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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

Objective

To assess the current literature on the impact of rheumatoid arthritis (RA) treatments on the humoral response to pneumococcal and influenza vaccines.

Methods

We systematically searched the literature for studies evaluating the immune response to vaccines in RA patients receiving methotrexate (MTX) and/or biologic agents. The efficacy of vaccination, assessed by the response rate based on increased antibody titers before and 3–6 weeks after vaccination, was extracted by one investigator and verified by another.

Results

In total, 12 studies were included. RA patients mainly received MTX, anti–tumor necrosis factor α (anti-TNFα), or rituximab (RTX). Influenza vaccination response was reduced for RTX (43 patients; pooled odds ratio [OR] 0.44 [95% confidence interval (95% CI) 0.17–1.12] for H1N1, OR 0.11 [95% CI 0.04–0.31] for H3N2, and OR 0.29 [95% CI 0.10–0.81] for B) but not for anti-TNFα (308 patients; OR 0.93 [95% CI 0.36–2.37] for H1N1, OR 0.79 [95% CI 0.34–1.83] for H3N2, and OR 0.79 [95% CI 0.37–1.70] for B). For MTX, results differed depending on the method of analysis (222 patients; OR 0.35 [95% CI 0.18–0.66] for at least 2 strains, ORs were close to 1.0 in the single strain analysis). Pneumococcal vaccination response was reduced for 139 patients receiving MTX compared with controls (OR 0.33 [95% CI 0.20–0.54] for serotype 6B and OR 0.58 [95% CI 0.36–0.94] for 23F) but not for anti-TNFα (258 patients; OR 0.96 [95% CI 0.57–1.59] for 6B and OR 1.20 [95% CI 0.57–2.54] for 23F). For RTX, the response was reduced (88 patients; OR 0.25 [95% CI 0.11–0.58] for 6B and OR 0.21 [95% CI 0.04–1.05] for 23F).

Conclusion

MTX decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination. The immune response to both vaccines is reduced with RTX but not with anti-TNFα therapy in RA patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

Patients with rheumatoid arthritis (RA) are at increased risk of infection, as compared with healthy individuals, so preventive measures such as vaccination are essential ([1]). This increased risk is due to the disease itself and due to immunosuppressive therapies. Recommendations for the management of RA include vaccination, particularly against pneumococcal disease and influenza ([2]).

Seasonal influenza vaccines are trivalent vaccines containing particles of 3 inactivated influenza virus strains: 2 A strains (H1N1 and H3N2) and 1 B strain. The 2 kinds of pneumococcal vaccines commonly used are the 23-valent pneumococcal polysaccharide vaccine (PPV23) and the pneumococcal conjugate vaccine (PCV), which can contain 7 (PCV7) or 13 (PCV13) pneumococcal serotypes. PPV does not induce immunologic memory and revaccination after 5 years is recommended, while PCV, based on the conjugation of polysaccharides to a protein carrier, induces a T cell–dependent immune response that leads to immunologic memory and boosting on repeated injections and therefore a better long-term immune response ([3]).

On December 30, 2011, the US Food and Drug Administration approved 13-valent PCV for preventing pneumonia and invasive disease among adults ages ≥50 years ([4]). The Advisory Committee on Immunization Practices recommends that adults ages ≥19 years with immunocompromising conditions receive a dose of PCV13 followed by a dose of PPV23 at least 8 weeks later ([5]). Despite these recommendations, vaccination coverage in RA patients is surprisingly low (25–30%), mainly because of a lack of awareness by health care professionals and a distrust in the safety and efficacy of vaccines ([6, 7]). Concerns about safety are not justified. Pneumococcal and influenza vaccines are inactivated vaccines; there is therefore no risk of viral reactivation after vaccination in RA patients. Moreover, several studies have shown no direct or causal relationship between these vaccinations and worsening disease ([8-10]).

