Introduction
Infections cause substantial morbidity and mortality among patients with immune-mediated inflammatory disorders [
1,
2]. In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), pneumonia accounts for up to 25 % of fatalities [
3]. One risk factor for infection in these patients is the frequent use of immunosuppressive therapies. Prednisone has been associated with pneumonia [
4,
5], and cyclophosphamide, azathioprine and newer biologic agents such as tumor necrosis factor (TNF)-α blockers have been shown to confer an increased risk of infection [
6‐
9]. Another risk factor arises from immune defects associated with the inflammatory disorder itself [
1,
10].
Guidelines recommend the administration of pneumococcal vaccines to patients from receiving immunosuppressive treatment [
11‐
14]. However, only a minority of patients are vaccinated against
Streptococcus pneumoniae [
15,
16]. Several factors may account for this low rate of vaccination. First, there are doubts concerning the immunogenicity of vaccines in patients undergoing immunosuppressive therapy [
17,
18]. The suppression of lymphocyte proliferation and function might control the underlying condition but simultaneously lead to impaired antigen responses. Second, there is lack of proof regarding the efficacy of pneumococcal polysaccharide vaccine (PPV) in preventing invasive pneumococcal disease (IPD), pneumonia and mortality for patients with chronic illnesses [
19]. There are also concerns about the duration of vaccine response in these patients. Indeed, PPV is based solely on capsular polysaccharides, which behave as T-cell-independent antigens and induce a limited humoral response without generation of memory B cells. It has been shown that post-vaccine antibodies wane faster in patients under immunosuppressive therapies than in healthy individuals [
20,
21]. Last, there have been case reports of a causal relationship between pneumococcal vaccination and the clinical onset or flare-ups of immune-mediated inflammatory disorders, in particular in autoinflammatory conditions [
22]. However, several prospective studies have shown that patients may be immunized without exacerbation of the underlying inflammatory disease [
11,
23,
24]. There are limited data on the utility of pneumococcal vaccines in adult patients undergoing immunosuppressive therapy for immune-mediated inflammatory disorders. A retrospective study in patients with RA treated with methotrexate found a significantly lower incidence of pneumonia over the previous 10 years in patients having received PPV compared with those never vaccinated [
25].
We conducted a prospective, single-center, observational study to address the following issues: What is the proportion of seronegativity to S. pneumoniae in a population of patients with immune-mediated inflammatory disorders under immunosuppressive treatment not vaccinated with PPV in the previous 5 years? Are there factors associated with seronegativity to pneumococcal antigens? Does immunization with PPV induce disease flare-up? Does PPV elicit sufficient responses to pneumococcal antigens under immunosuppressive therapy? How do antibody levels to S. pneumoniae evolve over time in patients vaccinated and observed?
We also wanted to assess the rate of clinically relevant infection over the course of 1 year with respect to pneumococcal serology and examine whether other factors were associated with a higher risk of infection.
Methods
Patients
We conducted an observational study in an outpatient setting. Between November 2008 and October 2011, adult patients followed at the University Hospital of Geneva were screened to participate. Inclusion criteria were a minimum age of 18 years, a diagnosis of immune-mediated inflammatory disorder and ongoing treatment with high-dose systemic corticosteroids (≥20 mg/day for ≥1 month) and/or immunosuppressive drugs (classical immunosuppressive drugs and/or biologic immunomodulatory agents). Exclusion criteria were vaccination with PPV in the previous 5 years, previous treatment with intravenous immunoglobulins and pregnancy. None of the patients was exposed to previous conjugate pneumococcal vaccine, which was limited to pediatric patients at the time of the study. The study was approved by the local ethics review board of the University Hospitals Geneva (Commission cantonale d’éthique de la recherche), and all patients gave their written informed consent to participate. Inclusion started in the Division of Clinical Immunology as a pilot study and was then extended to the divisions of rheumatology and dermatology.
