Authors: Brian Schonewald, Christopher Xie, Andrew Engel, Ross Summer, Giorgos Loizidis
Categories: Research, Interstitial lung disease, Sjogren’s syndrome, Chronic sinusitis, Unified airway hypothesis
Source: BMC Pulmonary Medicine
Authors: Brian Schonewald, Christopher Xie, Andrew Engel, Ross Summer, Giorgos Loizidis
Interstitial lung disease (ILD) is a leading cause of morbidity and mortality in Sjögren’s syndrome (SS), but its risk factors remain unclear. Although SS affects both the upper and lower respiratory epithelium, it is unknown whether this occurs simultaneously or separately. In other autoimmune conditions—such as eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis—upper airway disease precedes lower lung involvement by months or even years. We hypothesized that chronic rhinosinusitis (CRS), as an upper airway disease, may be a risk factor for ILD in SS.
We analyzed the TriNetX Research Network database to compare incident ILD in SS patients with or without CRS. Patients with pre-existing ILD or CRS were excluded, and all participants were being treated with Sjögren’s related immunosuppression or sicca therapies. Incident ILD and risk ratios (RR) were calculated at 5 and 10 years after adjusting for important confounding variables, such as age, gender, race, comorbid conditions, and other risk factors.
In matched cohorts, overall risk for developing ILD was significantly higher in patients with CRS. At 5 years, incidence of ILD was 2.56% in patients with CRS versus 1.66% in those without CRS (adjusted RR 1.57, p = 0.01, 95% CI: 1.09–2.27). Likewise, at 10 years, the ILD incidence was 3.01% in patients with CRS versus 1.96% in those without CRS (adjusted RR 1.53, p = 0.01, 95% CI: 1.09–2.13).
Our results suggest SS patients with CRS are at higher risk for developing ILD, indicating a possible need for more intensive screening in this population.
The online version contains supplementary material available at 10.1186/s12890-025-03992-4.
Sjögren’s syndrome (SS) is a chronic autoimmune disorder that primarily affects the lacrimal and salivary glands, often causing dryness of the eyes and mouth [1, 2]. It is one of the most common autoimmune conditions, impacting nearly 1% of United States population, with females being nine times more likely to develop disease [1]. Beyond the classic oral and ocular symptoms, patients may experience various extra-glandular manifestations, including joint pain, neuropathy, kidney dysfunction and lung disease [1–3]. Involvement of the respiratory tract affects not only the sinuses and upper airways but also the distal lung parenchyma. Parenchymal lung involvement can manifest as different forms of interstitial lung disease (ILD), including lymphocytic interstitial pneumonia, non-specific interstitial pneumonitis or usual interstitial pneumonia [4], all of which contribute to significant morbidity and mortality.
Risk factors for developing ILD in SS have not yet been defined. Moreover, it remains unclear whether SS affects multiple parts of the respiratory system simultaneously or at different stages of the disease. In allergic airway diseases, concurrent involvement of the upper and lower airways is well-established, described as the ‘one-airway, one disease’ concept [5]. In autoimmune diseases such as eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis, upper airway involvement typically precedes lower airway manifestations by months or even years [6–8], indicating that the upper airway is a risk factor for future lower airway disease in these patients.
Delayed diagnosis of ILD can lead to significant loss of lung function and functional impairments, underscoring the importance of identifying potential risk factors of disease. Given that upper airway involvement may signal the future development of parenchymal lung disease in conditions like EGPA and GPA, we hypothesized that a history of upper airway disease could indicate an increased risk of ILD in patients with SS. To test this hypothesis, we conducted a large multicenter investigation to assess the risk of ILD in SS patients with or without a prior history of chronic rhinosinusitis.
We conducted our study using the TriNetX Research Network, a database containing electronic health records (EHRs) from many different healthcare organizations [9]. For this analysis, we focused our investigation on U.S.-based healthcare organizations and data from 2004 to 2024, collected on April 8, 2024. This database is regularly updated and adheres to ISO 2013 standards and the HIPAA Security Rule. Since the data are fully de-identified, local Institutional Review Board approval was not required. More information about TriNetX can be found https://trinetx.com/real-world-resources/publications/trinetx-publication-guidelines/.
