Background/Purpose: Sarcoidosis is an inflammatory granulomatous disease of unknown etiology that can affect multiple organ systems. There is currently no standardized approach for measuring sarcoidosis disease activity. Serum tests lack sensitivity, specificity, and correlation with disease activity. Serial MRI, CT, and PET imaging can be used, but these modalities are constrained by cost and radiation exposure for the latter two. Adenosine deaminase 2 (ADA2) is expressed by and secreted from activated monocytes and macrophages into plasma. ADA2 activity correlates with disease activity in macrophage-activated diseases such as macrophage activation syndrome and tuberculosis, but ADA2 activity in sarcoidosis is less well-characterized. Given that monocyte/macrophage activation plays an important role in sarcoidosis pathogenesis, we hypothesize that ADA2 may serve as a biomarker of disease activity, burden of disease, and treatment response.

Methods: Patients with sarcoidosis were consented for study under IRB Pro00109933. Plasma samples were collected at enrollment, and disease activity was determined by chart review. Plasma ADA2 activity was measured in the presence of the ADA1 inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) by two independent assays of the inosine and ammonia products using high-performance liquid chromatography (HPLC) and spectrophotometry, respectively. Results of the two assays strongly correlated as measured by the Spearman correlation coefficient (R=0.98, p< 0.0001). Median ADA2 HPLC activity was compared across groups of patients using the Kruskal-Wallis test. For patients with serial ADA2 measurements, ADA2 HPLC activity following TNF inhibitor (TNFi) use was trended.

Results: Sixty-one patients with sarcoidosis were studied. There was a statistically significant difference in ADA2 activity between healthy controls, sarcoidosis patients without disease flare, and sarcoidosis patients with disease flare (Figure 1). There was a statistically significant difference in ADA2 activity across groups of patients with sarcoidosis based on the number of organs involved (Figure 2). Patients with liver, skin, and extrapulmonary lymph node involvement had statistically significantly higher ADA2 activity compared to those without (p=0.0006, p=0.0001, p=0.03, respectively), while patients with cardiac involvement had statistically significantly lower ADA2 compared to those without (p=0.02). Patients with serial ADA2 measurements had decreased ADA2 activity following TNFi treatment (Figure 3) that did not reach statistical significance due to small sample size.

Conclusion: Plasma ADA2 activity is elevated in patients with sarcoidosis, with differences in ADA2 observed based on the number and type of affected organs. There is a possible association between ADA2 activity and treatment response, but a larger sample size is needed to confirm these findings. These results suggest that ADA2 could serve as a plasma-based biomarker for sarcoidosis disease activity.

Figure 1. There was a statistically significant difference in plasma ADA2 activity between healthy controls (12.0 mU/mL (IQR 9.0-15.2), n=27), sarcoidosis patients without disease flare (17.5 mU/mL (IQR 13.3-24.4), n=29), and sarcoidosis patients with disease flare (17.8 mU/mL (IQR 12.2-30.7), n=32, p=0.001).

Figure 2. Plasma ADA2 activity was significantly different across groups of patients with sarcoidosis based on the number of organs involved (p=0.01). Median ADA2 activity by number of organs involved: 1 (16.1 mU/mL (IQR 11.2-23.3), n=8), 2 (15.7 mU/mL (IQR 12.5-21.1), n=31), 3 (18.1 mU/mL (IQR 14.7-27.3), n=10), 4+ (26.5 mU/mL (IQR 22.4-39.5), n=12).

Figure 3. Plasma ADA2 activity in patients with sarcoidosis decreased following TNF inhibitor treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/plasma-adenosine-deaminase-2-as-a-potential-disease-activity-biomarker-for-sarcoidosis/