The efficacy of vaccines in RA patients is uncertain; the impact of drugs commonly used in RA, such as methotrexate (MTX), tumor necrosis factor α (TNFα) blockers, and rituximab (RTX), on humoral response must be established. We performed a systematic review of the literature and a meta-analysis to achieve a better understanding of the effect of different RA drugs on the immune response to influenza and pneumococcal vaccines.

Box 1. Significance & Innovations

  • To our knowledge, this is the first meta-analysis comparing the response rate to pneumococcal and influenza vaccines specifically for rheumatoid arthritis patients by their ongoing treatment.
  • Rituximab and probably methotrexate have a negative impact on immune response to pneumococcal and influenza vaccination.
  • Humoral response to influenza and pneumococcal vaccines is not affected by anti–tumor necrosis factor α.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

Literature search

We systematically reviewed articles for studies of human subjects published in English or French up to March 2013 in Medline (via PubMed), EMBase, Cochrane Library, and databases for the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) annual meetings. The keywords were “influenza vaccines,” “pneumococcal vaccines,” and “rheumatoid arthritis,” with no limit on the date of publication.

Study selection

The population of interest was RA patients regardless of treatment, activity, and duration of the disease or age. The efficacy of a vaccine had to be compared with that for a control group of RA patients not receiving the treatment of interest. The criteria for the inclusion and exclusion of studies, established in advance of the search, are shown in Supplementary Table 1 (available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract). In addition, the reference lists of articles initially detected were manually searched to identify additional relevant articles. The trials were initially selected on the basis of their titles and abstracts, then on their full text; duplicates were removed.

Data extraction and quality assessment

Two investigators (CH and JM) collected the data using a predetermined form. Data were collected on the study design, sample size, treatments received, patient characteristics (age, sex, disease duration, MTX and biologic agent dose, and prednisone use and dose), control group definition, vaccination type, definition of the outcome measures, timing and unit of measurements, and statistical analyses performed. Disagreements were resolved by consensus. Observational studies and randomized controlled trials, but not case reports, were eligible. Study quality was evaluated according to a score composed of 5 items established in advance and based on the Newcastle-Ottawa Scale ([11]) (see Supplementary Table 2, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract).

Data synthesis and analysis

For practical reasons, immune response is often considered a substitute for efficacy of a vaccine. Several variables are predictors of immune response to a vaccine, including seroprotection, seroconversion, humoral response, and evaluation of the quality of produced antibodies. The primary outcome was the rate of response to the vaccine because it was available in most of the studies. Moreover, the rate of response does not depend greatly on antibody titers at baseline and its definition was the same in almost all studies. The response rate was based on the antibody response ratio (ARR), defined as the ratio of post- to prevaccination antibody levels. In all studies, serum samples were first collected immediately before vaccination and again after 3–6 weeks. This period corresponds to the peak of IgG vaccine antibody following vaccination, before the decrease of specific antibody levels ([12]). Moreover, international recommendations advocate this period for antibody doses in order to evaluate vaccine efficacy in nonclinical studies ([13, 14]). In the meta-analysis, as in most of the studies, positive response was defined as an ARR ≥2 for pneumococcal vaccines and an ARR ≥4 for influenza vaccines ([13, 15]). For the studies focusing on pneumococcal vaccines, the antibodies measured were not always against the same serotypes; however, for most studies, specific antibodies against serotypes 6B and 23F were measured. These 2 serotypes are frequently involved in invasive pneumococcal infections; thus, we pooled only results referring to pneumococcal serotypes 6B and 23F.