Assessment
Patients were assessed at baseline, 4–8 weeks after immunization and after 1 year. Clinical data included the nature of the underlying diseases, type and duration of immunomodulatory treatments, previous influenza and pneumococcal vaccination, disease activity and infections. Inflammatory disorders were categorized into five groups: (1) RA and spondylarthropathies, (2) psoriasis and psoriatic arthritis, (3) connective tissue diseases, (4) systemic vasculitis and (5) others. The last group included patients with rare inflammatory diseases that could not be classified into a larger group, such as bullous skin diseases and autoinflammatory syndromes. Information on previous vaccines was gathered by reviewing the certificate of vaccination or, if that was not available, by reviewing the clinical charts and by patient recall. Disease activity was assessed by using the Physician Global Assessment (PGA) score with a 4-point scale, ranging from 0 to 3 (0 = inactive disease, 1 = low disease activity, 2 = active disease and 3 = very active disease). PGA was scored at baseline, 4–8 weeks after immunization and at the end of follow-up. Infections were defined as infectious events needing medical attention, regardless of severity. This information was collected retrospectively at baseline and at the end of the study with a patient questionnaire (patients were asked about symptoms, diagnosis and medicines prescribed) by reviewing the electronic medical records and by contacting the primary care physician when needed. Safety aspects were based on assessment of disease activity 4–8 weeks after the immunization and oral questioning about systemic vaccine reactions. Changes in immunosuppressive treatment were assessed at the end of follow-up. Serum was sampled at each assessment.
Pneumococcal serology
Baseline serologies were performed in real time to allow decisions to be made regarding either vaccination or observation. Levels of specific immunoglobulin G (IgG) antibody against three pneumococcal serotypes (14, 19F and 23F) and three supplementary serotypes (1, 5, 7F or 9N, 11A and 17F) were determined by enzyme-linked immunosorbent assay (ELISA) according to the World Health Organization (WHO) consensus protocol [
26], which includes serum preadsorption with pneumococcal cell wall- and serotype 22F polysaccharides and uses 89-SF as a reference for antibody quantification. Supplementary serotypes 1, 5 and 7F were replaced in 2011 by 9N, 11A and 17F because the 13-valent conjugated vaccine had become available, although it was not used in this study. Patients with specific IgG levels ≥0.5 μg/ml to at least four of the six tested serotypes were empirically considered as having sufficient antibodies, as not requiring immunization and defined as “seropositive.” Positive vaccine response was defined by reaching seropositivity 4–8 weeks after PPV. Patients having received PPV off-protocol or treated with B-cell-depleting therapies within 6 months of the vaccine were not assessed for vaccine response.
Total serum immunoglobulins
Serum IgG, IgA and IgM were measured with an IMMAGE nephelometer (Beckman Coulter, Nyon, Switzerland) and specific anti-sera against heavy chains γ, α and μ, respectively. Normal values were established with sera of healthy blood donors.
Vaccination procedure
Seronegative patients were offered the 23-valent PPV (PNEUMOVAX 23; Merck, West Point, PA, USA), which was the sole pneumococcal vaccine licensed for adults at the time of the study. PPV contains 25 μg of pneumococcal capsular polysaccharides of 23 serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F) [
27]. The vaccine was given intramuscularly.
Objectives
The primary study objectives were to compare the proportion of seropositives at baseline and after 1 year in vaccinated and observed patients. The secondary objectives were the assessment of changes in disease activity before and after immunization and to compare the rate of infections in the respective groups.
Statistical analysis
Data were analyzed using the STATA statistical software package (version 13; StataCorp, College Station, TX, USA). Normally distributed data were described by means with standard deviations and skewed data by medians and interquartile ranges (IQRs). Non-parametric tests for significance (Wilcoxon rank-sum test for continuous data,
χ
2 test or Fisher’s exact test for categorical data) were conducted where appropriate. As IgG titers for individual serotypes relied on several real-time assessments and had censored values in the lower and upper ranges, we used reverse cumulative distribution curves [
28] and the paired Prentice–Wilcoxon test [
29]. Determinants for serological response at baseline were assessed with logistic regression analysis and for individual serotypes using a lognormal model. Predictors of vaccine response and infections were assessed using univariate log-binomial regression models. A
p-value less than 0.05 was considered statistically significant in all analyses.