All cohorts were identified using ICD-10, RxNorm, TNX-curated, and Logical Observation Identifiers Names and Codes (LOINC) for diagnoses, medications, comorbidities, and laboratory tests (see Supplemental Table 1 for the list of codes). Inclusion criteria required patients to have a diagnosis of SS that preceded the diagnosis of CRS and ILD (Fig. 1). Additionally, patients had to be on either immunosuppressive medication or medications that treat mucocutaneous or ocular dryness.
Fig. 1Flowchart of cohort formation and analysis framework
To address potential confounding variables, we excluded patients diagnosed with any other immune-related disorders. These included systemic sclerosis (scleroderma), rheumatoid arthritis, dermatomyositis/polymyositis, systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, giant cell arteritis, polymyalgia rheumatica, Takayasu arteritis, antineutrophil cytoplasmic antibody-associated vasculitis, sarcoidosis, multiple sclerosis, ankylosing spondylitis, and psoriasis. Additionally, patients with conditions associated with glandular dysfunction were excluded, such as graft-versus-host disease, human immunodeficiency virus infection, hepatitis C, IgG4-related disease, and those who had undergone organ transplantation.
The index event was defined as the initial documentation of SS in the electronic health records. This study included two distinct cohorts. The first cohort comprised patients diagnosed with SS who subsequently developed CRS at least one day to five years after their SS diagnosis. The second cohort consisted of patients diagnosed with SS who did not have a diagnosis of CRS at any time during the study period. Patients with a diagnosis of CRS prior to their SS diagnosis were excluded from both cohorts. This exclusion ensured that CRS developed after the onset of SS, allowing us to specifically examine whether new onset CRS is a risk factor for the development of ILD.
The primary outcome of our study was the incidence of a new diagnosis of ILD. ILD cases were identified using ICD-10 codes for pulmonary fibrosis, Sjögren’s syndrome with lung involvement, progressive fibrotic phenotype, and respiratory bronchiolitis-associated interstitial lung disease.
After defining cohorts, index events, outcomes, we adjusted results for relevant patient covariates. A logistic regression model was used to predict the probability (propensity score) of each patient belonging to cohorts based on their covariates. Using greedy nearest-neighbor matching with a caliper of 0.1 pooled standard deviations, the system matched patients from the smaller cohort with those in the larger cohort who had similar propensity scores.
The covariates used for PSM included age, race, gender, and body mass index (BMI). We also adjusted for various pulmonary conditions associated with airway symptoms, such as asthma, chronic obstructive pulmonary disease, and nicotine dependence (smoking). Additionally, we accounted for medications known to cause ILD, including nitrofurantoin, amiodarone, and bleomycin. Furthermore, cohorts were matched for immunosuppressive medications used to treat active Sjögren’s disease, such as methotrexate, azathioprine, mycophenolate, hydroxychloroquine, leflunomide, rituximab, sulfasalazine, tumor necrosis factor tumor necrosis factor-alpha inhibitors, and cyclophosphamide, as well as medications treating sicca symptoms, such as cyclosporine, pilocarpine, cevimeline, and lifitegrast.
All statistical analyses were performed using the TriNetX Advanced Analytics Platform. The precise methodologies for these computations are proprietary and protected under trade secret laws. This platform enabled us to calculate measures of association, including risk difference, risk ratio, and odds ratio, all with 95% confidence intervals and a significance threshold of p < 0.05 (two-sided).
Our database identified a total of 95,470 patients with Sjögren’s disease, of whom 40% (38,856) were receiving treatment with either immunosuppressive medications or sicca therapies. The average age of these patients was 63 years, with the majority being female (84%) and self-identifying as White, followed by Black and Hispanic.
