Identifying Unique Pathogenic Macrophages in Systemic Sclerosis-ILD

Completed

• Conditions: Fibrosis Lung; Systemic Sclerosis
• Interventions: Diagnostic Test: Bronchoscopy with lavage

• Registration Number: NCT03438032
• Lead Sponsor: Northwestern University

Brief Summary

Alveolar macrophages isolated from bronchoalveolar lavage (BAL) fluid from systemic sclerosis (SSc) patients with clinically significant lung fibrosis will be studied at baseline and at 6 months after enrollment to assess longitudinally the presence and persistence of an emergent, pro-fibrotic alveolar macrophage population, using single cell RNA-Seq technology to measure the individual transcriptome from each cell.

Detailed Description

Using cutting-edge single cell RNA-Seq technology, we will identify in the BAL fluid of subjects of SSc-ILD emerging pathogenic cell populations in the lung that were previously unrecognized using standard RNA-Seq and microarray technologies, which lack the resolution to analyze transcriptomes of individual cells. Alveolar macrophages isolated from bronchoalveolar lavage (BAL) fluid from SSc patients with clinically significant lung fibrosis will be studied at baseline and at 6 months after enrollment to assess longitudinally the presence and persistence of an emergent, pro-fibrotic alveolar macrophage population.

Subjects with SSc-ILD will be recruited from the Scleroderma Program. We will recruit adults who fulfill 2013 American College of Rheumatology (ACR) SSc criteria and clinically relevant SSc-interstitial lung disease. Patients will undergo bronchoscopy with bronchoalveolar lavage at month 0 and then at month 6. Healthy control subjects will complete demographic and basic medical forms to ensure health. Pertinent clinical data will be downloaded from the Enterprise Data Warehouse, an electronic database in use at Northwestern that was designed to aggregate and store patient data from various medical systems, or through manual chart review, and entered into a RedCap database created specifically for this project.

During an elective bronchoscopy procedure in SSc and healthy control subjects the bronchoscope will be wedged into an affected lung segment guided by CT scanning. After wedging the bronchoscope, 120ml of sterile 0.09% normal saline will be instilled. All subsequent aliquots will be pooled. Up to 40-60 mL of BAL fluid will be obtained for analysis during each sampling. Alveolar macrophages will be sorted on a fluorescence-activated cell sorter (FACS) Aria III instrument. High-throughput single cell transcriptomic (Drop-seq) data will be processed on Northwestern high-performance computational cluster using Cell Ranger pipeline and post-processed using modified AltAnalyze pipeline.

Study Timeline

• Study First Submitted: 2018-02-12
• Study First Submitted QC: 2018-02-15
• Study First Posted: 2018-02-19
• Study Start: 2018-06-28
• Primary Completion: 2022-10-12
• Study Completion: 2024-03-08
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-12
• Last Update Posted: 2024-11-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

• meet 2013 ACR criteria for diagnosis of SSc
• have radiographic evidence for ILD and a forced vital capacity <70% on PFT
• have not taken immune suppression in the last 2 months OR have taken a stable dose of mycophenolate mofetil, rituximab, or prednisone less than or equal to 10 mg for at least 6 months

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Exclusion Criteria

• diagnosis of an overlap syndrome, such as lupus or rheumatoid arthritis
• unable to provide informed consent in English
• currently pregnant or nursing
• current smoker or former smoker (greater than 10 pack years)
• leukopenia
• anemia
• comorbidities of uncontrolled congestive heart failure, cancer not in remission, HIV, or chronic liver disease
• known or suspected infection in the past 3 months
• BMI greater than or equal to 30 kg/m2

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Control	Bronchoscopy with lavage	Healthy control subjects recruited from the Northwestern community will complete demographic and basic medical forms to ensure health
SSc-ILD	Bronchoscopy with lavage	SSc-ILD subjects will be defined by those who fulfill 2013 American College of Rheumatology SSc criteria and have forearm modified Rodnan skin scores (mRSS) ≥1 (a validated, semi-quantitative scoring system for dermal fibrosis) and clinically relevant SSc-interstitial lung disease (ILD). A subject will be defined as having ILD if they have radiographic evidence for ILD and a forced vital capacity \<70% on pulmonary function test (PFT).

Primary Outcome Measures

Name	Time	Method
Single-cell RNA-seq analysis	Baseline and 6 months	Change in alveolar macrophage transcriptome at 6 months, as measured by single cell RNA-sequencing

Trial Locations

Locations (1)

Northwestern University; 🇺🇸 Chicago, Illinois, United States