Genomic Research in Sarcoidosis

Sarcoidosis is a systemic disease characterized by the formation of granulomatous lesions,
especially in the lungs, liver, skin, and lymph nodes, with a heterogeneous set of clinical
manifestations and a variable course 1. Despite significant progress in the understanding of
the genetic predisposition and role of immunity, it is still a challenge to explain the
clinical presentation of sarcoidosis. Standard clinical assessment, imaging, and pulmonary
function tests (PFTs) do not allow prediction of disease course and response to therapy.
Furthermore, there are no good long-term therapies. Considering that the interactions
between potential infections, changes in systemic inflammation, and patterns in lung
microbiome and the different and distinct disease phenotypes in sarcoidosis are not well
understood, the Sarcoidosis protocol for the Genomic Research in AAT Deficiency and
Sarcoidosis (GRADS) grant (hereafter called GRADS Sarcoidosis protocol) is designed to
address the following:

Hypothesis

Distinct patterns in lung microbiome are characteristic of sarcoidosis phenotypes and
reflected in changes in systemic inflammatory responses as measured by peripheral changes in
gene transcription.

Specific Aims

1. To identify peripheral blood mononuclear cell (PBMC) gene expression patterns that
characterize distinct sarcoidosis phenotypes.

2. To determine whether patterns in the lung microbiome are associated with sarcoidosis
severity and disease phenotypes

3. To correlate mRNA and microRNA expression patterns in sarcoidosis affected organs with
changes in microbiome, clinical parameters and PBMC gene expression patterns

4. To integrate clinical, transcriptomic, and microbiome data to identify novel molecular
phenotypes in sarcoidosis.

Focusing on accessible PBMCs should enable GRADS researchers to identify markers for disease
phenotypes, severity, and outcome. Analysis of lesional transcriptomes (mRNA, microRNA and
lincRNA) will add mechanistic insights. High throughput unbiased analysis of the lung
microbiome will potentially identify patterns in the lung microbiome that determine disease
activity and persistence, as well as response to therapy.

Participants are assigned a provisional clinical phenotype upon obtaining consent at time of
enrollment by the respective recruiting center. Clinical phenotypes will be reviewed,
confirmed, and monitored to ensure achievement of study objectives. Participants who cannot
be assigned a clinical phenotype after the initial study visit will be excluded from
additional study participation.

Inclusion Criteria:

1. Age between the ages of 18 and 85.

2. Have a diagnosis of sarcoidosis established by consensus criteria (ATS/ERS),
confirmed by either biopsy or by manifestations consistent with acute sarcoidosis
(Löfgren's syndrome) in absence of other known diagnosis.

OR Have a suspected diagnosis of sarcoidosis and is scheduled to undergo a biopsy
procedure to confirm a diagnosis of sarcoidosis using the same consensus criteria
(ATS/ERS).

3. Able to tolerate and willing to undergo study procedures.

4. Be capable of understanding study forms.

5. Provide signed informed consent.

Exclusion Criteria:

1. History of comorbid condition severe enough to significantly increase risks based on
investigator discretion.

2. Currently an active smoker.

3. Undergoing bronchoscopy (clinical or research) with any one of the following:

1. severe pulmonary impairment (<50% predicted FVC, <1 L FEV1; DLco <40% predicted,
resting hypoxemia <92% with or without supplemental oxygen)

2. other co-morbid disease that would preclude bronchoscopy.

3. hypersensitivity to or intolerance of any of the drugs required for sedation
during conscious sedation bronchoscopy.

4. Known systemic autoimmune disease such as rheumatoid arthritis, lupus, scleroderma,
Sjögrens, etc.

5. Found to have an alternative interstitial lung disease during evaluation and/or
screening.

6. Diagnosis of unstable cardiovascular disease including myocardial infarction in the
past 6 weeks, uncontrolled congestive heart failure, or uncontrolled arrhythmia

7. Use of anticoagulation (patients on warfarin or clopidogrel will be excluded,
patients on aspirin alone can be studied even with concurrent use)

8. Dementia or other cognitive dysfunction which in the opinion of the investigator
would prevent the participant from consenting to the study or completing study
procedures

9. Non-Sarcoidosis pulmonary disease (e.g., rheumatoid arthritis, lupus, scleroderma)
that, in the opinion of the investigator, limits the interpretability of the analysis
of sarcoidosis pulmonary disease

10. Primary biliary cirrhosis or autoimmune hepatitis

11. Crohn's disease

12. Chronic beryllium disease

13. Have an active bacterial or viral infection at time of screening.

14. Have an active or ongoing serious infection, including HIV, HBV and HCV

15. Active tuberculosis or are taking any medication for tuberculosis

16. Have a history of demyelinating diseases, lymphoproliferative diseases, or other
malignancies other than presumed cured non-metastatic skin cancer

17. Have evidence of a likely malignancy on chest x-ray

18. Are currently pregnant at time of screening

19. Currently institutionalized (e.g., prisons, long-term care facilities)

20. Hypersensitivity to or intolerance of albuterol sulfate or propellants or excipients
of the inhalers

21. History of Lung volume reduction surgery, lung resection or bronchoscopic lung volume
reduction in any form.

22. History of lung or other organ transplant

23. Unable to comprehend consent document and/or questionnaires

Conditional Exclusions:

1. Participants who present with an upper respiratory infection or pulmonary
exacerbation, either solely participant-identified or that has been clinically
treated, in the last four weeks can be rescreened for the study once the four-week
window has closed.

2. Participants who present with current use of acute antibiotics or have acute
antibiotics within the past four weeks can be rescreened for the study ≥28 days after
discontinuing acute antibiotics.

3. Female participants who present <3 months after giving birth will be asked to
reschedule their visit until three months have passed since the birth.

4. Former smoker who quit < 3months prior to enrollment