Background The cytokine Flt3 ligand is an important cofactor for early hematopoiesis by mainly driving the development of lymphoid and early B-cell precursors. In the periphery functions of Flt3 are more pleiotropic involving the differentiation of regulatory T-cells, dendritic cells as well as peripheral B-cells. Besides its well-known roles in hematological disorders and as an indicator of bone marrow (BM) output capacity, the possible involvement of FLT3 ligand in autoimmune disorders was only discovered recently.
Objectives Our primary aim was to analyze if FLT3 ligand serum concentrations are affected in AAV patients. Secondary aims were to correlate the FLT3 ligand serum concentrations with clinical and laboratory parameters. And, since FLT3 ligand concentrations are elevated in different states of bone marrow failure, we also wanted to evaluate FLT 3ligand as a marker for treatment related BM toxicity in AAV patients.
Methods We performed a cross sectional study using a sandwich ELISA to determine FLT3 ligand concentrations in the serum of 98 well characterized AAV patients (69 GPA, 20 MPA and 9 EGPA) and 144 healthy controls (HC). Statistical evaluation was done using Mann-Whitney or unpaired, two-tailed Student's t-test.
Results In patients with AAV, FLT3 ligand concentrations were significantly elevated (207 pg/ml +/- 116.2 in AAV versus 142.5 pg/ml +/- 65.98 in HC; p<0.0001). Disease specific analysis revealed significantly elevated FLT3 ligand concentrations in GPA (217.6 pg/ml +/- 123; p<0.0001), but no significant differences for MPA and EGPA when compared to HC. FLT3 ligand concentrations did not correlate to serological or clinical markers of disease activity, however, overall disease activity was low in the studied cohort. To assess the influences of treatment regimen on FLT3 ligand concentrations, we focused our analysis on treatment histories of cyclophosphamide (CYC) and azathioprine (AZA) and grouped the patient cohort according to the cumulative CYC dose (< or >5g) and/or duration of AZA therapy (< or >6 months). AZA and CYC naïve patients (n=10) showed FLT3 concentrations comparable to HC (121 pg/ml +/- 42.3), but in patients with low dose CYC and short term AZA therapy FLT3 concentrations were significantly higher (176.6 pg/ml +/- 51.6), both compared to treatment naïve patients and HC (p=0.0095 vs. AZA/CYC naïve, p=0.0105 vs HC). Intensified treatment was associated with even further increased concentrations of FLT 3 ligand with highest concentrations found in patients treated with >5g CYC cumulative dose or AZA treatment for >6 months (263.4 pg/ml +/- 172.6; p=0.0024 vs. AZA/CYC naïve, p<0.0001 vs HC).
Conclusions Flt3 ligand concentrations are elevated in patients with AAV, especially in patients with GPA. The elevation more likely reflects the therapeutic regimen and history than disease activity as we could show that patients with more intensive treatment including both CYC and AZA show higher FLT3 ligand serum levels when compared to patients with less intense therapy.
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Disclosure of Interest None declared