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Marloes Heijstek

Tuesday 25 March 2014

Vaccination of paediatric patients with rheumatic diseases navigating through turbulent waters

Promotor: Prof. dr N.M. Wulffraat
Defence: 25 March 2014

There are several issues that need consideration when vaccinating paediatric patients with rheumatic diseases. The efficacy of vaccinations might be reduced due to the underlying diseases or its immunosuppressive treatment. Also, the safety profile of vaccines may differ from that of healthy controls. Safety not only comprises adverse events, it also encompasses the detrimental effect of vaccinations on the underlying disease and the risk of vaccination-induced infections with attenuated pathogens in immunosuppressed patients.

In part I of this thesis, we present the European League Against Rheumatism (EULAR) recommendations for vaccination of paediatric patients with rheumatic diseases based on available evidence. Generally, vaccines were immunogenic and non-live vaccines were safe, even in patients using glucocorticosteroids, disease modifying antirheumatic drugs (DMARDS) or biological agents. Fifteen recommendations were developed. As evidence was lacking for numerous vaccines, diseases and immunosuppressive drugs, most recommendations had strength C (based on descriptive studies) or D (based on expert opinion). The studies presented in part II to IV of this thesis fill some of the gaps in current knowledge on the safety and immunogenicity of vaccines in paediatric patients with rheumatic diseases.

In part II, we focus on the safety and efficacy of the live-attenuated measles, mumps, rubella (MMR) vaccine in patients with juvenile idiopathic arthritis (JIA). In chapter 4, the safety of MMR vaccination was analysed in an observational retrospective cohort of 207 patients with JIA, including 49 patients using methotrexate. No increase in disease activity or medication use was seen in the 6 months after MMR vaccination. Also, disease activity in 108 vaccinated patients did not significantly differ from 86 patients who were not vaccinated. Next, we performed a multicenter randomised open-label trial to assess the safety and short-term immunogenicity of the MMR booster vaccination in 137 patients with JIA, including 60 patients using methotrexate and 15 using biologic agents (chapter 6). Patients aged 4 to 9 years were recruited from five academic hospitals in the Netherlands, and were randomly assigned to receive MMR booster vaccination or no vaccination. Disease activity, as measured by the Juvenile Arthritis Disease Activity Score (JADAS-27), in the year following randomisation did not differ between 63 revaccinated patients (JADAS-27 2.8; 95% CI, 2.1-3.5) and 68 controls (JADAS-27 2.4; 95% CI, 1.7-3.1), with a difference in JADAS-27 of 0.4 (95% CI, -0.5 to 1.2) within the predetermined equivalence margin of 2.0. As expected, seroprotection rates and antibody concentrations were higher in revaccinated patients than in controls. Methotrexate and biologic agents did not affect humoral responses, but low patient numbers precluded definite conclusions. Besides the short-term immunogenicity of MMR vaccination, we evaluated the long-term kinetics of the MMR-specific antibody responses in a large cross-sectional cohort (chapter 5). MMR and diphtheria-tetanus toxoid (DT) specific immunoglobulin G antibody concentrations were compared between 400 patients with JIA aged 1-19 years and 2176 age-matched healthy controls. Patients with JIA had significantly lower antibody concentrations and seroprotection rates than healthy controls against mumps, rubella, diphtheria and tetanus. Methotrexate and glucocorticosteroids did not affect pathogen-specific antibody concentrations or seroprotection rates. Based on chapter 4 to 6 we conclude that MMR booster vaccination does not aggravate disease in patients with JIA, including patients using methotrexate. Larger studies are needed to assess MMR effects in patients using biologic agents. The lower long-term MMR-specific antibody levels enforce a pro-active approach in the immune surveillance of patients with rheumatic diseases to detect waning immunity.
To assess whether in individual JIA patients MMR vaccination can contribute to excessive effector T cell activation, we analysed the quantity and quality of MMR booster induced T cell-mediated immune responses in 18 JIA patients and compared it with 13 healthy adult controls (chapter 7). MMR booster vaccination induced a non-significant increase in RV-specific effector T cell proliferation with a mixed RV-specific cytokine signature and case-to-case differences in cytokine expression in RV-specific T cells, similar in patients and healthy controls. No significant increase in T cell proliferation or cytokine production towards non-related antigens (tetanus toxoid and the arthritis-related regulatory autoantigen heat shock protein 60) was detected. Thus, the MMR booster does not contribute to a dysregulation of the immune system in the majority of patients with JIA. However, a small subset of patients, including those with active arthritis, exemplified increased effector T cell proliferation and intracellular IL-17 and INFγ production in RV-specific T cells compared with healthy controls. This indicates that in a subset of individual susceptible patients, MMR vaccination may induce excessive effector T cell responses creating a risk for disease flares. As yet, we are not able to identify these individuals before vaccination.

In part III we focus on the immune response to the bivalent human papillomavirus (HPV)16/18 AS04-adjuvanted vaccine in patients with JIA (chapter 8), systemic lupus erythematosus (SLE) and juvenile dermatomyositis (JDM) (chapter 9). The immunogenicity and safety of the in these patients was compared to healthy female adolescents in a prospective controlled observational cohort study. Patients with JIA (n=68), SLE (n=6) and JDM (n=6) and healthy girls (n=55) aged 1218 years were vaccinated at 0, 1 and 6 months and were followed for 12 months. All participants were seropositive for HPV16 and HPV18 after three vaccinations, except for one JIA patient and one JDM patient. Although non-significant, HPV-specific antibody concentrations were consistently lower in patients, especially in patients with SLE and JDM. No effect of methotrexate or anti-TNFα treatment on HPV-specific antibodies was detected. Regarding safety, no relevant differences in adverse events between patients and controls were found and HPV vaccination did not aggravate JIA, SLE or JDM disease. We therefore conclude that the bivalent HPV16/18 vaccine is immunogenic and well tolerated in patients with JIA, SLE and JDM. However, as HPV-specific antibodies tended to be lower in patients, protective immunity against HPV might not be guaranteed over time. Immunosurveillance post-vaccination and continued secondary prevention via cervical smears may be prudent, especially in patients with SLE or JDM.

In part IV, chapter 10, we focus on the response to the meningococcal serogroup C (MenC) conjugate vaccine in JIA patients and describe the long-term kinetics of meningococcal-specific antibodies in a retrospective cohort of 127 JIA patients and compare it to 1527 age-matched healthy controls obtained from a large nationwide cross-sectional cohort study. Persistence of MenC-specific IgG antibodies 4 years post-vaccination in JIA patients was similar to healthy controls. However, treatment with biologicals induced a trend towards accelerated antibody waning, resulting in unprotected patients who may need revaccination. Especially in these JIA patients, monitoring MenC-specific antibodies or routine revaccination in endemic areas seems warranted for better protection against meningococcal serogroup C disease.

The data described in this thesis show that vaccinations should generally be advocated rather than feared in paediatric patients with rheumatic diseases. Multiple studies show that vaccinations are generally effective and/or immunogenic in these patients. Also, vaccinations are usually safe and do not have detrimental effects on the underlying rheumatic disease. A pro-active approach is warranted, with regular immune surveillance to detect patients with waning immunity who need revaccination. Future studies should focus on safety and long-term efficacy of vaccines, especially in patients using biologic agents, and on identifying patients at risk of vaccination-induced adverse events or disease flares.