pulmonary manifestations in Sjogren's may improve early identification, evaluation, and uniformity of care by primary care physicians, rheumatologists, and pulmonologists. Full clinical rationales and references developed by the TRG for these recommendations may be viewed in e-Appendix 5. The guidelines process also has led to identification of high priorities for future research (e-Appendix 8). These priorities include epidemiological and risk analyses, blood-based and noninvasive biomarkers, quantitative imaging tools, optimal frequency of repeat PFTs and HRCT testing for each pattern of pulmonary disease, studies on etiology and treatment, and specifically on antifibrotics for Sjogren's-ILD.
[fig] Figure 1 -: Respiratory evaluation for Sjogren's patients. a The benefit of obtaining baseline PFTs in asymptomatic Sjogren's patients regarding long-term outcomes is not clear. This paucity of evidence and the potential costs of the test should be taken into account and discussed with individual patients prior to proceeding with PFTs. Complete PFTs includes spirometry, DLCO, and lung volumes, ideally measured by body plethysmography. CXR 14 chest radiograph; DLCO 14 diffusing capacity of the lung for carbon monoxide; HRCT 14 high-resolution CT; PFTs 14 pulmonary function tests. [/fig]
[fig] Figure 2 -: Evaluation and management of patients with Sjogren's who exhibit symptoms and/or physical examination signs of airway disorders.25,26 Details regarding PFTs and HRCT examination are given inFigure 1. HRCT 14 high-resolution CT; pulmonary function tests.chestjournal.org [/fig]
[fig] Figure 3 -: Evaluation and management of patients with Sjogren's who exhibit symptoms and/or physical examination signs of interstitial lung disease. Details regarding PFTs and HRCT examinations are given inFigure 1. a The dose and duration of corticosteroids in Sjogren's-ILD is not standardized. [/fig]
[table] TABLE 1 ]: Recommendations for Evaluating Patients With Sjogren's [/table]
[table] TABLE 2 ]: Evaluating for Potential Sjogren's in Patients with Pulmonary Symptoms Do you get frequent dental cavities, particularly gumline cavities? Do your teeth tend to chip, crack, and/or erode on the surfaces? Do you suffer from gum inflammation or receding gums (gingivitis?) Ocular symptoms Do your eyes frequently feel dry, irritated, itchy, or painful? Do you have a sensation that there might be a foreign body in your eye? Are your eyes light sensitive? Do you frequently use eye drops for irritation or dryness? Is your vision frequently blurry, or do you have unexplained vision changes? Other symptoms Have you noticed gland swelling in your face or along the jaw line (swollen parotid and/or submandibular glands)? Do you suffer dryness of the vagina (is intercourse painful?) or skin (is your skin itchy or flaking?)? Do your feet, legs, or hands ever feel numb, have a change in sensation, or have burning pain (peripheral neuropathy)? Do you suffer from extreme fatigue? Do your joints or muscles ache when you are not sick (arthralgias, myalgias)? Do you ever notice your fingers turning pale or blue in the cold (Raynaud's disease)? [/table]
[table] TABLE 3 ]: Recommendations for Assessment and Management of Upper and Lower Airway Disease in Sjogren's Patients Recommendations: Assessment and Management of Upper and Lower Airway Disease in Sjogren's Patients Strength of Evidence Strength of Recommendation 1. In Sjogren's patients with symptomatic vocal cord cystic lesions ("bamboo nodules"), less aggressive interventions, including voice therapy, inhaled corticosteroids, or intra-lesional corticosteroid injection, should be tried first. Surgical resection should be considered if initial measures fail, with consultation by a laryngologist with experience in Sjogren's. LOW MODERATE 2. Sjogren's patients with dry bothersome cough and documented absence of lower airway or parenchymal lung disease must be assessed for treatable or preventable etiologies other than xerotrachea, including gastroesophageal reflux, postnasal drip, and asthma. In a Sjogren's patient with dry, nonproductive cough, humidification, secretagogues, and guaifenesin may be empirically initiated after exclusion of other causes. INSUFFICIENT WEAK 4. The use of humidification for improving positive airway pressure tolerance and compliance may be recommended in Sjogren's patients.6A. In Sjogren's patients with symptomatic small airway disease, bronchoscopic biopsy is not recommended as part of routine assessment or evaluation.INSUFFICIENT STRONG6B. In Sjogren's patients with symptomatic small airway disease, complete pulmonary function testing must be performed to assess severity of small airway disease, and high-resolution CT imaging with additional expiratory views can be helpful in suggesting its presence.INSUFFICIENT STRONG7. In Sjogren's patients with small airway disease, time-limited empiric therapy in newly diagnosed and previously untreated disease may include: A short course of systemic steroids for 2-4 weeks with a repeat spirometry to determine reversibility, especially if uncontrolled asthma is suspected  Nebulized or inhaled short or long-acting bronchodilators and/or inhaled corticosteroids if there is physiological obstruction [/table]
[table] TABLE 4 ]: Recommendations for ILD in Sjogren's PatientsRecommendations: ILD-diagnosis, evaluation, and management 1. In a Sjogren's patient with suspected ILD, an HRCT with expiratory views is recommended. months to establish disease trajectory and initiation of pharmacotherapy only if serial studies document a significant decline in lung function.INTERMEDIATE STRONGRecommendations: ILD-nonpharmacological and other management 1. Vaccination: All Sjogren's patients must be immunized against influenza and pneumococcal infection (Prevnar and Pneumovax) in accordance with Centers for Disease Control and Prevention guidelines. [/table]
[table] TABLE 5 ]: Recommendations for Lymphoproliferative Disease in Sjogren's Patients Diagnosis, Evaluation, and Management for Lymphoproliferative Disease in Sjogren's Patients Strength of Evidence Strength of Recommendation 1. The possibility of lymphoma must be further investigated in a Sjogren's patient with symptoms such as unexplained weight loss, fevers, night sweats, and/or the presence of head and neck lymphadenopathy and/or parotitis. HIGH STRONG 2. All Sjogren's patients must be clinically monitored for signs and symptoms of pulmonary lymphoproliferative disorders, including lymphoma and amyloid. HIGH STRONG 3. In Sjogren's patients suspected of having lymphoproliferative complications, a HRCT chest scan should be considered more appropriate than a baseline CXR at the time of initial diagnosis. INTERMEDIATE MODERATE 4. In a Sjogren's patient with pulmonary lesions (nodules > 8 mm, consolidations, or lymphadenopathy) in whom a neoplasm is suspected, a PET scan should be considered. INTERMEDIATE MODERATE 5. In Sjogren's patients with lymphadenopathy, growing lung nodules, and/or progressive cystic lung disease, a biopsy should be recommended. Clinical and radiographic observation may be appropriate in select patients with incidental subcentimeter nodules, stable cysts, and isolated PET-negative subcentimeter lymphadenopathy. INTERMEDIATE MODERATE 6. In a Sjogren's patient in whom a neoplasm has been confirmed or suspected, multidisciplinary review involving rheumatologist/primary care physician, pulmonologist, pathologist, radiologist, and hematologist/oncologist is recommended.CXR 14 chest radiograph; HRCT 14 high-resolution CT. [/table]