Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine
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.
References (41)
- et al.
Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial
Lancet
(2004) - et al.
The effect of tumor necrosis factor blockade on the response to pneumococcal vaccination in patients with rheumatoid arthritis and ankylosing spondylitis
Semin Arthritis Rheum
(2004) - et al.
Antibodies against pneumococcal polysaccharides after vaccination in HIV-infected individuals: 5-year follow-up of antibody concentrations
Vaccine
(1999) - et al.
Regulation of human B cell function by sulfasalazine and its metabolites
Int Immunopharmacol
(2002) Treatment of rheumatoid arthritis
BMJ
(2006)Inflammatory bowel disease
N Engl J Med
(2002)- et al.
Infliximab and methotrexate in the treatment of rheumatoid arthritis
N Engl J Med.
(2000) - et al.
The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment
Arthritis Rheum
(2006) - et al.
Updated consensus statement on biological agents, specifically tumour necrosis factor alpha (TNF alpha) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2005
Ann Rheum Dis
(2005) - et al.
Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent
N Engl J Med
(2001)
Infections in patients with rheumatoid arthritis treated with biologic agents
Arthritis Rheum
Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials
JAMA
Granulomatous infections due to tumor necrosis factor blockade: correction
Clin Infect Dis
Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept?
Clin Infect Dis
Severe pneumococcal pneumonia following treatment with infliximab for Crohn's disease
Inflamm Bowel Dis
Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of 709 patients
Rheumatology (Oxford)
Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy
Rheumatology (Oxford)
Guideline for anti-TNF-alpha therapy in psoriatic arthritis
Rheumatology
Guidelines for immunizations in patients with inflammatory bowel disease
Inflamm Bowel Dis
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