Baseline characteristics varied between patients with and without chronic sinus disease. Patients with chronic sinus disease were younger and more likely to be male and White (Table 1). Additionally, they had a higher prevalence of comorbidities, including gastroesophageal reflux disease and respiratory conditions such as asthma, chronic obstructive pulmonary disease, and chronic cough, as well as a reported history of cigarette smoking. In terms of rheumatological characteristics, these patients had a higher prevalence of Raynaud’s phenomenon and were twice as likely to be on immunosuppressive medications—including hydroxychloroquine, cyclosporine, methotrexate, azathioprine, mycophenolate, and rituximab—as well as sicca therapies such as pilocarpine, cevimeline, and lifitegrast (supplemental Table 2). Antibody testing results were unavailable for most patients, but differences between groups were largely consistent (supplemental Table 3).
Table 1Baseline characteristics of patients with Sjögren’s syndrome with or without chronic rhinosinusitis (CRS)VariableSjögren’s with CRSSjögren’s without CRSp-valueStd diff.(n = 3,114)(n = 35,742)Age at Index (mean ± SD)58.7 ± 14.956.5 ± 16.0< 0.0010.1Sex Female2,765 (88.79%)31,087 (86.98%)0.0040.1 Male234 (7.51%)3,354 (9.38%)0.0010.1Race White2,306 (74.05%)24,920 (69.72%)< 0.0010.1 Black or African American237 (7.61%)2,579 (7.22%)0.410.02 Hispanic or Latino163 (5.23%)2,216 (6.20%)0.030.04 Asian109 (3.50%)1,585 (4.44%)0.010.05Comorbidity Gastro-esophageal Reflux Disease1,439 (46.21%)6,286 (17.59%)< 0.0010.6 Asthma710 (22.80%)2,718 (7.60%)< 0.0010.4 Personal history of nicotine dependence299 (9.60%)1,668 (4.67%)< 0.0010.2 Raynaud’s syndrome261 (8.38%)1,556 (4.35%)< 0.0010.2 Other chronic obstructive pulmonary disease192 (6.17%)1,036 (2.90%)< 0.0010.2 Nicotine dependence164 (5.27%)1,115 (3.12%)< 0.0010.1 Chronic cough101 (3.24%)269 (0.75%)< 0.0010.2 BMI (mean ± SD)28.1 ± 6.927.8 ± 6.70.030.1
We applied propensity score matching to our two patients with SS and CRS and patients with SS without CRS. This matching process successfully balanced the previously observed differences in baseline covariates between the groups, resulting in each group consisting of 3,047 patients. After matching, none of the covariates—including demographic factors, comorbidities, and medication use—were statistically significantly different between the SS-CRS and SS without CRS groups (supplemental Table 4). This adjustment ensures that the comparison of risk ratios for ILD is based on cohorts with similar baseline characteristics, thereby reducing potential confounding and allowing for a more accurate assessment of the association.
Regarding ILD risk in patients with and without chronic sinus disease, unadjusted analysis revealed a higher incidence of ILD among patients with chronic sinus disease (Table 2). After propensity score matching, and consistent with results from unadjusted cohorts, we found that the incidence of ILD was significantly higher in patients with chronic sinus disease at both 5 years (2.56% vs. 1.66%) and 10 years (3.01% vs. 1.96%) after Sjögren’s diagnosis (Table 2). These correspond to risk ratios of 1.57 (p = 0.01, 95% CI: 1.09–2.27) at 5 years and 1.53 (p = 0.01, 95% CI: 1.09–2.13) at 10 years, respectively.
