Vaccination of paediatric patients with rheumatic diseases. Navigating through turbulent waters

Abstract

In this thesis we focus on the safety and efficacy of vaccinations in paediatric patients with rheumatic diseases. With the European League Against Rheumatism (EULAR), we constructed recommendations for vaccination of paediatric patients with rheumatic diseases based on available evidence. Evidence was lacking for numerous vaccines, diseases and immunosuppressive drugs. The studies in this thesis fill several gaps in current knowledge. First, we analysed the safety and immunogenicity of the live-attenuated measles, mumps, rubella virus (MMR) vaccine in patients with juvenile idiopathic arthritis (JIA). MMR booster vaccination did not negatively affect JIA disease activity in a retrospective cohort of 207 patients. Next, we performed a multicenter randomised open-label trial in 137 patients. Patients aged 4-9 years were randomly allocated to receive MMR booster vaccination or no vaccination. Disease activity did not differ between 63 revaccinated patients and 68 controls. We subsequently assessed MMR vaccination-induced effector T cell responses in 18 JIA patients and 13 healthy controls. In the majority of patients, MMR booster vaccination induced a mixed rubella virus (RV)-specific T cell response with a balanced cytokine signature and case-to-case differences in cytokine expression in RV-specific T cells. In a small subset of patients, including some patients with a disease flare post vaccination, MMR booster induced excessive T cell responses with increased proliferation and intracellular interleukin-17 and/or interferonγ production. Whether these excessive T cell responses create a risk of clinical derailment in individual susceptible patients requires further study. In our randomised trial, short-term MMR booster immunogenicity was good, without detrimental effects of methotrexate and biologicals on humoral responses. We studied the long-term kinetics of vaccine-specific antibody concentrations in a cross-sectional cohort of 400 patients and 2176 age-matched healthy controls. Patients had significantly lower antibody concentrations and seroprotection rates than healthy controls against mumps, rubella, diphtheria and tetanus, irrespective of methotrexate and glucocorticosteroids use. Thus, long-term protection against infections may be hampered. Second, we assessed the immunogenicity of the bivalent human papillomavirus (HPV)16/18 vaccine in 68 patients with JIA, six with systemic lupus erythematosus (SLE) and six with juvenile dermatomyositis (JDM) in comparison to 55 healthy female adolescents in a prospective controlled study. All participants were seropositive for HPV16/18 after three vaccinations, except for one JIA patient and one JDM patient. HPV-specific antibody concentrations were consistently lower in patients with SLE and JDM, irrespective of treatment. HPV vaccination did not aggravate JIA, SLE or JDM disease and adverse events were mild. Third, we analysed the kinetics of the humoral response to the meningococcal serogroup C (MenC) conjugate vaccine. In a retrospective cohort of 127 JIA patients, persistence of MenC-specific IgG antibodies 4 years post-vaccination was similar to 1527 age-matched healthy controls. Treatment with biologicals induced a trend towards accelerated antibody waning.