Introduction
Over the years, awareness of vaccine-preventable infection in rheumatic diseases has increased. At the same time, the safety of vaccines is still a hot topic in the public arena. Large-scale registries with data on children with juvenile idiopathic arthritis (JIA) treated with the combination of methotrexate and biologics have demonstrated an increased incidence of infections [1,2]. In a recent discussion at the 2018 Paediatric Rheumatology European Society (PReS) annual meeting (see www.PRES.eu), an international group of pediatric rheumatologists and parents of children with rheumatic diseases stated that they strongly support vaccination in children with chronic rheumatic conditions, and that this is especially important in children treated with antirheumatic medications.
Safety of vaccines in children with rheumatic conditions
In a chronic relapsing condition such as JIA or systemic lupus erythematosus (SLE), it is always possible that an immunization precedes a flare and may thus be associated with it. However, several large studies have found that immunizations do not cause an increase in the number of disease flares following an immunization [3,4]. As in healthy individuals, immunizations may have side effects in children with rheumatic conditions, but these are no more frequent than in the healthy population.
In the medical literature, many studies exist on safety and efficacy of vaccination in children with pediatric rheumatic conditions who are using antirheumatic medication [3–8]. In particular, there have been recent studies into the effects of immunosuppressant drugs such as methotrexate (MTX) and the newer, biologic drugs, such as tumor necrosis factor (TNF) blockers [1,6]. Most studies show that MTX and biologics do not greatly influence the vaccine response. Future research should focus on the use of live vaccines such as the measles, mumps, and rubella (MMR) or Zoster vaccines.
An additional concern is the possibility that biologic therapy used in rheumatic conditions may induce a faster decline of antibody titers. A recent review found that whilst the antibody concentrations of most patients taking biologics reached protective levels following vaccination, these levels were lower, and showed a more rapid decline, compared with those of patients not using biologic medications [9]. A lower initial geometric mean titer (GMT), and a more rapid decline in antibody levels will lead to a faster decrease in seroprotection rate in these patients. Vaccine protection may therefore be less optimal and booster vaccination should be considered in these patients.
Only three studies have reported MMR booster immunization during use of biologics [5,6,8]. This is explained by the fact that the labels of both the MMR vaccine and biologics state that live-attenuated vaccines are contraindicated when taking biologics. In a revision of the vaccination recommendations for pediatric rheumatic diseases, it is suggested that immunization with booster MMR under biologic therapy “can be considered on a case by case basis” (manuscript in preparation). Based on this recommendation, the PReS working party on vaccinations is investigating the experiences of specialized centers in Europe on safety and efficacy of the MMR booster in patients with JIA being treated with biologics. Furthermore, the international expert group within PReS is coordinating an international study on this topic as an extension to earlier Dutch, German, and Brazilian studies on the safety of the MMR booster in 10-year-old arthritis patients.
Recommendations for children with rheumatic conditions
The most recent EULAR recommendations for vaccination in pediatric patients with rheumatic diseases, published in 2011, provide guidance based on data from published studies on the safety and efficacy of vaccinations in children with pediatric rheumatic conditions [10]. These recommendations state that non-live vaccines are generally considered to be safe and immunogenic. Live-attenuated vaccines are also considered safe to administer, except in patients taking high-dose immunosuppressant medications or biologics, where data on safety is scarce. They also reccomend that live-attenuated booster vaccinations may be considered on an individual basis [9].
For most inactive vaccines, we consider it safe to continue with biologic medications. In an earlier trial to assess the effects of the live-attenuated MMR booster vaccine, we interrupted the dosing regimen of the biologic medication prior to vaccination, and found no increase in disease activity [5]. However, the number of patients treated in this study is too small to base firm recommendations on. In general it is safe to conclude the following recommendations: If possible, patients should be vaccinated before starting biologic therapy. If therapy has already been initiated, wait for a stable phase with low disease activity before initiating vaccination. This should be done in close collaboration with an experienced academic pediatric rheumatology center. In general, it is not necessary to interrupt biologic therapy.
Factors influencing parents’ decision to vaccinate
The decision regarding whether to vaccinate children with rheumatic diseases on an individual basis will be influenced by data on safety and efficacy, but emotional and psychological factors also come into play. The history of the MMR vaccine illustrates this clearly. The live-attenuated MMR vaccine was introduced some 50 years ago. Following a suggestion of the development of autism in 12 children after measles vaccination published in The Lancet in 1998, there was much uncertainty around the safety of the vaccine [11]. Although the Wakefield article was later withdrawn, it has undermined public confidence in the measles vaccine, and in vaccinations in general [12].
The recently introduced inactive vaccine against human papilloma virus (HPV) initially showed a reasonable uptake in the general population based on a clear rationale (reduction of mortality due to HPV-associated cervical cancer) [13]. However in the years following, uptake of this vaccination for girls aged 12–15 years has declined, despite excellent safety studies performed by the University Medical Center Utrecht and the Dutch National Institute for Public Health and the Environment in healthy girls, and girls with rheumatic conditions such as JIA and SLE [9,14]. In a recent article in a Dutch newspaper, the reasons for poor uptake were explored [15]. The author notes the public’s lack of trust in statements of health authorities and local physicians. This is also fueled by internet communications by anti-vaccination advocacy groups, claiming new side effects and long-term risks. There are also reports on the occurrence of chronic fatigue in adolescent girls following HPV vaccination [16], in addition to a medical report by the Shoenfeld group on vaccines inducing an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) syndrome [17].
Discussing HPV vaccination with parents implicates discussion regarding future sexual activities of their daughter at a young age, as well as risk for possible short- and long-term side effects of the vaccine. Many parents believe that their child is not sexually active and does not need a vaccine, or have concerns that the vaccine is ineffective. These are for many parents, reasons not to have their daughter vaccinated [18].
The history of both the MMR and HPV vaccines clearly illustrates the need for further investigation into the beliefs and motivations of the general public on vaccinations. The factual, scientific approach of the authorities to the general public may have missed addressing parental, emotional concerns. At the same time, anti-vaccination advocacy groups have had a strong dialogue with the public. Instead of a more scientific top-down approach from our healthcare authorities to the public, a different approach is now used by general youth healthcare providers; a more nudging approach. General healthcare workers for youth are well-equipped to perform such interactions with parents and children. The decreasing trend of vaccine coverage in the general population has initiated a debate in many EU countries on whether to make participation to the national vaccination schedules mandatory for admittance to daycare centers or schools. The discussion on potential side effects of vaccines has also initiated investigations on safety of immunizations in children with rheumatic conditions. Clearly, a decreasing herd immunity has placed patients using immunosuppressive medication at increased risk for infection.
Conclusion
In conclusion, there are several factors to consider regarding the vaccination of children with rheumatic diseases, including risk for increased disease activity, the impact of biologic medication on seroprotection rate, as well as risk for side effects. However, decreasing vaccination coverage will put vulnerable individuals at greater risk for severe vaccine-preventable infections. As indicated above, a detailed publicity campaign must address objections raised by the public as well as scientific information in order to be convincing for both the general public and families of patients.