Another Beneficial Effect of Rituximab on Refractory <scp>ANCA</scp>‐Associated Vasculitis: The Role of Interleukin‐17 Suppression?

We read with great interest the recent contribution by Pullerits et al. 1. They reported on the beneficial effects of rituximab treatment in patients with cyclophosphamide-resistant antineutrophil cytoplasmic antibodies (ANCA)-positive vasculitis and speculated that rituximab might decrease the ANCA production by eliminating the precursors of potential ANCA-producing plasma cells and inhibit the role of B lymphocytes such as antigen presentation, cytokine production and costimulatory signalling of T cells. However, we would like to add another possible mechanism of the beneficial effect of rituximab on ANCA-associated vasculitis. Recently, there have been some reports showing that cellular immunity appears to play a major role as well in addition to humoral immunity, particularly via interleukin (IL)-17-producing T cells, in the pathogenesis of ANCA-associated vasculitis 2-5. Hoshino et al. reported that the activated neutrophils produce IL-17A and IL-23 in response to myeloperoxidase (MPO) ANCA via their Fc-region and classical complement pathway, which initiates the first steps of chronic autoimmunity by changing the local environment to develop Th17-mediated autoimmunity 3. Gan et al. showed that immunized mice with MPO resulted in systemic IL-17A production with MPO-specific dermal delayed-type hypersensitivity 4. In their study, wild-type mice developed necrotizing glomerulonephritis with an influx of glomerular leucocytes and albuminuria, but mice deficient in the IL-17A were nearly completely protected 4. Nogueira also demonstrated that serum IL-17A and IL-23 levels were significantly elevated in acute stage of ANCA-associated vasculitis patients compared with healthy controls (P < 0.01 and P < 0.001, respectively), and conventional immunosuppressive therapies could not always effectively suppress IL-23 or IL-17 production 5. Recently, van de Veerdonk et al. reported that rituximab inhibited the Th17 response in humans and demonstrated that rituximab reduced the local Th17 response in rheumatoid arthritis patients, resulting in a decrease in inflammation and better clinical outcome 6. They described that the effect of rituximab was interestingly Th17 specific, because rituximab had no effects on tumour necrosis factor-α, Th1 cell or regulatory T (Treg) cell response 6. They also speculated that the effects of rituximab might be due to B cell depletion, because inhibition of the Th17 response by rituximab was lost in the absence of B cells 6. Therefore, we speculate that the beneficial effect of rituximab on ANCA-associated vasculitis might be due to suppression of IL-17, which could be involved in the development of the disease, in addition to depletion of ANCA-producing plasma cells. However, further studies are necessary to evaluate serial changes in IL-17 after rituximab treatment in ANCA-associated vasculitis and the precise role of IL-17 in the pathogenesis of ANCA-associated vasculitis in the future.