Background/Purpose:

Granulomatosis with polyangiitis (GPA) is a relapsing autoimmune disease affecting small- to medium-sized blood vessels. B cells are thought to play an important antibody-independent role in GPA patients. Immunosuppressants are used to induce remission at initial onset of disease, and subsequently used as maintenance treatment. Mycophenolate mofetil (MMF) was found to be effective for both induction and maintenance of remission in GPA; although, azathioprine (AZA) is superior as maintenance therapy compared to MMF. Little is known about the effect of these commonly used drugs on B cell cytokine production. We hypothesized that the differences in the efficacy of MMF and AZA could be the result of differential effects on B cell cytokine production. Therefore, we studied the effects of MMF and AZA on in vitro B cell cytokine production.

Methods:

We assessed the in vitro effect of the active compounds of MMF (MPA) and AZA (6-MP) on B cell cytokine production. PBMCs of twenty untreated GPA patients in remission and twenty age- and sex-matched healthy controls (HCs) were isolated. PBMCs were cultured with CpG and 3 uM MPA or 6-MP. After 3 days, PBMCs were restimulated with Ca-I and PMA for 5h in the presence of BFA, stained for intracellular IL-6 and IL-10 and measured by flow cytometry. In addition, to determine whether in vivo use of MMF or AZA influences in vitro B cell cytokine production, PBMCs from 14 patients in stable remission were cultured and stimulated as mentioned above. From each patient two samples were analyzed, one when patients were not treated and one when patients were receiving either MMF (n=4) or AZA (n=10). For comparison, PBMCs from 14 matched HCs were analyzed simultaneously.

Results:

MPA significantly decreased the frequency of IL-10+ and IL-6+ B cells in HCs and GPA patients, compared to CpG alone (p<0.001) and CpG+6-MP (p<0.001). PBMCs from GPA patients that were actively treated with MMF or AZA, tended to have a reduced IL-10+ B cell frequency compared to PBMCs from the same donors that did not receive treatment (p=0.1) or healthy controls (p=0.09). This reduction in IL-10+ B cells was only seen in MMF- and not in AZA-treated patients (p=0.09). In contrast, no effect of MMF or AZA was found on IL-6+ B cells (%).

Conclusion:

The decrease in in vitro B cell cytokine production in the presence of mycophenolic acid might explain why this agent is less effective as maintenance therapy in GPA. Further research is needed to elucidate whether this in vitro finding is clinically relevant.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/mycophenolic-acid-decreases-il-10-and-il-6-production-by-b-cells-of-granulomatosis-with-polyangiitis-patients-and-healthy-controls-in-vitro/