Pooled odds ratios (ORs) were calculated by meta-analysis, using the generic inverse variance approach. Estimates and their SEs could be entered directly; for ratio measures of intervention effect, the data should be entered as natural logarithms (e.g., as a log OR and SE of the log OR). ORs and 95% confidence intervals are shown by forest plots for each vaccine studied. The statistical heterogeneity of studies was assessed by the chi-square Cochran's Q test, with a significance level of 0.05, and the I2 statistic, with high values indicating high heterogeneity. All meta-analyses were carried out with use of a random-effects model, in case of significant heterogeneity. TheRevMan, version 5.1.6 was used for statistical analyses. A P value less than 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

Literature search results and study characteristics

Initially, 77 potentially relevant articles were screened; from them, 71 were excluded. Finally, after manually searching the reference lists and the ACR and EULAR annual meeting databases, 12 studies were included: 6 for influenza vaccination, 5 for pneumococcal vaccination, and 1 for both vaccines (the selection process is shown in Figure 1). Therefore, this systematic review included 1,303 patients. Concerning the immune response to influenza vaccine, the influence of MTX was evaluated in 222 RA patients, and the influence of anti-TNFα and RTX was evaluated in 308 and 43 RA patients, respectively. Concerning the immune response to pneumococcal vaccine, the influence of MTX was evaluated in 139 RA patients, and the influence of anti-TNFα and RTX was evaluated in 258 and 88 RA patients, respectively. The mean ± SD age of these patients was 56.9 ± 5.27 years and 809 patients (62%) were women. The characteristics of the studies are shown in Tables 1 and 2, and the patients' characteristics are shown in Supplementary Tables 3 and 4 (available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract). The methodologic quality was satisfactory for 5 studies and good for 7 studies (see Supplementary Table 2, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract).

image

Figure 1. Flow chart of studies in the meta-analysis. ACR = American College of Rheumatology; EULAR = European League Against Rheumatism.

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Table 1. Characteristics of studies on the effect of therapy for RA on humoral response with influenza vaccine*
Author, year (ref.)Group 1, experimental groupGroup 2, control groupRates of responders, %
Group 1Group 2
  1. RA = rheumatoid arthritis; MTX = methotrexate; anti-TNFα = anti–tumor necrosis factor α; U = unknown (some patients receiving the treatment, exact number not known); ETA = etanercept; IFX = infliximab; DMARDs = disease-modifying antirheumatic drugs; NR = none reported, only odds ratio given in the study; ADA = adalimumab; CZB = certolizumab; RTX = rituximab.

  2. a

    Values are H1N1/H3N2/B.

