Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

A population-based surveillance over 4 years after licensure of the 7-valent pneumococcal conjugate vaccine (Prevenar, PCV7) for children in the USA showed a significant decrease of invasive pneumococcal disease (IPD) among adults 50 years and older, but also an increase of IPD caused by serotypes not included in the vaccine [1]. A new pneumococcal conjugate vaccine containing 13 different pneumococcal capsular antigens 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F has recently been approved by the authorities in USA and Europe for primary and secondary immunization in children. The Centre for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices recently updated recommendations for pneumococcal vaccination, and these include immunization with a dose of 13-valent pneumococcal conjugate vaccine in adults with diseases requiring immunosuppressive treatments and long-term systemic corticosteroids [2].

Pneumococcal vaccination is strongly encouraged by the European League Against Rheumatism (EULAR) for patients with inflammatory rheumatic diseases [3]. Data on the benefit of pneumococcal conjugate vaccine in immunosuppressed patients with rheumatic disease are scarce. Our group has reported on antibody response following vaccination with PCV7 in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA) including ankylosing spondylitis and psoriatic arthritis treated with different anti-inflammatory remedies. Methotrexate (MTX), but not anti-TNF drugs, was associated with decreased antibody response [4].

Along with anti-TNF drugs newer treatment modalities have been available for treatment of RA in the last decade. These include a chimeric anti-CD20 monoclonal antibody rituximab, a selective T-cell co-stimulation modulator (abatacept) and a humanized anti-IL-6 receptor monoclonal antibody (tocilizumab). Studies on antibody response following pneumococcal vaccination in patients with established arthritis receiving these treatments are scarce.

The present work is an extension of a report on antibody response following pneumococcal vaccination using 7-valent conjugate vaccine in arthritis patients treated with TNF-inhibitors [4]. The objective of the study was to investigate the immunogenicity and tolerability of the 7-valent pneumococcal conjugate vaccine in patients with established RA treated with biologic remedies other than TNF-inhibitors.

RA patients regularly monitored at the Department of Rheumatology, Skåne University Hospital in Lund and Malmö, Sweden, were invited to participate in the study as previously described [4]. The Regional Ethic Review Board at Lund University approved the study (file number 97/2007). The study was conducted as an investigator-driven clinical trial, registered online at EudraCT EU 2007-006539-29 [5] and at NCT00828997, and approved by the Swedish Medical Products Agency (MPA; file number 151: 2007/88047). Informed written consent was obtained from all subjects before study entry. Initially, 505 patients with RA or spondylarthropathy participated in the study [4]. In the extended part of the study, RA patients receiving treatment with biologic remedies other than TNF antagonists were offered vaccination. Only RA patients being on the biologic drug for at least 4 weeks were eligible for the study. The vast majority of these patients had previously been treated with one or more anti-TNF remedies and the number of previously given biologic treatments was calculated. All patients received one dose (0.5 ml) of heptavalent pneumococcal conjugate vaccine (Prevenar) intramuscularly. Blood samples were drawn at vaccination and 4 to 6 weeks thereafter. Immunoglobulin (Ig)G antibodies specific for Streptococcus pneumoniae capsular polysaccharides 6B and 23F were measured using ELISA as previously described [6]. Briefly, ELISA plates were coated with the polysaccharides 23F or 6B. Dilutions of human sera absorbed with pneumococcal cell wall polysaccharide were then added to the ELISA plates. A reference serum was included on all plates. The serotype-specific antibodies for 23F and 6B were detected using alkaline phosphatase-conjugated goat anti-human IgG (-chain specific) F(ab’)2 fragments, followed by addition of the substrate p-nitrophenyl phosphate. The optical density at 405 nm was measured with an ELISA plate reader. The optical density of the colored end-product is proportional to the amount of specific antibodies present in the serum. The lower limit of detection was 0.02 mg/L for serotype 6B and 0.01 mg/L for 23F.

Geometric mean antibody levels (GML) prior to and after vaccination were calculated from log-transformed values and compared to previously reported GML of MTX-treated patients and controls (SpA patients on non-steroidal anti-inflmmatory drugs (NSAIDs)/analgesics). Antibody response (AR) was defined as the ratio between post- and prevaccination antibody levels and a positive AR (posAR) as at least two-fold increase in AR as described [4].

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 [8]. 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 [8]. 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 [9]. A randomized controlled study investigating AR following pneumococcal vaccination using 23-valent polysaccharide vaccine also showed impaired response in RA patients on rituximab [10].

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 [11]. 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 [9]. 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 [12]. 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 [12]. 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 [13].

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 [15].

IL-6 plays an important role in differentiation of B-cells into antibody producing plasma cells [16]. 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 [17]. 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 [19]. 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 [20]. 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.

In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with impaired antibody response following protein-polysaccharide antigen challenge, but the impact of rituximab was more substantial. The IL-6 receptor blockade did not hamper antibody response in these patients. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment. Pneumococcal vaccine administered during ongoing anti-IL-6 receptor treatment seems to be associated with sufficient immune response in patients with RA.