Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: results of a randomised controlled trial (VISARA)

Abstract

Objective: To evaluate the effect of tocilizumab (TCZ), an interleukin 6 receptor inhibitor, on humoral immune responses to immunisations in patients with rheumatoid arthritis (RA).

Methods: Patients with RA with inadequate response/intolerance to one or more anti-tumour necrosis factor-α agents were randomly assigned (2:1) to TCZ 8 mg/kg intravenously every 4 weeks plus methotrexate (MTX) or MTX alone up until week 8. Serum was collected before vaccination at week 3, antibody titres were evaluated at week 8, and then all patients received TCZ+MTX through week 20. End points included proportion of patients responding to ≥6/12 pneumococcal polysaccharide vaccine (PPV23) serotypes (primary) and proportions responding to tetanus toxoid vaccine (TTV; secondary) at week 8.

Results: 91 patients were randomised. At week 8, 60.0% of TCZ+MTX and 70.8% of MTX patients responded to ≥6/12 PPV23 serotypes, with insufficient evidence for any difference in treatments (10.8% (95% CI -33.7 to 12.0)), and 42.0% and 39.1%, respectively, responded to TTV. Two of three TCZ+MTX patients with non-protective baseline TTV antibody titres achieved protective levels by week 8. The safety profile of TCZ was consistent with previous reports.

Conclusions: Short-term TCZ treatment does not significantly attenuate humoral responses to PPV23 or TTV. To maximise vaccine response, patients should be up to date with immunisations before starting TCZ treatment.

Clinicaltrialsgov identifier: NCT01163747.

Keywords: Methotrexate; Rheumatoid Arthritis; Vaccination.

Figure 1

Study flow for patients included in intention-to-treat (ITT) analysis. MTX, methotrexate; PnP, pneumococcal polysaccharide vaccine; PP, per-protocol; SF, safety follow-up; TCZ, tocilizumab; TT, tetanus toxoid. *Before randomisation, did not discontinue etanercept for ≥2 weeks; infliximab, adalimumab, certolizumab or golimumab for ≥8 weeks; or anakinra for ≥1 week.

Figure 2

(A) Proportions of patients responding to pneumococcal serotype combinations from ≥1 to ≥12. Tocilizumab 8 mg/kg+methotrexate (tocilizumab (TCZ)+methotrexate (MTX); n=54) versus methotrexate (MTX; n=27). In this secondary end point analysis, the results show that, overall, a greater proportion of MTX-treated patients responded to serotype combinations. Error bars represent the 95% CIs, which indicate a notable degree of variation. (B) Proportions of patients responding to individual pneumococcal antigen serotypes. TCZ+MTX (n=54) versus MTX (n=27). In this secondary end point analysis, the results show that the proportion of responders to serotypes 3, 4, 7f, 12f, 14 and 23f was comparable (<10% difference) between that of the TCZ+MTX and MTX treatment groups, whereas the proportion of responders to serotypes 1, 6b, 8, 9n, 18c and 19f was lower in the TCZ+MTX treatment group than in the MTX treatment group (>10% difference). For serotypes 9n and 12f: MTX, n=23; for serotype 14: MTX, n=21; for serotypes 1, 3, 7f, 8 and 12f: TCZ+MTX, n=49.