Studies conducted to evaluate the impact of MTX    
Fomin et al, 2006 ([16])N = 56: MTX (n = 56), anti-TNFα (n = U: ETA and IFX), other DMARDs (n = U)N = 26: anti-TNFα (n = U: ETA and IFX), other DMARDs (n = U)54/54/68a52/52/61a
Kapetanovic et al, 2007 ([17])N = 50: MTX (n = 50), anti-TNFα (n = 50: 37 IFX and 13 ETA), other DMARDs (n = 12)N = 62: anti-TNFα (n = 62: 27 IFX and 35 ETA), other DMARDs (n = 14)NRNR
Kaine et al, 2007 ([18])N = 59: MTX (n = 59), other DMARDs (n = U)N = 50: other DMARDs (n = U)≥2 strains: 56≥2 strains: 72
Kivitz et al, 2011 ([19])N = 57: MTX (n = 57), other DMARDs (NR)N = 27: other DMARDs (NR)3 strains: 513 strains: 85
Studies conducted to evaluate the impact of anti-TNFα    
Fomin et al, 2006 ([16])N = 22: anti-TNFα (n = 22: IFX), MTX (n = U), other DMARDs (n = U)N = 55: MTX (n = U), other DMARDs (n = U)56/55/77a44/42/65a
Kapetanovic et al, 2007 ([17])N = 50: anti-TNFα (n = 50: 37 IFX and 13 ETA), MTX (n = 50), other DMARDs (n = 12)N = 37: MTX (n = 37), other DMARDs (n = 10)NRNR
Kaine et al, 2007 ([18])N = 99: anti-TNFα (n = 99: ADA), MTX (n = 55), other DMARDs (n = 17)N = 109: MTX (n = 59), other DMARDs (n = 32)50/59/49a ≥2 strains: 7356/68/61a ≥2 strains: 74
Kivitz et al, 2011 ([19])N = 110: anti-TNFα (n = 110: CZB), MTX (n = 72)N = 114: MTX (n = 78)3 strains: 543 strains: 62
Kubota et al, 2007 ([20])N = 27: anti-TNFα (n = 27: 11 IFX and 16 ETA), MTX (n = 16), other DMARDs (n = U)N = 36: MTX (n = 25), other DMARDs (n = U)44/44/30a22/33/22a
Studies conducted to evaluate the impact of RTX    
Oren et al, 2008 ([21])N = 14: RTX (last infusion: <6 months n = 7, 6–18 months n = 7), MTX (n = 12), other DMARDs (n = 4)N = 29: MTX (n = 22), other DMARDs (n = 17)36/21/21a37/67/30a
Arad et al, 2011 ([22])N = 29: RTX (last infusion: <5 months n = 16, >5 months n = 13), MTX (n = 11), other DMARDs (n = U)N = 17: MTX (n = 9), other DMARDs (n = U)25/15/35a60/65/75a
Table 2. Characteristics of studies of effect of therapy for RA on humoral response with pneumococcal vaccine*
Author, year (ref.)Group 1, experimental groupGroup 2, control groupRate of responders, %a
Group 1Group 2
  1. RA = rheumatoid arthritis; MTX = methotrexate; anti-TNFα = anti–tumor necrosis factor α; IFX = infliximab; ETA = etanercept; DMARDs = disease-modifying antirheumatic drugs; U = unknown (some patients receiving the treatment, exact number not known); ADA = adalimumab; NR = none reported, only odds ratio given in the study; RTX = rituximab.

  2. a

    Values are 6B/23F.

  3. b

    23-valent pneumococcal polysaccharide vaccine study.

  4. c

    7-valent pneumococcal conjugate vaccine study.

Studies conducted to evaluate the impact of MTX    
Kapetanovic et al, 2006 ([23])bN = 50: MTX (n = 50), anti-TNFα (n = 50: 37 IFX and 13 ETA), other DMARDs (n = 12)N = 62: anti-TNFα (n = 62: 27 IFX and 35 ETA), other DMARDs (n = 14)47/5570/67
Kapetanovic et al, 2011 ([24])cN = 89: MTX (n = 89), anti-TNFα (n = 89), other DMARDs (n = U)N= 79: anti-TNFα (n = 79)20/4349/56
Studies conducted to evaluate the impact of anti-TNFα    
Kapetanovic et al, 2006 ([23])bN = 50: anti-TNFα (n = 50: 37 IFX and 13 ETA), MTX (n = 50), other DMARDs (n = 12)N = 37: MTX (n = 37), other DMARDs (n = 10)47/5543/24
Kapetanovic et al, 2011 ([24])cN = 89: anti-TNFα (n = 89), MTX (n = 89), other DMARDs (n = U)N = 85: MTX (n = 85), other DMARDs (n = U)20/4327/49
Kaine et al, 2007 ([18])bN = 99: anti-TNFα (n = 99: ADA), MTX (n = 55), other DMARDs (n = 17)N = 109: MTX (n = 59), other DMARDs (n = 32)NR/44NR/38
Visvanathan et al, 2007 ([25])bN = 20: anti-TNFα (n = 20: IFX), MTX (n = 20)N = 14: MTX (n = 14)30/1914/43
Studies conducted to evaluate the impact of RTX    
Bingham et al, 2010 ([26])bN = 63: RTX (last infusion: 28 weeks n = 63), MTX (n = 63)N = 28: MTX (n = 28)38/2161/36
Kapetanovic et al, 2011 ([27])cN = 25: RTX (n = 25), MTX (n = 10)N = 85: MTX (n = 85), other DMARDs (n = U)0/NR27/NR

