Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis receiving baricitinib: results from a long-term extension trial substudy

Abstract

Background: Clinical guidelines recommend pneumococcal and tetanus vaccinations in patients with rheumatoid arthritis (RA). Baricitinib is an oral, selective Janus kinase (JAK) 1/JAK 2 inhibitor and is approved for the treatment of moderately to severely active RA in adults in over 50 countries including European countries, the USA, and Japan. This substudy evaluated pneumococcal conjugate and tetanus toxoid vaccine (TTV) responses in patients with RA receiving baricitinib. These vaccines elucidate predominantly T cell-dependent humoral antibody response.

Methods: Eligible RA patients receiving baricitinib 2 mg or 4 mg with or without concomitant methotrexate (MTX) were enrolled in a phase 3 long-term extension trial (RA-BEYOND; ClinicalTrials.gov, NCT01885078) in USA/Puerto Rico. Patients were vaccinated with 13-serotype pneumococcal conjugate vaccine (PCV-13) and TTV. Primary endpoints were the proportion of patients achieving a satisfactory humoral response for PCV-13 (≥ 2-fold increase in anti-pneumococcal antibody concentrations in ≥ 6 serotypes) and TTV (≥ 4-fold increase in anti-tetanus concentrations) at 5 weeks post-vaccination. Secondary endpoints included humoral responses at 12 weeks and functional responses of serotypes 4, 6B, 14, and 23F (twofold and fourfold increases in opsonic indexes at 5 and 12 weeks).

Results: Of 106 patients with a mean duration of RA of approximately 12 years, 80% were female, 30% were taking corticosteroids, and 89% (N = 94) were taking baricitinib plus MTX; most patients (97% PCV-13/96% TTV) completed the evaluations. Overall, 68% (95% CI 58.4, 76.2) of patients achieved a satisfactory response to PCV-13, 43% (34.0, 52.8) achieved a ≥ 4-fold increase in anti-tetanus concentrations, and 74% (64.2, 81.1) achieved a ≥ 2-fold increase. PCV-13 response was similar for patients taking corticosteroids (71%; 53.4, 83.9) vs those not (67%; 55.2, 76.5). The percentage of sera with a ≥ 2-fold increase in post-vaccination opsonic indexes at week 5 ranged from 47% (serotype 14) to 76% (serotype 6B). Through 12 weeks post-vaccination, seven patients (6.6%) reported injection-site events. There were no deaths during the substudy, and three patients experienced a serious adverse event.

Conclusions: Approximately two thirds of patients on long-term baricitinib achieved satisfactory humoral and functional responses to PCV-13 vaccination, while TTV responses were less robust. PCV-13 response was not diminished in those taking concomitant corticosteroids.

Trial registration: ClinicalTrials.gov, NCT01885078 . Registered on 24 June 2013.

Keywords: DMARDs (biologics); Janus kinase inhibitors; Rheumatoid arthritis; Vaccination.

Conflict of interest statement

Ethics approval and consent to participate

The study was designed by the sponsor, Eli Lilly and Company, an academic advisory board that included non-Lilly authors of this manuscript, and Incyte Corp. The study was conducted in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by Quorum Review IRB (#28020). Ethics approvals were obtained for all study sites, up to 405, in this on-going long-term extension study. All patients provided written informed consent for both the long-term extension study as well as the vaccine sub-study.

Consent for publication

Not applicable.

Competing interests

KLW is a consultant for AbbVie, Amgen, BMS, Eli Lilly and Company, Pfizer, and UCB and has received grants from BMS and Pfizer. COB is a consultant for Eli Lilly and Company. WJK, JB, MI, and CEK are employees and stockholders of Eli Lilly and Company. RK is an employee of IQVIA, with which Eli Lilly and Company contracts for statistical support.

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Figures

Fig. 1

RA-BEYOND vaccine substudy design. Primary assessment was satisfactory humoral response to PCV-13 and TTV. *Background conventional synthetic disease-modifying antirheumatic drugs allowed except cyclosporine, azathioprine or leflunomide. MTX = methotrexate; PCV-13 = 13-serotype pneumococcal conjugate vaccine; TTV = tetanus toxoid vaccine

Fig. 2

Satisfactory humoral responses at weeks 5 and 12. CI = confidence interval; IgG = immunoglobulin G; PCV-13 = 13-serotype pneumococcal conjugate vaccine; TTV = tetanus toxoid vaccine

Fig. 3

Concentrations for serotype-specific anti-pneumococcal (a) and anti-tetanus (b) IgG antibodies. All concentrations were significantly higher compared to baseline (p ≤ 0.001). CI = confidence interval; PCV-13 = 13-serotype pneumococcal conjugate vaccine; TTV = tetanus toxoid vaccine

Fig. 4

Pneumococcal serotype-specific geometric mean fold rise from baseline to week 5 and week 12. CI = confidence interval

Fig. 5

Percentage of patients with a ≥ 2-fold or ≥ 4-fold increase in opsonization index in four serotypes. CI = confidence interval