Discussion
Pneumococcal vaccines are infrequently administered to patients with immune-mediated inflammatory disorders, despite an associated increased risk of pneumonia and IPD. This is likely due to concerns about vaccine safety and efficacy. Recommendations regarding pneumococcal vaccination rely on weak evidence, and there are doubts about the efficacy of polysaccharide vaccines in adults undergoing immunosuppressive treatment. In this prospective study, we recruited 201 adults with immune-mediated inflammatory disorders undergoing immunosuppressive treatment, to whom no pneumococcal vaccine had been administered in the previous 5 years. Most if not all of these patients had never been immunized against S. pneumoniae. Less than 60 % of patients had received influenza vaccines, despite these vaccines’ being actively promoted in this risk group, confirming the low compliance with vaccine guidelines.
We found that 70 % of patients had antibodies to the six
S. pneumoniae serotypes assessed. Seronegative patients had more active disease and accordingly were more often treated with systemic corticosteroids. They also had lower total serum IgG levels. Patients with systemic vasculitis were more often seronegative, in contrast to those with psoriasis. This finding is probably due to predominant use of corticosteroids and cytotoxic drugs in vasculitis patients, compared with patients with psoriasis and arthritis, who were frequently treated with TNF-α-blocking agents alone. Others have assessed prevaccination antibody levels to
S. pneumoniae in patients with RA and SLE without noticing significant differences according to disease or immunosuppressive treatment [
30,
31]. We also found significantly lower prevaccination antibody titers to serotypes 19 and 23F in patients older than 65 years of age. Other studies have addressed serological responses in the elderly, which has led to recommendations to give persons over 65 years of age PPV [
12,
13].
PPV was well tolerated, with no reports of systemic reaction. Only a few patients had an increase in disease activity after vaccination. Other prospective studies, including our previous work on a similar population, have shown that vaccines does not usually trigger disease flares in patients with chronic inflammatory diseases [
11,
23,
24,
32,
33].
Serological responses assessed shortly after PPV were good, with 87 % of the vaccinated patients reaching seropositive thresholds. Non-responders had higher corticosteroid doses. Others have linked diverse immunosuppressants to reduced vaccine response. Elkayam et al. showed that in patients with RA and SLE treated with various disease-modifying antirheumatic drugs, up to one-third of patients vaccinated with PPV had an insufficient response: 14 (33.3 %) of 43 patients with RA and 5 (20.8 %) of 24 patients with SLE responded to 0 or 1 of 7 vaccine serotypes assessed [
30]. In particular, combination treatment with methotrexate and TNF-α-blocking agents resulted in poor vaccine responses [
23,
31,
34‐
36], whereas this was not seen in patients treated solely with TNF-α-blocking agents [
24,
31,
34,
37,
38]. In our patients, methotrexate was not associated with poor response to PPV, nor were there other predictors of short-term vaccine response besides corticosteroids, which is possibly due to the small number of immunized patients in our sample. In healthy individuals, antibody levels toward PPV serotypes remain high for at least 5 to 10 years postvaccination [
39]. A small study on 19 patients with SLE showed a decrease in antibody levels below the protective level in 42 % of patients 3 years after PPV [
20]. A more rapid decline was shown in patients with RA undergoing immunosuppressive treatment [
21]. In our study, 90 % of the initially seropositive patients maintained specific antibody titers over the course of 1 year without vaccination. In contrast, those patients initially seronegative and who responded to PPV had a significant decrease in antibody titers over the next year. This rapid loss of serological response was also associated with corticosteroids.