Influenza vaccination

Patients receiving MTX

The first analysis involved 2 studies comparing the response rate to each influenza strain for the experimental group comprising RA patients receiving MTX and for the control group comprising RA patients treated without MTX ([16, 17]). The pooled OR for these 2 studies was not significant for any of the 3 strains (Figure 2). The second analysis involved 2 other studies comparing the response rate to at least 2 of the 3 influenza strains between RA patients receiving MTX and RA patients not receiving MTX ([18, 19]). The pooled OR for these studies was significant for a negative impact of MTX on the humoral response (Figure 3).

image

Figure 2. Forest plot for the odds ratios of response rate for influenza H1N1 (A), H3N2 (B), and B (C) strains between rheumatoid arthritis patients receiving methotrexate, rituximab, or anti–tumor necrosis factor α (anti-TNF) and controls. IV = instrumental variable; 95% CI = 95% confidence interval.

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image

Figure 3. Forest plot for the odds ratios of response rate for at least 2 strains between rheumatoid arthritis patients receiving methotrexate or anti–tumor necrosis factor α (anti-TNF) and controls. M-H = Mantel-Haenszel test; 95% CI = 95% confidence interval; IV = instrumental variable. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract.

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Patients receiving anti-TNFα.

We included 5 studies reporting on the immune response to influenza vaccine in an experimental group comprising RA patients receiving anti-TNFα and a control group of RA patients not receiving TNFα blockers. Of these studies, 4 gave a response rate for each of the 3 influenza strains ([16-18, 20]). The pooled OR showed no significant influence of TNFα blockers on the humoral response to the vaccine (Figure 2). Three studies gave a response rate to at least 2 strains ([17-19]). The immune response was affected, but not significantly, with anti-TNFα therapy (Figure 3).

Patients receiving RTX

Two studies assessed the humoral response to influenza vaccine with (experimental group) and without (control group) RTX treatment ([21, 22]). The response rate was reduced with RTX, but the pooled OR was not significant for the H1N1 strain (Figure 2).

Pneumococcal vaccination

Patients receiving MTX

In 2 studies by Kapetanovic et al ([23, 24]), MTX seemed to reduce the immune response of the experimental group as compared with the control group comprising patients not receiving MTX. This effect was confirmed by the meta-analysis: the pooled ORs were significant for both serotypes 6B and 23F (Figure 4).

image

Figure 4. Forest plot for the odds ratios of response rate for pneumococcal serotypes 6B (A) and 23F (B) between rheumatoid arthritis patients receiving methotrexate, rituximab, or anti–tumor necrosis factor α (anti-TNF) and controls. M-H = Mantel-Haenszel test; 95% CI = 95% confidence interval; A&R = Arthritis & Rheumatism article; ACR = American College of Rheumatology meeting abstract; IV = instrumental variable. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract.

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Patients receiving anti-TNFα.

Three studies investigated the influence of anti-TNFα on the humoral response to pneumococcal vaccination for serotype 6B ([23-25]), and another study also investigated serotype 23F ([18]). The specific results of the response rates between the experimental groups receiving anti-TNFα and the control groups not receiving TNFα blockers, as well as the pooled ORs, were not significant for both serotypes, which suggests a lack of effect of TNFα blockers on the humoral response (Figure 4).

Patients receiving RTX

For the 2 studies evaluating the response to pneumococcal vaccine in patients receiving B cell depletion therapy ([26, 27]), the response rate was reduced for both serotypes in the experimental group with RTX treatment as compared with the control group not receiving RTX, but the pooled OR did not reach significance for serotype 23F (Figure 4).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

Our systematic review and meta-analysis showed that MTX decreases the immune response to pneumococcal vaccination and may also impair the humoral response to influenza vaccination, although with influenza vaccination, the data were contradictory and did not allow us to make a conclusion. We did not demonstrate any effect of anti-TNFα therapy on immune response to both vaccines. Immune response to influenza and pneumococcal vaccines is reduced by RTX treatment in patients with RA.

