Here we report a study on AR following pneumococcal vaccination using pneumococcal conjugate vaccine in RA patients treated with biologic remedies other than TNF inhibitors.
In this cohort of patients with established RA, who were previously exposed to up to six other biologic drugs, ongoing treatment with abatacept and rituximab impaired the antibody response. The negative impact was most pronounced in rituximab-treated patients and additionally diminished when concomitant MTX was used. AR in patients on tocilizumab was as good as that of arthritis patients not receiving immunosuppressive drugs.
T-cell-dependent mechanisms are important for AR following immunization with protein antigen . Antigen-presenting cells, including B-cells, are required for presentation of protein antigens to naive T-cells which thereby stimulate secretion of different cytokines and activate B-cells to differentiate into antigen-specific Ig-producing plasma cells. A lack of mature B-cells results in a lower amount of plasma cells and as a consequence lower production of serotype-specific antibodies . As pneumococcal conjugate vaccine consists of capsular polysaccharides conjugated to a protein carrier, this could be one possible mechanism for reduced AR following B-cell depletion therapy using rituximab. Our results are in line with previously reported diminished IgG response following immunization with protein antigen (influenza vaccination) in RA patients on rituximab . A randomized controlled study investigating AR following pneumococcal vaccination using 23-valent polysaccharide vaccine also showed impaired response in RA patients on rituximab .
Our findings of modestly decreased levels of circulating IgG, IgM and IgA among rituximab treated patients are in line with those previously reported in RA patients after subsequent rituximab courses . Indeed, patients participating in this study had received at least two rituximab treatments at the time of vaccination and a substantial number was treated with subsequent courses every 6 months. Thus, low levels of serotype-specific antibodies already present before vaccination might be explained by universal depletion of B-memory cells. In contrast to results from van Assen et al. no significant correlation between timing of vaccination in relation to administration of rituximab was found in our study . Long-lasting depletion of the whole pool of B-memory cells and not only circulating B-cells caused by repeated rituximab treatments might explain the diverging results.
The abatacept-treated RA patients had decreased antibody response compared to controls and tocilizumab-treated patients with RA. Abatacept attenuates activation of naive T-cells by blocking the interaction between CD80/86 and CD28, a co-stimulation signal required for full T-cell activation. RA patients have many CD28-null T-cells. In addition, abatacept (CTLA-4Ig) also prevents CTLA-4 binding to its ligand . This may result in inhibition of T-cell proliferation and subsequently inadequate stimulation of B-cells. Diminished B-cell immunological response might be a consequence of inadequate stimulation needed for their differentiation into plasma cells. Results from our study are in accordance with another study investigating AR following pneumococcal vaccination after administration of abatacept to healthy adults, where a diminished AR in subjects immunized after administration of one dose of abatacept was reported . The negative impact of abatacept on AR was significantly less prominent compared to that of rituximab. Despite the limited number of abatacept-treated patients participating in the study our results suggest that the inhibition of the secondary co-stimulation signal does not appear to have a critical role in antibody production following conjugated polysaccharide-protein antigen challenge. On the other hand, AR after influenza vaccination in RA patients on abatacept was found to be severely impaired .
In contrast to the effects of rituximab and abatacept on AR, we previously reported that the response in arthritis patients on anti-TNF treatments was not significantly different from that in arthritis patients not receiving immunosuppressive drugs immunized with pneumococcal conjugate vaccine, or healthy individuals immunized with polysaccharide vaccine [4, 14]. These results are in line with earlier experimental data published by Cope et al. showing that anti-TNF treatment in RA did not impair, but enhanced T-cell responses to polypeptide antigen towards normal response .
IL-6 plays an important role in differentiation of B-cells into antibody producing plasma cells . Thus blockade of IL-6 would be expected to diminish antibody production. However, antibody response after influenza vaccination was not hampered in patients with RA treated with tocilizumab . Antibody response among patients treated with tocilizumab in our study, immunized after an average of 7 days following the last treatment course, was similar to controls (SpA patients not treated with immunosuppressive drugs). Along with results from Mori et al. our results suggest that IL-6 is not essential for antibody production after conjugated polysaccharide-protein challenge, which is consistent with previously reported experimental data [17, 18]. IL-6 may still have an impact on IgG production by influencing IgG subclasses differently, but this is not possible to assess from our results.
Ongoing rituximab treatment was identified as a predictor of insufficient AR. Patients with higher disease activity and longer disease duration had decreased response but no effect of age and sex was observed. The majority of patients enrolled in the present study were women and differences in age between treatment groups were rather small. Thus the impact of age and sex might be difficult to discern.
MTX was identified as a predictor of impaired positive AR in a multivariate logistic regression model, which is in accordance with our previous reports including arthritis patients treated by anti-TNF remedies [4, 14]. The number of patients treated with abatacept and tocilizumab was limited in the present study, precluding the separate analysis of effect of MTX on AR in these groups. Among rituximab-treated patients those receiving concomitant MTX had a lower antibody response, which also confirms our previous results [4, 14].
The AR is a surrogate marker of protection against infection. The correlation between certain antibody levels and protection has been reported for several vaccines, including pneumococcal vaccine . However, results from the present study do not exclude the possibility that rituximab- and abatacept-treated patients would mount the appropriate immune response when exposed to Streptococcus pneumoniae.
In addition, antibody response to two of seven serotypes included in the vaccine was studied. Serotypes 6B and 23F are shown to be associated with invasive pneumococcal disease in Sweden, which was the reason for choosing these serotypes . Although response to other serotypes may differ, we hypothesize that the effects of different biologic treatments would influence AR to other serotypes in a similar fashion.
The disadvantage of the present study is the small sample size in groups treated with abatacept and tocilizumab compared to RA patients on MTX, and controls. Further research including larger groups of patients on newer biologics given as monotherapy and in combination with conventional disease-modifying anti-rheumatic drugs is needed.