In this report we investigate the effectiveness of one dose of PCV7 among patients with inflammatory arthritis and ongoing anti-rheumatic treatments by assessing the number of registered putative pneumococcal infections up to ten years before and after vaccination, comparing event rates with non-vaccinated reference subjects. The main results were relative risk reductions of pneumonia as well as all serious pneumococcal infections of 53% and 46%, respectively, among all vaccinated arthritis patients.
The RA patients, who were 10 years older than the SpA patients and affected by the majority of events, showed a relative risk reduction of the two endpoints of 46% and 37% respectively. The relative risk reduction of pneumonia among SpA patients was 70%, however not statistically significant, probably due to a low number of events. The incidence of events among the vaccinated SpA patients was higher than their references before vaccination, but lower after vaccination resulting in the absolute risk reduction of all serious pneumococcal infections of 3%, and NNT of 34. Time to first event before vaccination was significantly shorter among the patients, however no significant difference was seen after vaccination. Treatment with rituximab and higher disease activity at vaccination were associated with contracting infection after vaccination, but after adjustment for age, these factors were no longer significant predictors, possibly due to lack of power. As expected, higher age predicted a significant increase in risk of infection, as well as the diagnosis RA, use and dose of Prednisolone, adjusted for age.
Several studies have evaluated the antibody levels before and shortly after different kinds of pneumococcal immunizations among arthritis patients, concluding that most bDMARDs including anti-TNF does not significantly hamper the antibody reaction, whereas MTX and RTX usually does. (7, 9) Previous studies have indicated preserved antibody levels following PPV up to 5-10 years, resulting in the recommendation of the polysaccharide revaccination strategy after about 5 years. (10–11) Broyde et al suggested that antibody levels are preserved up to ten years following PPV23 among RA, SpA and AS patients on bDMARD and MTX, questioning the need of revaccination. (12) In 2013, Kapetanovic et al reported a decline in serotype specific antibody back to pre-vaccination levels 1.5 years following immunization with PCV7 among arthritis patients on anti-TNF and MTX, (13) but more studies of long-term preservation of antibody levels following PCV are needed. Our clinical results indicating a long-term protective effect, suggest preserved antibody levels for several years after PCV.
PCV7 includes only seven of the thirty most pathogenic pneumococcal serotypes; 4, 6B, 9V, 14, 18C, 19F, and 23F. After the introduction of PCV7, several versions of the vaccine with a larger number of serotypes included have been developed: PCV 10, -13, and -15. Studies indicate however cross-reactivity after both PPV and PCV between vaccine serotypes and nonvaccine serotypes. (14–17) Although this phenomenon seems to decrease with age, (18) it could be suggested to be part of the protective effect of immunization seen in our study. While the live attenuated tuberculosis vaccine (BCG) has been shown to induce a non-specific cross-protection against other pathogens through so called trained innate immunity (19), this has not been shown in pneumococcal vaccines to this date. One could however argue that preventing one infection regardless of the pathogen, reduces the risk of contracting another. Even though this study was performed before the covid -19 pandemic, it could also be worth mentioning the significant inverse correlation shown between rates of pneumococcal vaccination and rates of SARS-CoV-2 infections and death. (20)
Our study is not without important limitations. The calculations of event rates based on ICD-codes from a diagnostic register have weaknesses. Apart from pneumococcal infections, the registered events could obviously be representing illness caused by alternative pathogens. However, this possibility of misclassification is estimated to be alike in both patients and reference subjects.
Before inclusion started in 2008, 6 different treatment groups were predefined in order to ensure the inclusion of arthritis patients with a variety of ongoing treatment (see methods). Previous studies have shown reduced antibody response among patients with ongoing methotrexate and rituximab (21), therefore we wanted to include patients with an expected benefit of an immunization. All patients meeting the inclusion criteria and concurrently fitting in to one of the treatment groups were consecutively offered to enter, when arriving for their regular follow-up at the Department of Rheumatology in Lund. However, RA patients in remission without DMARD, on only salazopyrine, hydroxychloroquine or glucocorticoids were not offered to be included, nor were patients not showing up to their doctor’s appointments due to low or absent disease activity. 75% of the included patients were on treatment with bDMARD at the time of vaccination, in comparison to on average 25% in Swedish RA patients at the time. (22–23) The reference subjects however, were included strictly on the matching criteria (age, sex, arthritis diagnosis) and were to be registered as living in Skåne county 3 years before and 3 years after index date, for the purpose of obtaining their events in the Skåne health care register, implying residual confounding (confounding by indication).
The study protocol did not enable review of the medical records of the reference subjects, limiting the comparisons possible on a treatment group level between vaccinated and non-vaccinated. The number of reference subjects receiving a polysaccharide pneumococcal vaccine (PPV) or a conjugated pneumococcal vaccine (PCV) of any kind during the course of the study is unknown. In 2011 the EULAR recommendations included pneumococcal vaccine in the guidelines (24) but based on previous assessments of pneumococcal vaccine coverage during this time and later, (25–27) and the results presented in this study, we would argue that it probably was a minor proportion.
Overall, we interpret the differences between the groups regarding burden of infectious disease before vaccination date and mortality rate after vaccination date despite the matching on arthritis diagnosis, age, sex and geographical area as a consequence of confounding by indication, including the reference subjects having to be alive at least 3 years after index date (immortal time bias).
Before vaccination, the incidences of events were higher, and the time to first event was shorter among the vaccinated patients compared to the references. The time to first event after vaccination did not differ between the groups on a statistically significant level but the estimates still suggested a tendency of 8-9 months shorter time for the vaccinated. The mortality rates were higher and time to death was shorter in the vaccinated group. Specific information of causes of death was not available to our group, but only a minor number of patients (n=8) and references (n=8) deceased within 30 days following a registered serious infection. The calculations are adjusted for a shorter time of follow-up among the vaccinated patients, due to this difference in mortality. Despite the mismatch however, the relative risk reduction of infection was significant among the vaccinated patients. The differences at baseline are clearly a weakness of the study but could be argued to strengthen the result and could possibly underestimate the vaccine efficacy.
In summary, our study showed significant relative risk reductions of both endpoints; pneumonia and all serious putative pneumococcal infections up to ten years after immunization in RA and SpA patients on different antirheumatic treatments despite a higher burden of disease at baseline among the vaccinated patients compared to non-vaccinated reference subjects with arthritis. Higher age, RA diagnosis, and use as well as higher dose of prednisolone were associated with increased risk of infection after vaccination, whereas treatment with methotrexate, rituximab or bDMARD were not.