Recent EULAR recommendations on vaccinations in adults with rheumatic diseases, based on a systematic literature review, showed similar conclusions ([2]). The novelty of our approach is that we pooled the patient series reported in the various studies on this topic and that we included more recent studies. Therefore, our meta-analysis gives added weight to the previous recommendation.

This meta-analysis has several limitations, notably due to the number of studies and patients being limited and rather heterogeneous. Concerning the impact of MTX on influenza vaccination, our meta-analysis data were inconclusive because we found discordant results depending on the method of analysis. Data from studies in the literature were also rather conflicting; in 2 studies that could not be included in our meta-analysis because of their design, Elkayam et al did not find any influence of MTX on humoral response to influenza vaccination ([8, 28]). However, findings of the detrimental effect of MTX were suggested in 4 studies of the vaccine against pandemic 2009 influenza A, indicating that MTX was a predictor of lower immune response ([28-31]). This negative impact of MTX was also suggested by the analysis of seroprotection rates against influenza at baseline (before vaccination). Indeed, influenza vaccination is seasonal, so seroprotection rates at baseline actually reflect the immune response to the vaccination the previous year and are a marker of long-term response. In 3 studies, seroprotection rates at baseline were compared between patients receiving MTX and healthy controls, and the meta-analysis of their results showed lower seroprotection induced by MTX ([17, 30, 32]) (see Supplementary Figure 1, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract).

Part of the heterogeneity of the meta-analysis about the impact of anti-TNFα therapy on the humoral response to influenza vaccination may be due to the study by Kapetanovic et al ([17]). Indeed, removal of this study reduced the heterogeneity (see Supplementary Figure 2, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22246/abstract). In the study by Kapetanovic et al, ORs for responders were calculated only for patients who did not achieve seroprotection at baseline, whereas in other studies, the response rate included patients who already had seroprotective levels of antibody titers at baseline. The heterogeneity may also be explained by the different anti-TNFα therapies used in the studies and disparities between the duration of administration. Another explanation for the heterogeneity may be that anti-TNFα was mainly associated with a synthetic disease-modifying antirheumatic drug and the proportion of patients receiving MTX differed between studies, which can alter the results because MTX may have an impact on humoral response. This treatment combination may also explain the trend toward an impaired immune response to influenza vaccination observed in anti–TNFα–treated patients that could actually be related to MTX therapy and not to TNFα blockers. Data from other studies in the literature confirmed our results and did not find any influence of anti-TNFα on humoral response to influenza vaccine. In their study, Kapetanovic et al found similar or better seroconversion rates after influenza vaccination in a group of 62 patients receiving anti-TNFα without MTX (50% for H1N1, 51.6% for H3N2, and 58.1% for B) than in 18 healthy controls (50% for H1N1, 44.4% for H3N2, and 5.6% for B) ([17]). Moreover, in 3 studies that could not be included in the meta-analysis because the population included a combination of several inflammatory diseases, anti-TNFα did not reduce vaccine responsiveness ([28, 29, 33]).

Significant heterogeneity was also found in the analysis of the response to pneumococcal serotype 23F in patients receiving anti-TNFα, possibly because of the same reasons of differences between the types of anti-TNFα used and disparities between the duration of administration. Last, there was significant heterogeneity for the analysis of the effect of RTX on the response to pneumococcal serotype 23F, which can be explained by the results of the Kapetanovic et al study being extracted from an abstract, and the information on the period of the last RTX infusion was not available and may be a factor of the heterogeneity ([27]).

Another limitation of our meta-analysis is that, in the studies included, either PPV or PCV was used, which could make the comparison of the results difficult. However, the main difference between the 2 vaccines concerns the long-term immune response, and so the humoral response at 1 month should not be affected too much. Moreover, another study by Kapetanovic et al comparing the antibody response to PPV23 and heptavalent PCV showed that both vaccines elicited a similar response in RA patients ([34]).

