Objective To investigate the association between vaccinations in adults and the risk of developing rheumatoid arthritis (RA).
Methods Data from the Swedish population-based Epidemiological Investigation of RA case-control study encompassing 1998 incident cases of RA aged 18–70 years and 2252 randomly selected controls matched for age, sex and residency were analysed. Those vaccinated within 5 years before disease onset were compared with those not vaccinated by calculating OR with 95% CI.
Results Vaccinations neither increased the risk of RA overall (OR 1.0, 95% CI 0.9 to 1.1) nor the risk of two major subgroups of RA (antibodies to citrullinated peptide-positive (ACPA-positive) and ACPA-negative disease). Furthermore, vaccinations did not increase the risk of RA in smokers or carriers of HLA-DRB1 shared epitope alleles, two groups with established risk factors for RA.
Conclusions In this case-control study of incident cases of newly diagnosed RA, no increased risk of RA following immunisation was observed for vaccinations overall or for any specific vaccination. This indicates that immunological provocation of adults with commonly used vaccines in their present form carries no risk of RA. These findings should be implemented among public healthcare providers in order to encourage vaccinations according to recommended national vaccination schedules.
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Vaccinations are among the events frequently considered as inciting agents for rheumatoid arthritis (RA) as well as for other chronic inflammatory diseases.1,–,7 Many vaccination protocols make use of adjuvants—that is, substances which non-specifically activate the innate immune system and enhance the adaptive immune response against the immunogen in the vaccine.8,–,10 However, to our knowledge, no appropriately powered epidemiological studies have been published which address whether vaccinations commonly used in industrialised societies constitute risk factors for RA.
Against this background, we aimed to elucidate whether common vaccinations given to adults were associated with an increased risk of RA by using data from a large population-based casecontrol study on incident cases of RA. Specific vaccinations studied were flu, tetanus, diphtheria, tickborne encephalitis, hepatitis (A, B, C), polio and pneumococcus. In addition, we investigated whether vaccinations have a different impact on two subsets of RA characterised by the presence or absence of antibodies to citrullinated peptides (ACPA).11 Furthermore, since recent findings have shown a strong interaction between smoking and HLA-DRB1 SE alleles in providing a high risk of ACPA-positive RA, and as additional exposures such as vaccinations might interact with known genetic and environmental risk factors, we examined potential interactions between vaccinations and smoking and between vaccinations and HLADRB1 SE alleles with regard to the risk of ACPApositive RA.12,–,14
This study is based on the Epidemiological Investigation of RA (EIRA) and comprised a population aged 18–70 years living in parts of Sweden during 1996–2006.15 All cases were diagnosed by rheumatologists according to the American College of Rheumatology criteria of 1987 and controls were randomly selected from the study base with consideration taken of sex, age and residential area.16 In total, 2097 cases and 2770 controls were identified.
Information on environmental exposures was collected using an identical questionnaire given to the cases shortly after the diagnosis and sent by mail to the controls. Cases and controls were also asked to provide a blood sample. In all, 95% of the cases (n=1998) and 81% of the controls (n=2252) answered the questionnaire and 98% (n=1958) and 55% (n=1239) of participating cases and controls, respectively, donated blood.
The study subjects reported whether they had been vaccinated in the 5 years before completion of the questionnaire and, if so, which vaccine they had taken and in which year. For each case, the year when the first symptoms of RA occurred was defined as the index year and the same index year was used for the corresponding control. Only data on vaccinations before the index year were analysed since only vaccinations received before symptom onset are aetiologically relevant. The individuals were accordingly classified as exposed to any vaccine and to specific vaccines (flu, tetanus, diphtheria, tickborne encephalitis, hepatitis (A, B, C together), polio, pneumococcus) if they had been vaccinated sometime between 1 January (5 years before questionnaire completion) and 31 December (the year before the index year).
Genotyping and antibody assays
Blood samples were genotyped for shared epitope (SE) alleles, defined as DRB1*01, DRB1*04 and DRB1*10 in the HLA-DRB1 gene, by using sequence-specific primer PCR (DR low-resolution analysis).17 18 Subjects with SE alleles were classified as having single or double SE alleles and we assumed a dominant SE allele model.13 14 The cases were also subgrouped according to ACPA status.18 19
ORs with 95% CI were calculated for RA overall, ACPA-positive RA and ACPA-negative RA associated with vaccinations by means of unconditional logistic regression models. Women and men were analysed separately, but there were no major differences between the sexes. We adjusted for the design variables (age, gender, residential area) and for social class. Adjustment for social class only marginally changed the estimates and was not retained in the final analyses.
Biological interaction, defined by departure from additivity of effects, was evaluated between vaccination and smoking and between vaccination and HLA-DRB1 SE alleles.20 Smokers were categorised as ever smokers (current/past cigarette smokers) and never smokers. The proportion attributable to interaction (AP) was calculated together with its 95% CI. The AP between two interacting factors reflects the joint effect beyond the sum of the independent effects. All analyses were performed using the Statistical Analysis System (SAS) Version 9.2.
