Elsevier

Vaccine

Volume 26, Issues 27–28, 25 June 2008, Pages 3528-3533
Vaccine

Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine

https://doi.org/10.1016/j.vaccine.2008.04.028Get rights and content

Abstract

Introduction

The efficacy of the immune response upon vaccination in patients treated with anti-tumor necrosis factor-alpha (anti-TNF) with or without methotrexate is the subject of debate. We studied the effect of immunosuppressive treatment, including anti-TNF and methotrexate, on the response to pneumococcal polysaccharide (PPS) vaccine.

Methods

Fifty-two patients treated with immunosuppressives including anti-TNF (anti-TNF group), 41 patients given a similar immunosuppressive regimen without anti-TNF (no anti-TNF group), and 18 healthy controls were vaccinated with a 23 valent PPS vaccine. The percentage of patients treated with methotrexate in the anti-TNF and no anti-TNF group was 65% and 76%, respectively. Antibodies against four of the vaccine antigens (PPS 6B, 9V, 19F and 23F) were measured before and 4 weeks after vaccination. The primary outcome was the response rate, defined as the percentage with a postvaccination titer 0.35 μg/ml in combination with at least a twofold increase in antibody titer. The protection rate was defined as a postvaccination titer ≥0.35 μg/ml.

Results

The use of methotrexate was the strongest predictor of impaired vaccination outcome. Anti-TNF caused an additional immunosuppressive effect in the presence of methotrexate, leading to the lowest response percentages in patients using the combination of these two drugs. The underlying disease, other immunosuppressives such as prednisone or type of anti-TNF agent used did not influence vaccination outcome.

Conclusions

Patients who were treated with the combination of methotrexate and anti-TNF demonstrated a significantly impaired immune response following pneumococcal polysaccharide vaccination as compared to patients treated with either methotrexate or anti-TNF only or immunosuppressives excluding these two compounds.

Introduction

Anti-tumor necrosis factor-alpha (anti-TNF) treatment is effective in the treatment of autoimmune disorders like rheumatoid arthritis (RA), ankylosing sponylarthropathy, psoriasis and Crohn's disease [1], [2]. A growing number of patients are treated with one of the three compounds currently registered for clinical usage: infliximab (Remicade™), a chimeric monoclonal antibody against TNF; etanercept (Enbrel™), a soluble TNF receptor; adalimumab (Humira™), a humanized monoclonal anti-TNF antibody [3], [4], [5], [6]. Although highly beneficial in the treatment of these autoimmune diseases, blocking the effects of TNF also leads to a specific defect in the cell-mediated host immunity, most notably leading to severe infections with intracellular micro-organisms, such as tuberculosis [7], [8], [9], [10]. The three available compounds differ in the rate at which complications, such as tuberculosis, occur underlining subtle immunological differences in their mode of action [11]. Common respiratory tract infections occur two to four times more frequent among patients treated with anti-TNF and severe bacterial infections, including invasive pneumococcal disease, have been reported during anti-TNF treatment [12], [13], [14]. Guidelines indicate that vaccination with the pneumococcal polysaccharide (PPS) vaccine should be considered in rheumatic or inflammatory bowel disease (IBD) patients treated with immunosuppressive medication, including anti-TNF [15], [16], [17], [18]. The use of immunosuppressives however can reduce the response upon vaccination. We reported earlier that anti-TNF has a modest, but significant, negative impact on the response to the T-cell-dependent influenza vaccine [19]. Other studies reported no significant negative impact of treatment with anti-TNF on the response upon the pneumococcal polysaccharide vaccine while some have identified methotrexate as an inhibitor of this response [20], [21], [22], [23], [24], [25].

The aim of the present study is to establish the influence of anti-TNF either alone or in combination with methotrexate on the antibody response upon vaccination with the 23 valent pneumococcal polysaccharide vaccine (PPS23).

Section snippets

Subjects

Patients, 18 years of age or older, treated with anti-TNF at the Leiden University Medical Center, The Netherlands, were invited to participate in this open-label study, when visiting either the rheumatology or gastro-enterology outpatient clinic. Pregnancy and an active infectious disease were the only exclusion criteria. From approximately 1000 patients with Crohn's disease and 2000 patients with rheumatoid arthritis who visit these outpatient clinics a small proportion (<7%, n = 207) was

Baseline characteristics

Ninety-three patients (70% female, mean age 49 years, range 18–83) and 18 healthy controls (78% female, mean age 47 years, range 21–75) were evaluated (Table 1). Of these 93 patients 80% had a rheumatologic disease (mostly chronic RA) and 20% had inflammatory bowel disease (mostly chronic Crohn's disease) as underlying disease. All patients were treated with immunosuppressive drugs such as methotrexate, prednisone or azathioprine; 52 of them (56%) were currently treated with anti-TNF, or had

Discussion

The main finding of the present study is the synergistic immunosuppressive effect of combined methotrexate and anti-TNF use on the antibody response upon pneumococcal polysaccharide vaccination. In patients receiving both drugs response rates were low (<30% for PPS 9V and 23F), and even almost absent (3%) for both PPS 6B and 19F. This effect was similar with all three currently available anti-TNF agents. Response rates in patients not using the combination of anti-TNF and methotrexate (either

Acknowledgments

We thank Corine Prins, Sandra Numan and Annemiek Versluis, research nurses, LUMC, for their contributions to the collection of materials. J.M. de Jonge-Bok, rheumatologist, Groene Hartziekenhuis, Gouda and M.L. Westedt, rheumatologist, Bronovo ziekenhuis, The Hague, both contributed to patient recruitment. We thank Ronald Brand, medical statistician, LUMC, for his comments on our analysis.

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