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

Patients with rheumatoid arthritis (RA) have an increased risk for a variety of infections due to diminished immune responses from their disease, associated comorbid conditions, and the immunosuppressive therapies used to treat RA [1‐3]. Both RA management guidelines and recommendations from the Advisory Committee on Immunization Practices suggest vaccinating patients with RA against pneumococcal disease [4] with 13-serotype pneumococcal conjugate vaccine (PCV-13) and 23-serotype pneumococcal polysaccharide vaccine (PPSV-23) [5, 6]. There are no specific recommendations for tetanus toxoid vaccine (TTV) in patients with RA, but the CDC recommends that adults should receive a booster of tetanus and diphtheria every 10 years after the first dose of tetanus, diphtheria, and pertussis as a child or adult [5].

Baricitinib is an oral, selective inhibitor of Janus kinase (JAK)1 and JAK2 [7]. JAKs mediate signal transduction for a variety of cytokines [8], including those involved in T cell activation and proliferation, and inhibition of such pathways could theoretically diminish vaccine responses. Baricitinib is approved for the treatment of moderately to severely active RA in adults in over 50 countries including European countries, the USA, and Japan [9‐12]. Given the mechanism of action of baricitinib, this study was conducted to evaluate the immunogenicity of the largely T cell-dependent vaccines PCV-13 and TTV in RA patients receiving treatment with baricitinib [13, 14].

A total of 106 patients enrolled in the vaccine substudy. Patients had been in the parent LTE trial for up to 4 years at the time of vaccination. Most patients were female and white with a mean age of 55.1 years and mean duration of RA of 12.1 years; patients had good control of disease activity as measured by validated composite indexes including the SDAI (Table 1).

Most patients (96.2%) completed both the 5- and 12-week visits. No patients discontinued participation due to adverse events. At week 5, 103 (97.2%) and 102 (96.2%) patients were evaluable for PCV-13 and TTV, respectively.

In this substudy of an ongoing phase 3 LTE in patients with RA, we evaluated the effect of baricitinib on vaccine responses to PCV-13 and TTV. At 5 weeks post-vaccination, we observed approximately two thirds of patients to have satisfactory humoral responses to PCV-13, while responses to TTV were somewhat less robust. Lower vaccine responses in RA populations are generally expected, depending on RA disease control, as compared to the healthy adults [31]. Responses to PCV-13 were maintained through week 12, while we observed some diminishment in humoral responses to TTV over this time period. Importantly, we found little or no negative effects of corticosteroid use on PCV-13 titer rise or functional antibody responses. Further, we identified a subset of individuals that lacked satisfactory IgG response, but in whom a satisfactory functional response was observed. This suggests that some patients identified as having poor PCV-13 vaccine responses still generate functional responses that are likely protective. There are few studies evaluating immune responses to PCV-13 within the inflammatory disease setting. Conversely, a number of studies have been performed evaluating responses to PPSV-23 in the context of biologic therapy. Our findings are similar to those reported for pneumococcal vaccine in the context of biologics, as well as TTV [13, 22, 23, 32]. First, for PCV-13, there is only one other study evaluating responses in those using JAK inhibitors, although it is a study of patients with psoriasis. The majority of patients in this study mounted an adequate response to PCV-13, with > 80% patients achieving measurable titers for each of the 13 serotypes and 60% mounting a > 4-fold response to TTV [24]. While a number of factors would likely explain the greater immunogenicity seen in this study (e.g., patients were younger, had a different underlying disease, and there was very little or no concomitant csDMARD or corticosteroid use), both this study and ours observed reasonably high proportions of patients mounting satisfactory responses to conjugate vaccines while receiving JAK inhibitors. For PPSV-23, a number of studies have been conducted among RA patients. With anti-TNF therapy, for example, the majority of patients mount satisfactory responses and such therapy seems to interfere little with the immunogenicity of the vaccine. In one study with RA patients using etanercept, there was an overall 2.6-fold increase in IgG antibody levels 4 weeks after vaccination. Other studies have examined RA patients using tofacitinib, where PPSV-23 responses ranged from 45 to 89% [22] and tocilizumab+MTX where PPSV-23 responses were 60% [23]. Published literature has shown that MTX can further decrease antibody response following vaccination with 7-serotype pneumococcal conjugate vaccine (PCV-7) [25, 26] or PCV-13 [27] when administered with background rituximab, abatacept, or tocilizumab; concomitant MTX when administered with tofacitinib can decrease antibody response to pneumococcal vaccine (PPSV-23) and to a lesser extent, influenza vaccine [22]. In addition, among RA patients taking rituximab and tocilizumab, TTV responses were 39% and 42% respectively, similar to that observed in our study [13, 23].

Functional responses to pneumococcal vaccine have received little prior study among RA patients. One such study evaluated RA patients taking abatacept and found a positive OI response for serotype 6B in some patients who did not have optimum IgG responses [18]. These findings were similar to our study in which we assessed four serotypes and also found that some baricitinib-treated patients mounted OI responses when an IgG response was not present. These results demonstrate that satisfactory functional pneumococcal antibody response could be attained even in some patients who lack an adequate IgG titer response and suggest the importance of measuring functional antibody responses in vaccine studies, particularly in the setting of immunosuppression where antibody titer responses could be less robust.

There were several limitations to this study. Because it was an LTE subpopulation and the sample size for the baricitinib 2-mg dose was too small for analysis, there was no control group for evaluation. Also, in our study, we were limited in evaluating the effect of MTX on vaccine response, due to the small size of the non-MTX group. Small sample size also hampered some of the other planned subgroup analyses. Additionally, current guidelines recommend administration of PPSV-23 following vaccination with PCV-13 for optimal vaccine response [5, 17] which was not within the scope of this substudy.

In this sample of patients from the USA and Puerto Rico, administration of pneumococcal and tetanus vaccines during long-term treatment with baricitinib was well tolerated. Satisfactory pneumococcal humoral responses were demonstrated with both baricitinib 2 mg and 4 mg and were not affected by concomitant low-dose corticosteroid usage while TTV responses were less robust. Additionally, sustained functional response of the pneumococcal antibodies was demonstrated at week 5 and week 12.