PET/CT Scan as a Surrogate for Treatment Outcomes in Pulmonary Sarcoidosis

Background: One of the challenges in treating sarcoidosis is that there is currently no reliable modality to measure disease activity and prognosis. This study was conducted to determine if PET/CT scans could be used to evaluate clinical response to sarcoidosis treatment. Methods: In a retrospective cohort study, subjects with symptomatic pulmonary sarcoidosis followed by the University of Miami Sarcoidosis program from 2015 through 2018 were assessed. Inclusion criteria were subjects ≥ 18 years who had histologically-conrmed pulmonary sarcoidosis for ≥ 2 years. Subjects that had PET/CT scans completed prior to starting treatment and approximately one year later were enrolled. Demographics, circulatory blood biomarkers, subjective symptoms, and medications were recorded at baseline (T0) and a year later (T1). Results: Ten subjects with symptomatic pulmonary sarcoidosis were enrolled. All subjects had at least one organ affected by sarcoidosis and a highest of ve organs involved (mean 2.75, SD 1.21). Mean serum angiotensin-converting enzyme (ACE) level was 56.0 U/L (SD 43.08), mean lysozyme was 7.78 µg/mL (SD 3.78), and mean C-reactive protein (CRP) was 0.73 mg/dL (SD 0.85) at T0. Further, mean number of positive lesions was 4.27 (SD 2.65) and mean highest SUV was 5.59 (SD 3.59), with a highest of 14.5 at T0. After one year of therapy, a signicant improvement in measured outcomes was noted. Dyspnea was absent in all subjects at T1 and only 1 (10%) reported cough at T1. The mean ACE was 42.17 U/L (SD 20.24), mean lysozyme was 6.24 µg/mL (SD 0.80), and mean CRP was 1.67 mg/dL (SD 1.60) at T1. Furthermore, ve (50%) subjects were receiving a reduced dose of their respective medication at T1. In terms of PET/CT ndings, the mean number of positive lesions decreased at T1 to 1.73 (SD 2.87) and the mean highest SUV decreased to 2.18 (SD 3.3). Conclusion: PET/CT scans can be used as a surrogate modality to help guide treatments in those subjects affected by sarcoidosis, as shown by signicant reductions in the involvement of multiple organs. Further studies with larger sample sizes are necessary to explore the potential PET/CT scans have to inuence treatment outcomes in sarcoidosis.

serum angiotensin-converting enzyme (ACE) level was 56.0 U/L (SD 43.08), mean lysozyme was 7.78 µg/mL (SD 3.78), and mean C-reactive protein (CRP) was 0.73 mg/dL (SD 0.85) at T0. Further, mean number of positive lesions was 4.27 (SD 2.65) and mean highest SUV was 5.59 (SD 3.59), with a highest of 14.5 at T0. After one year of therapy, a signi cant improvement in measured outcomes was noted.
Dyspnea was absent in all subjects at T1 and only 1 (10%) reported cough at T1. The mean ACE was 42.17 U/L (SD 20.24), mean lysozyme was 6.24 µg/mL (SD 0.80), and mean CRP was 1.67 mg/dL (SD 1.60) at T1. Furthermore, ve (50%) subjects were receiving a reduced dose of their respective medication at T1. In terms of PET/CT ndings, the mean number of positive lesions decreased at T1 to 1.73 (SD 2.87) and the mean highest SUV decreased to 2.18 (SD 3.3).
Conclusion: PET/CT scans can be used as a surrogate modality to help guide treatments in those subjects affected by sarcoidosis, as shown by signi cant reductions in the involvement of multiple organs. Further studies with larger sample sizes are necessary to explore the potential PET/CT scans have to in uence treatment outcomes in sarcoidosis.

