The 23-valent pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis: a double-blinded, randomized, placebo-controlled trial

The effectiveness of PPSV23 in preventing pneumococcal pneumonia remains controversial, especially in high-risk individuals [14]. Although several studies have demonstrated the effectiveness of PPSV23 [15], few studies have focused on patients with autoimmune diseases. To our knowledge, this is the first RCT to evaluate this concern in patients with RA. We demonstrated previously that PPSV23 vaccination induced the serotype-specific IgG and functional opsonization index responses were not impaired even in RA patients receiving immunosuppressive treatments [11]. However, we were unable to show that PPSV23 was effective in the prevention of pneumonia overall or pneumococcal pneumonia. This might be because of lack of power and shortened follow-up periods. The fundamental difficulty in obtaining a definitive pathological cause of pneumonia may also be related to these negative data. Definitive pneumococcal pneumonia (positive blood or sputum culture) is the most specific outcome to evaluate vaccine effectiveness; however, it has a low sensitivity. Therefore, we used the BinaxNOW® S. pneumoniae Antigen Card test for diagnosis [16]. However, 13 of 34 pneumonia cases did not receive this urinary antigen test and only a fraction of pneumonia cases caused by S. pneumoniae were included in our analysis. A Cochrane review also failed to show any protective efficacy of PPSV23 in patients with chronic pulmonary diseases [17]. Further high-quality trials with sufficient sample size would be useful to confirm our findings. Pneumococcal conjugate vaccines offer an alternative approach to prevent pneumococcal disease. The seven-valent pneumococcal conjugate has been shown to protect HIV-infected adults from recurrent pneumococcal infection [18]. The effectiveness of PPSV23 preventing pneumococcal infections among patients with chronic pulmonary diseases is unclear [19]. However, the efficacy and cost-effectiveness of PPSV23 in preventing IPD among the general population had been demonstrated [20]. Based on the new guidelines, the sequential administration of conjugate and polysaccharide pneumococcal vaccines has recently been the most appropriate approach for the prevention of pneumonia in the general population [21]. Our study confirmed that polysaccharide vaccine alone is not effective for prevention of pneumonia. Therefore, sequential administration of PCV13 and PPSV23 could also be an appropriate approach for the prevention for pneumonia in RA patients receiving immunosuppresssive treatments.

Pneumonia is the most common type of infection in RA [22]. Previous studies demonstrated increased frequencies of pneumonia with higher mortality in RA patients [23]. Our data showed that the incidence of pneumonia was 2.14 per 100 person-years in RA patients with a relatively high risk for infections. Glucocorticoid use was also shown to increase the risk of serious infections in a dose-dependent manner in RA patients [24]. The magnitude of the risk of infection associated with prednisolone dose??10 mg/day was similar to that associated with TNF-? antagonists [25]. However, neither glucocorticoid dosage nor bDMARD use was demonstrated to be a predictor of pneumonia risk in our study. Of note, we found no evidence for increased rates of pneumonia associated with bDMARD use. However, our data are inconsistent with a recent meta-analysis of RCTs of RA patients who received bDMARDs [26]. Nevertheless, the included patients and analytical methods in previous studies differed significantly from those in this study. Additionally, the relatively lower corticosteroid dosage prescribed to our RA patients may have influenced the association between glucocorticoid dosage and the occurrence of pneumonia.

As reported for RA patients, older age and pulmonary disease were found to be independently associated with bacterial infection. Among variables, preexisting interstitial pneumonia and older age were demonstrated to be associated with the risk of pneumonia [27]. Among the extra-articular manifestations of RA, there has been renewed interest in pulmonary complications directly associated with RA, which manifest as a variety of clinical signs such as pleural disease, pulmonary nodules, interstitial lung disease (ILD), and airway disease [28]. A large observational cohort study in Japan showed that the presence of ILD is one of the factors associated with increased mortality in RA patients [29]. Our data are consistent with these previous studies. Although the pathophysiologic mechanism for this finding has not been elucidated, decreased ciliary and respiratory epithelial function seen in patients with interstitial pneumonia may contribute to the higher frequency of pneumonia [30].

There are several limitations associated with this study. First, the forced discontinuation of follow-up is unusual and the disconfirmation rates were high. Thus, potential bias introduced by the discontinuation group (?65 years of age) should be considered. Second, our sample size was limited. For sample size calculation, we assumed, from previously published data on RA patients under biologic treatment [31], a rate of pneumonia of 2.5/100 patient-years. Based on these assumptions, we primarily calculated that we needed 714 patients receiving PPSV23 and 714 patients receiving placebo to confirm 50% reduction of pneumonia occurrence during 2 years of follow-up at an ? error of 0.10 and a ? error of 0.80. However, we could not reserve sufficient sample size, and the possibility of an underpowered study cannot be denied. Third, our RA population consisted of groups at high risk for infections, and thus our results may not be generalizable to other RA populations. Fourth, we cannot rule out the imprecision of our complete data due to unreliability in the diagnosis of pneumonia.

The strengths of our study include examination of an RA patient cohort using data captured from the largest NHO data center. Laboratory results and physician notes are available in this data resource and allow for examination of potential risk factors that are not typically available when using only administrative claims data. Our study represents the most comprehensive, hospital-based study with the outcomes in all enrolled patients followed completely. The participants in this study, in contrast to those in many clinical trials, were similar demographically to general RA patients. Our data can therefore provide a great deal of useful information about generalizability.