We did not find many studies of other biologic agents, so we could not perform a meta-analysis of these therapies. In an abstract from the 2012 ACR Annual Scientific Meeting and in a recent study by Ribeiro et al, abatacept (ABA) seemed to compromise the immune response to influenza vaccination in RA patients ([35, 36]). In an abstract from the 2007 ACR Annual Scientific Meeting, tocilizumab (TCZ) did not affect the antibody response to pneumococcal vaccination in patients with RA ([37]). Two abstracts from the 2012 ACR Annual Scientific Meeting and a recent Japanese study revealed a lack of an influence of TCZ on the immune response to influenza and pneumococcal vaccines in RA patients ([35, 38, 39]). Thus, immune response to vaccination is not influenced in the same way by biologic agents. Indeed, therapy with biologic agents targeting B cells (RTX) or T cells (ABA) seems to have a deleterious impact, whereas anticytokine therapies (anti-TNFα and TCZ) do not impair the humoral response to the vaccines.

Because MTX decreases the ability to respond to vaccination, whenever possible, RA patients should be vaccinated before starting MTX. However, if patients are already receiving MTX, this should not preclude vaccination because a large proportion of these patients will still have a response. Similarly, vaccination should occur sometime after RTX infusion. In the included studies concerning RTX, the delay between vaccination and infusion varied, and in the Bingham et al study, the immune response was decreased even with infusion up to 7 months earlier ([26]). In the study by Arad et al, the response rate was higher for RTX-treated patients vaccinated later (>5 months) after RTX administration than those vaccinated earlier after treatment ([22]). In contrast, the study by Oren et al found no correlation between humoral response and the time interval since receiving RTX ([21]). Concerning influenza vaccine, if the period of vaccination occurs at the same time as a course of RTX, then the decision to postpone the infusion for 2–3 weeks to vaccinate before RTX administration would depend on disease activity. Pneumococcal vaccination is not a seasonal vaccination and therefore should be programmed sometime after RTX administration. Concerning anti-TNFα, the delay between administration of treatment and vaccination was often not specified in the studies, but anti-TNFα drugs did not seem to affect the response to vaccination.

Moreover, the low response rates to pneumococcal and influenza vaccination in RA patients receiving MTX or RTX may imply substantial numbers of immunosuppressed individuals at risk of infection despite vaccination, which highlights the need for specific immunization strategies in this population. Injection of a second dose, 1 month after the first dose, of pandemic H1N1 influenza vaccine was found to be more efficient than an injection of a single dose in patients with rheumatic inflammatory diseases ([29]). However, additional studies assessing the need of second booster doses in RA patients receiving treatments responsible for an impaired immune response are needed. The prime-boost strategy (presentation of an antigen in 2 different forms) in immunocompromised patients was mostly evaluated for pneumococcal vaccination and consisted of injection of a PCV dose for better immune response, followed by a PPV dose to expand the serotypic coverage. In a study of patients with human immunodeficiency virus, the immune response was better for patients vaccinated according to this strategy than in those vaccinated with only a dose of PPV ([40]). Similar results were found in a population of elderly adults ([41]). Studies evaluating this prime-boost strategy in RA patients are needed.

In summary, our meta-analysis suggests that, unlike anti-TNFα, RTX and probably also MTX have an influence on vaccine response. However, even with these treatments, vaccination still provides protection in a number of cases and must be proposed to every RA patient, and the vaccination schedule should be adapted to the current or future treatment. Awareness of these results is useful to the clinician in order to propose vaccination strategies for RA patients according to their treatment.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Morel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Hua, Combe, Morel.

Acquisition of data. Hua, Morel.

Analysis and interpretation of data. Hua, Barnetche, Combe, Morel.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

This work was initiated during sessions on performing meta-analysis organized by Abbott. Abbott had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Abbott.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgments
  10. REFERENCES
  11. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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