224. Investigating adenosine deaminase 2 activity in ANCA and large vessel vasculitis
Creators: name: Porter1, Andrew
name: Maughan1, Robert
name: Pericleous1, Charis
name: Jingwen Xu1
name: Kiprianos1, Allan
name: Jee2, Hyuk
name: Prendecki1, Maria
name: McAdoo1, Stephen
name: Lee2, Pui
name: Youngstein1, Taryn
name: Mason1, Justin
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Deficiency of adenosine deaminase 2 (DADA2) manifests broadly, in some leading to vasculitis affecting small, medium, or large vessels with fever, rash, and stroke and in others immunodeficiency and haematological manifestations. In contrast, plasma ADA2 activity is elevated in inflammatory conditions including systemic lupus erythematosus and systemic juvenile idiopathic arthritis with macrophage activation syndrome. The role of ADA2 in the vasculitides is not yet understood. Using two well-characterised cohorts of large vessel and anti-neutrophil cytoplasmic antibody associated (ANCA) vasculitis, we sought to establish the potential role of ADA2 activity and deficiency. <strong>Methods: </strong>ADA2 activity was measured in adults with Takayasu arteritis (TA) (n=135), large vessel giant cell arteritis (LV-GCA) (n=44), ANCA vasculitis (n=116, 59 PR3+, 44 MPO+, 13 ANCA negative), intracranial vasculitis (ICV) (n=7) and healthy control (HC) (n=52) subjects, using a published coupled spectrophotometric assay. Plasma from 11 patients with genotyped DADA2 and 10 patients heterozygous for pathogenic variants in ADA2 defined thresholds for deficiency and carrier status respectively. Activity levels above the upper limit of normal (ULN) were defined as &gt;99<sup>th</sup> percentile of the HC activity. To assess potential associations with TA and ANCA disease status, ADA2 was measured prospectively in matched active and remission samples (TA n=29, ANCA n=15). TA disease activity was determined as active, grumbling or stable and ANCA as active or remission using clinical and radiological features, physician impression, CRP and Indian Takayasu clinical Activity Score (ITAS) for TA and using the Birmingham Vasculitis Activity Score (BVAS) for ANCA. Differences between groups were analysed using non-parametric tests, P&lt;0.05 was considered significant. <strong>Results:</strong> In 302 vasculitis patients tested, none were found to have ADA2 deficiency, while 9 subjects had activity within the carrier range (1 HC (1.9%), 5 TA (3.7%), 1 LV-GCA (2.3%), 2 ANCA (1.7%)). Compared to HC levels (median value 17.43 U/L [14.11 – 20.78]), activity in the TA and ANCA groups were significantly increased (TA 19.68 U/L [6.6 – 54.16], p=0.0113; ANCA 20.62 U/L [8.5 – 77.2], p=0.0002), while LV-GCA and ICV were not significantly different. In 50 cases, activity exceeded the upper limit of normal; 16 TA (11.9%, p=0.0068; 4 active, 2 grumbling, 10 stable), 30 ANCA (25.9%, p&lt;0.0001, 14 active, 16 remission) and 4 LV-GCA (9.1%, p=0.0409). There was no correlation between ADA2 activity and either disease activity score (ITAS and BVAS) or CRP in TA and ANCA patients. Subgroup analysis within the TA group revealed that ADA2 activity was most prominently elevated in the TA stable group relative to HCs (TA stable 20.54 U/L [8.08 - 48.66], median +17.8%, p= 0.0006), with no significant difference in active or grumbling TA. In ANCA, activity was elevated in both the active and remission groups (active 21.04 U/L [8.48 – 77.22], p= 0.0008, remission 19.88 U/L [12.12 – 47.82], p= 0.0021). Prospective analysis in the TA group demonstrated significant increase in ADA2 activity in remission vs active disease (p=0.024), with activity increasing in 18 (62%) patients achieving remission. No significant change was observed between matched active and remission ANCA samples. <strong>Conclusions</strong>: There were no cases of ADA2 deficiency in this cohort. Consistent with other inflammatory conditions, ADA2 activity was elevated in TA and ANCA patients. In TA, increased ADA2 activity was linked to stable disease in both cross-sectional and prospective analyses. In ANCA, ADA2 activity was elevated in both active and remission groups. Future work will aim to understand the mechanism and significance of elevated ADA2 enzymatic activity in vasculitis. <strong>Disclosures: </strong>None <strong>Figure 1</strong><strong>. </strong>ADA2 activity in groups Upper limit normal - &gt;99<sup>th</sup> percentile of HC activity; 30.3 U/L. Upper and lower carrier level (2.02 – 10.62 U/L) – determined from 10 patients heterozygous for pathogenic variants in ADA2 *p&lt;0.05 ** p&lt;0.001