On average, patients were included 10 months after having their first symptoms of RA and 62% were ACPA-positive.
Vaccination and risk of RA overall, ACPA-positive RA and ACPA-negative RA
Up to 5 years before the index year, 582 (31%) of the RA cases had been vaccinated compared with 617 (31%) controls, resulting in an OR of 1.0 (95% CI 0.9 to 1.1) for RA overall (table 1). When exposure to any vaccine was analysed in relation to the incidence of ACPA-positive and ACPA-negative disease, no associations were observed.
Specific vaccinations and risk of RA overall, ACPA-positive RA and ACPA-negative RA
The most frequent vaccines were flu, tetanus, diphtheria, tickborne encephalitis and hepatitis (A, B, C) (table 2). For all specific types of vaccinations the relative risk (RR) of RA were close to one, except from a moderate but not statistically significant decreased risk among those vaccinated against tickborne encephalitis (OR 0.8 (95% CI 0.6 to 1.1)). No relation between any specific vaccination and the risk of ACPA-positive or ACPAnegative RA was found, except for a moderately decreased risk of both subsets with tickborne encephalitis vaccine.
Vaccination, smoking, HLA-DRB1 SE alleles and risk of ACPA-positive RA
The interaction analyses between vaccinations and smoking and between vaccinations and HLA-DRB1 SE alleles were performed only for ACPA-positive disease since smoking and SE alleles are only related to this subset of RA.13 No interaction was found between any vaccination and smoking or between any vaccination and SE alleles (table 3). No specific vaccination interacted with either smoking or SE alleles according to the incidence of ACPA-positive RA (data not shown).
The main finding of this study was that vaccinations commonly used in adults administered within 5 years before onset of disease did not increase the risk of RA overall or the risk of two major subgroups of RA (ACPA-positive RA and ACPA-negative RA). This result does not rule out the possibility that vaccinations taken earlier in life or vaccinations that are rare may trigger development of RA. Furthermore, the vaccinations did not increase the risk of RA in smokers or carriers of HLA-DRB1 SE alleles, two groups with established risk factors for RA.
Cases and controls reported vaccinations received during the past 5 years. Given the present results, a potential non-differential misclassification (generally leading to a bias towards the null value) of vaccinations would probably be dependent on the length of time to recall. However, in a separate analysis the OR of RA for vaccinations taken during the year before the index year compared with those not vaccinated within 5 years before the index year was 0.9 (95% CI 0.8 to 1.1) (see tables S1 and S2 in online supplement).
Non-participation may result in selection bias. In a separate study we concluded that associations in EIRA between exposures and disease are probably only marginally biased due to differences between participants and non-participants.15 The high participation rate in the study also makes it less vulnerable to selection bias. In the analysis we investigated potential confounding by social class but found no additional influence of social class on the estimates of RR. We therefore consider that bias due to systematic errors is probably of limited importance in the present study.
Vaccinations have long been considered as possible inciting agents for RA, but no sufficiently powered epidemiological study has been published on this issue. Reactive arthritis, RA or chronic arthritis following vaccinations have been observed in case reports without controls.2 3 5 6 Our study does not exclude the existence of such cases, only that they are relatively rare. Our study is also compatible with the only published epidemiological study on vaccinations and RA which, however, used a relatively small sample of cases.7
Based on the results of our study which comprised a large number of RA cases and controls (the study has overall sufficient power (>80%) to detect a RR of 1.19), it is unlikely that vaccinations in general should be considered as a major risk factor for RA. In a separate analysis we found no association between a high number of vaccines and the risk of developing RA (see table S3 in online supplement), which further strengthens our conclusion. This has practical implications for what advice on vaccinations should be given to the general population, and in particular to groups at risk of RA such as children of patients with RA, since there are frequently public concerns on associations between vaccinations and various diseases.
In conclusion, our results indicate that immunological provocation of adults with common vaccines in their present form is not a major risk factor for RA. In addition, our results indicate that active immunisation does not increase the risk of RA in individuals with established risk factors (ie, smokers or those carrying HLA-DRB1 SE alleles). These findings should be implemented among clinicians and healthcare providers in order to encourage vaccination according to recommended schedules.
The authors thank Marie-Louise Serra and Lena Nise for their assistance in the collection of data.
Funding The study was supported by grants from the Swedish Medical Research Council; from the Swedish Council for Working Life and Social Research; from King Gustaf V's 80-year foundation; from the Swedish Rheumatism Foundation; from Stockholm County Council and from the insurance company AFA.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of Regionala etikprövningsnämnden (EPN), Stockholm, Sweden.
Provenance and peer review Not commissioned; externally peer reviewed.