Table 2Risk of ILD development in patients with Sjögren’s syndrome with and without chronic rhinosinusitis (CRS) at 5 and 10 years after index event before and after propensity score matching (PSM)5 years after index eventBefore PSMAfter PSMSS with CRS(n = 2,927)SS without CRS(n = 34,465)p valueRisk ratio (RR)Confidence interval (CI)SS with CRS(n = 2,870)SS without CRS (n = 2,886)p valueRisk ratio (RR)Confidence interval (CI)75 (2.56%)571 (1.66%)< 0.0011.551.21, 1.9672 (2.51%)46 (1.59%)0.011.571.09, 2.27187 patients in Cohort 1 and 1,277 patients in Cohort 2 were excluded from results because they had the outcome prior to the time window 177 patients in Cohort 1 and 161 patients in Cohort 2 were excluded from results because they had the outcome prior to the time window 10 years after index eventBefore PSMAfter PSMSS with CRS (n = 2,927)SS without CRS (n = 34,465)p valueRisk ratio (RR)Confidence interval (CI)SS with CRS (n = 2,870)SS without CRS (n = 2,886)p valueRisk ratio (RR)Confidence interval (CI)88 (3.01%)677 (1.96%)< 0.0011.531.23, 1.9185 (2.96%)56 (1.94%)0.011.531.09, 2.13187 patients in Cohort 1 and 1,277 patients in Cohort 2 were excluded from results because they had the outcome prior to the time window 177 patients in Cohort 1 and 161 patients in Cohort 2 were excluded from results because they had the outcome prior to the time window
This study is the first to demonstrate that CRS is a significant risk factor for the development of ILD in patients with SS. While CRS has previously been identified as both a potential precursor to SS and a frequent comorbid condition [10, 11], its relationship with ILD had not been explored. Our results indicate that SS patients with CRS have nearly a 50% greater risk of developing ILD compared to those without CRS, even after adjusting for key confounding factors. These findings suggest a potential pathogenic link between upper airway involvement and lower respiratory complications in SS, warranting further investigations into the mechanisms causing respiratory disease in these patients.
Several mechanisms may explain the link between CRS to ILD in SS. This includes the possibility that glandular dysfunction contributes to both conditions [12]. Reduced production of surface fluids could desiccate the airways, resulting in drier and more viscous mucus that impairs mucociliary clearance and predisposes to tissue injury – paralleling complications seen in other forms of ciliary dysfunction [4, 13, 14]. Additionally, disturbances in mucus homeostasis such as polymorphisms in the MUC5B gene promoting mucus hypersecretion, have already been linked to idiopathic and autoimmune forms of pulmonary fibrosis [15, 16]. Second, it seems plausible that altered mucosal immunity may contribute to disease by predisposing to more frequent and/or more severe viral infections [17, 18], which would directly contribute to epithelial damage and upper and lower airway pathology. Consistent with this, several epidemiology studies have linked certain viral infections, such as the Epstein-Barr virus, to the origins of SS autoimmunity [17].
A notable finding in our study, which warrants further investigation, was the observation that patients with SS and CRS had a higher prevalence of several comorbid conditions, including gastroesophageal reflux disease. Esophageal dysmotility is recognized as a common complication of SS [19–21]. For instance, a large Spanish registry of SS patients found that nearly 1/5 of patients had digestive tract involvement or esophageal motility dysfunction [22, 23]. Furthermore, patients with digestive tract involvement were more likely to require glucocorticoids, immunosuppressants, and biologic therapies, suggesting that autoimmune epithelitis may extend beyond the respiratory tract.
Our study undertook extensive efforts to rule out alternative factors that may contribute to the development of ILD in our population. Key risk factors for ILD include advanced age, environmental exposures such as asbestos, silica dust, and cigarette smoke, as well as a wide range of medications, including chemotherapeutic agents and antibiotics. Despite our thorough attempts to account for these variables, we cannot entirely exclude the possibility that unmeasured confounding factors may have influenced our findings.
While the large sample size was a notable strength of our study, several weaknesses must be acknowledged. For instance, our results may be affected by inaccuracies in diagnostic coding, a common issue with retrospective investigations. Recent research indicates that many Sjögren’s patients do not meet classification criteria in large population studies, highlighting potential discrepancies in diagnostic accuracy with this disease. Additionally, our database lacked information on autoantibody testing, making it difficult to exclude other rheumatological conditions, although we did exclude patients with diagnostic codes for other autoimmune diseases. We also could not account for socioeconomic factors that might have influenced our results or for the potential impact of disease severity on the incidence of ILD. Lastly, the generalizability of our results may be limited due to limiting our investigation to healthcare centers within the US. However, we believe this approach was necessary owing to differences in the way healthcare organizations are structured in- and outside the US.
In summary, this report is the first to identify CRS as a potential risk factor for ILD in patients with SS. These findings may have important clinical implications for the screening and monitoring of patients with SS. Further research, including prospective investigations are necessary to confirm this association and to develop improved diagnostic tools to identify SS patients at risk for ILD.
Supplementary Material 1.