There were no differences in the rate of clinical infections in patients vaccinated and observed during follow-up. No pneumococcal infection was documented. Overall, infectious events were, however, associated with seronegativity. This suggests that pneumococcal serology is a marker of the degree of immunosuppression in our population, with those treated with high-dose corticosteroids having lower titers of pneumococcal IgG. Sustained corticotherapy was also associated with an increased rate of infection, as shown by others [
5,
25]. This poses a clinical dilemma. On the one hand, although PPV seems safe in patients with active disease, concomitant treatment with corticosteroids may hamper vaccine response. On the other hand, these patients are also at greatest risk for infections. With the serological results shown, one would be tempted to postpone PPV until corticosteroids have been lowered. However, those who stayed seropositive 1 year after PPV tended to have fewer respiratory infections than seronegative patients (
p = 0.07). Thus, some of these patients may benefit from PPV in the short term through a reduction of non-invasive pneumococcal infections. Conjugated pneumococcal vaccines are currently being studied in adults with immunosuppression and may increase the likelihood of sustained serological response.
One of the greatest difficulties in the evaluation of vaccine response is to determine whether serum antibody titers correlate with clinical protection. Functional antibodies measured by opsonophagocytosis may be more relevant for protection against pneumococcal infections than antibodies assessed by ELISA. Limited resources did not allow us to include either this assay or the analysis of antibodies to more than six serotypes. Another possible limitation of the present study is our definition of serological response. The WHO considers levels of IgG antibodies to individual pneumococcal serotypes of 0.35 μg/ml or greater as protective against IPD [
40]. However, serotype-specific antibody levels correlating with protection differ for each serotype and each clinical endpoint, as well as in various populations. Healthy individuals are expected to respond to at least half of the evaluated serotypes following vaccination [
37]. We therefore chose to define seropositivity and vaccine response as a specific IgG level greater than or equal to 0.5 μg/ml to at least four of the six tested serotypes, being aware that these are empirical criteria. The absence of documented pneumococcal infections may be seen as another limitation of the study, but the expected incidence of pneumococcal disease in this population was low, particularly over the observation period of 1 year. In addition, pneumococcal infections can be somewhat difficult to prove, as cultures or urinary pneumococcal antigen testing are not always performed.
The strength of our study lies in the combination of serologies and clinical assessment, in particular regarding disease activity, immunosuppressive treatment and infectious complications. Patients were prospectively followed, and only a few were lost to follow-up by the end of the study. We did not randomize patients at inclusion to receive PPV, which would have been unethical. Only seronegative patients received the vaccine, which we thought would be those most in need of protection. The heterogeneity in immune-mediated inflammatory disorders and treatments may be seen as a limitation, but it reflects a real-life setting.
Acknowledgments
The authors thank all the patients, investigators and support staff who participated in the study; Christoph Combescure, Division of Clinical Epidemiology, Department of Health and Community Medicine, for his critical input on data analysis; Danielle Gascon and Chantal Pahud, study nurses; Stéphanie Lopes, Rui Ribeiro and Dany Minetto, graduate students, and Ilias Lazarou, Division of Rheumatology, for their help in patient recruitment and clinical assessment; and Pascale Roux-Lombard, Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, for nephelometric studies. This study was supported by internal research grants from the University Hospitals Geneva (Department of Internal Medicine, Department of Laboratory and Genetics and Research & Development Grant).
Competing interests
CAS has received research support, unrelated to this work, from Sanofi Pasteur. The other authors declare that they have no competing interests.
Authors’ contributions
LF recruited and assessed study subjects and drafted the manuscript. PFG participated in the recruitment and assessment of study subjects and statistical analysis and revised the manuscript. AP performed the statistical analysis and helped to revise the manuscript. CAS participated in the design of the study, carried out the immunoassays and revised the manuscript. EL participated in the design of the study and helped revise the manuscript. CG and EL participated in the recruitment and assessment of study subjects and helped revise the manuscript. JDS participated in the design of the study, contributed to the recruitment of study subjects and helped revise the manuscript. CR conceived the study, participated in its design and statistical analysis and drafted the manuscript. All authors read and approved the final manuscript.