Antibody response to the A/H1N1 and A/H3N2 strains in the TCZ and TCZ+MTX groups met all three requirements of the European Medicines Agency (EMA) guidance for assessment of influenza vaccines specified by the Committee for Proprietary Medical Products (CPMP).12
For the B/B1 strain, these treatment groups met two of the EMA/CPMP criteria. The MTX group fulfilled two of the EMA/CPMP criteria for all strains. Multivariate logistic analysis confirmed that TCZ use is not a predictive factor for inadequate antibody response for any influenza strain.
IL-6 works as a B cell differentiation factor, which induces activated B cells to produce immunoglobulin.10
The blockage of IL-6 activity following TCZ therapy, therefore, would be expected to reduce humoral immune response to influenza vaccination. Kopf et al13
indicated that T cell-dependent antibody response against virus infection is impaired in IL-6-deficient mice. Unlike anti-infliximab or antiadalimumab antibodies, anti-TCZ antibodies rarely developed in RA patients receiving 8 mg/kg of TCZ, even as monotherapy.14
Nevertheless, the present study has clearly indicated that RA patients receiving TCZ therapy can be effectively and safely immunised with influenza vaccine. One possible explanation may be that, unlike rituximab, TCZ is not a B cell-targeting antibody that can induce B cell depletion. Given that a variety of cytokines are released from activated helper T cells, antibody production may not depend simply on IL-6. Costelloe et al16
showed that IL-6 is not required for antigen (influenza virus)-specific antibody responses by non-fractionated tonsillar mononuclear cells or by T cell-depleted B cells in the presence of IL-2. Another explanation may be that IL-6 signalling is not inhibited completely in lymphoid tissue, locations in which vaccination-mediated immune response is initiated, even when maximum saturation of soluble IL-6 receptors in the circulation is achieved with TCZ. Uchiyama et al17
reported that anti-TCZ antibodies are induced in monkeys receiving 30 mg/kg of TCZ weekly, suggesting that IL-6 does not play a crucial role in antibody production.
Most previous studies have shown that the use of MTX is unlikely to affect antibody response to influenza vaccine.2–4
However, Gabay et al19
have indicated that MTX significantly reduced responsiveness to AS03-adjuvanted pandemic H1N1 2009 (A/H1N1/2009) vaccine in patients with rheumatic diseases. The mechanism by which MTX impairs antibody response following vaccination is unknown, but several studies have proposed that MTX prevents proliferation of T cells and induces apoptosis in these cells.20
In conclusion, despite TCZ therapy, the immunogenicity of influenza vaccination appears to be conserved and sufficient in RA patients. MTX had a negative impact on vaccination efficacy, but adequate immune responses for protection were achieved by RA patients in the MTX and MTX+TCZ groups. Neither severe adverse effects nor RA flares were observed following vaccination. RA patients, even those receiving TCZ as monotherapy or in a combination therapy with MTX, should therefore be encouraged to receive influenza vaccination.