Background
Sarcoidosis is a multi-organ disease of unknown etiology, characterized by the formation of nonnecrotizing epithelioid granulomas which can affect any organ, but has a predilection for lung involvement (1,2). Epidemiologically, sarcoidosis affects approximately 10 out of every 100,000 subjects per year in the United States, is present in all ethnic groups, and has a peak onset in adults between 20 and 40 years of age (3)(4)(5). Sarcoidosis has an unpredictable clinical presentation, ranging from incidentally discovered radiographic abnormalities in an asymptomatic patient to chronic progressive illness affecting multiple organ systems (6).
The initial evaluation of patients with suspected sarcoidosis involves a battery of tests, including blood cell counts, serum chemistry, urinalysis, and biomarkers (7,8). In those with pulmonary symptoms, pulmonary function tests (PFTs) and chest images are usually obtained. However, one of the di culties in treating this condition is that there is currently no single test to monitor the response to therapy or monitor disease activity.
Positron emission tomography (PET)/computed tomography (CT) scans are widely used in the assessment of subjects with suspected or con rmed malignancies. There are limited small series and case reports addressing the use of PET/CT scans with a glucose analogue of 18F-uorodeoxyglucose (18-FDG) for the assessment of in ammatory diseases (9)(10)(11). The advantage of PET/CT scans is that it visualizes FDG accumulation in activated in ammatory cells and provides whole-body images, allowing clinicians to assess the activity of sarcoidosis throughout the body. However, little is known regarding the role of PET/CT scans in the evaluation of the response to sarcoidosis treatment. The aim of this study was to understand whether PET/CT scans can be used to monitor disease outcomes and treatment responses.

Methods
This is a retrospective case series which included ten subjects with symptomatic pulmonary sarcoidosis that were followed by the University of Miami (UM) Sarcoidosis Program from 2015 to 2018. Subjects were ≥ 18 years and had histologically-con rmed pulmonary sarcoidosis for ≥ 2 years. Our sarcoidosis program has an active patient registry that has been approved by the Institutional Review Board (IRB) of the university and all participants have provided written consent. Subjects that had PET/CT scans completed prior to starting treatment and approximately one year later were enrolled. Patients who were unwilling to consent to the IRB-approved protocol were excluded. In addition, patients without evidence of pulmonary sarcoidosis, patients with a history of cancer, or patients who had PET/CT scans done > 1 year apart were excluded.
Demographics, symptoms, biomarkers, medications and imaging were recorded at baseline (T 0 ) and approximately one year after starting therapy (T 1 ). Positive pulmonary lesions were de ned as either involving the parenchyma, mediastinal lymph nodes, or both. The study outcomes were symptom resolution, radiological (PET/CT) improvement, and reduction in the total dose of medication.
After one year of therapy, a signi cant improvement in measured outcomes was noted. Dyspnea was absent in all subjects at T 1 compared to 6 (60%) at T 0 , 1 (10%) had cough at T 1 compared to 5 (50%) at T 0 , and the same number of subjects reported fatigue at T 1 as they did at T 0 . Furthermore, 5 (50%) subjects were receiving a reduced dose of their respective medication at T 1 . The mean ACE was 42.17 U/L (SD 20.24), mean lysozyme was 6.24 µg/mL (SD 0.80), and mean CRP was 1.67 mg/dL (SD 1.60) at T 1 . Regarding the PET/CT ndings, the mean number of positive lesions decreased to 1.73 (SD 2.87) and the mean highest SUV decreased to 2.18 (SD 3.3). Figure 1 shows a representative PET/CT scan imaging at baseline T 0 and after one-year T 1 . Given the small sample size of this case series, we cannot correlate biomarker activity or changes in pulmonary function with PET/CT scans.

Conclusions
The current study suggests PET/CT scans can be used as a surrogate modality to help guide treatments in those subjects affected by sarcoidosis, as shown by signi cant reductions in the involvement of multiple organs. Larger longitudinal studies are necessary to explore the potential of PET/CT scans to in uence sarcoidosis treatment protocols. The sarcoidosis program at the University of Miami has an active patient registry that has been approved by the Institutional Review Board (IRB) of the University of Miami (IRB: 20150612) and all participants have provided written consent.

Consent for Publication
Consent for publication has been obtained.

Availability of Data and Materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.  PET/CT scan imaging at baseline T0 (left) and after one year T1 (right). PET/CT imaging shows signi cant improvement after one year from the initial scan.