Live-attenuated measles, mumps, and rubella booster vaccine in children diagnosed with rheumatic disease: A single-center study

To evaluate the safety profile of measles, mumps and rubella (MMR) booster in children diagnosed with rheumatic diseases receiving biological agents. The study included retrospective safety data of children administered MMR booster dose receiving biologics or biologics with methotrexate. The files of 182 patients were accessed from the pediatric rheumatology biological therapy archive, and the vaccination status of these children was obtained by accessing electronic records. Of 182 patients, 14 patients were vaccinated with MMR booster dose. Thirteen of the patients were followed up with a diagnosis of juvenile idiopathic arthritis and one with colchicine-resistant familial Mediterranean fever. None of the patients had disease exacerbation after vaccination, and three patients had mild side effects consisting of rash, angioedema, joint pain, and fatigue. Conclusion: This study supports the data regarding evidence of the safety of MMR booster dose administration in children with rheumatic diseases receiving bDMARDs. What is Known: • MMR booster is avoided in immunocompromised pediatric patients receiving bDMARDs except in specific conditions. What is New: • The MMR booster dose may be safe in children with PedRD receiving bDMARDs or bDMARDs with MTX. These bullets can be added to the manuscript. What is Known: • MMR booster is avoided in immunocompromised pediatric patients receiving bDMARDs except in specific conditions. What is New: • The MMR booster dose may be safe in children with PedRD receiving bDMARDs or bDMARDs with MTX. These bullets can be added to the manuscript.


Introduction
Pediatric rheumatic diseases (PedRDs) are a group of chronic and heterogeneous conditions, mainly composed of patients with juvenile idiopathic arthritis (JIA), periodic fever syndromes (PFS), primary vasculitis, juvenile systemic lupus erythematosus (jSLE), and juvenile dermatomyositis (JDM) [1]. Biological disease-modifying antirheumatic drugs (bDMARDs) and conventional disease-modifying antirheumatic drugs (cDMARDs), or a combination of both are used as effective therapeutic alternatives in PedRD to reduce morbidity and improve quality of life [2,3]. Despite their substantial benefits, biologics act as immunomodulators in cytokine pathways, which may predispose patients to serious bacterial and viral infections [4,5]. The value of the vaccines in the prevention of infectious diseases gains even more importance in these children who are prone to infections than their healthy peers [6,7].
Vaccines have contributed conspicuously to public health by reducing the burden of childhood infectious diseases so far [8]. However, the safety profiles of live attenuated vaccines are challenging in children with PedRD. Former recommendations were to withhold vaccination with live attenuated vaccines during disease exacerbations in patients with rheumatic diseases receiving high-dose cDMARDs, high-dose glucocorticosteroids (GCS), or bDMARDs [9]. Recently, the recommendations have been in accordance with small case series and expert opinions. Favoring the administration of live attenuated vaccines after a careful patient-specific evaluation by the rheumatologists was deemed appropriate [10,11].
The live-attenuated measles-mumps-rubella (MMR) vaccine is administered to children worldwide via national immunization programs (NIPs). According to NIP of Turkey, a booster dose of MMR is applied at the age of 5-7 years. However, the safety and immunogenicity data of live-attenuated vaccines in children with PedRD are limited, and the risk of post-vaccine disease exacerbations remains obscure, so the administration of live-attenuated vaccine booster doses in PedRD is still controversial [11][12][13]. As the benefits of infection prevention significantly outweigh the acceptable risk of disease exacerbations in these patients, the theoretical possibility of disease flares should not be underlined as a definite argument for vaccine avoidance.
In this study, retrospective data on MMR booster dose safety and adverse events in children with PedRD receiving bDMRADs are presented. It is aimed to shed light on local and systemic side effects, and disease exacerbations after vaccinations, if any.

Study design and participants
Among 72 children diagnosed with PedRD receiving bDMARDs or combined therapy (bDMARDs and cDMARDs), 14 patients who got the MMR booster dose between June 2011 and June 2019 were included, while 58 patients who did not get an MMR booster dose were excluded. In this period, in line with EULAR recommendations, MMR booster dose was not suggested to our patients receiving bDMARDs or combined therapy. However, during outpatient visits, we noticed that some patients received booster doses of MMR without contacting their rheumatologist and interrupting their current treatment.
The files of patients using bDMARDs (anti-IL1, anti-IL-6, etanercept, adalimumab, abatacept) were accessed from the pediatric rheumatology patient archive. From the files of all patients receiving bDMARDs, those who received biologic treatment between the ages of 5 and 7, that is, during the period in which MMR booster was administered according to the NIP of our country, were extricated. Vaccination status of these children and dates for MMR booster were obtained by accessing the vaccine data from the electronic records of the Ministry of Health. Vaccination dates were confirmed by checking the vaccination cards filled and delivered to the families during the vaccination applications. Patient files and electronic documents were handled retrospectively in detail, according to the dates of vaccination.

Study procedures
The demographic and clinical data were abstracted from patients' files by the pediatric rheumatologists. Age, gender, current diagnosis, and treatment regimens were recorded. Disease activity scores, physical examination findings, and laboratory data including acute phase reactants (CRP, ESR), complete blood count, liver and kidney function tests, and urinalysis were documented both 6 months before and 6 months after MMR booster dose. The juvenile arthritis disease activity score 27 (JADAS-27) for patients with juvenile idiopathic arthritis (JIA) and the autoinflammatory disease activity score (AIDAI) for patients with familial Mediterranean fever (FMF) were used to evaluate disease activity.
In our country, NIP is well-designed and controlled by the family doctor following the child routinely, and the records on vaccine side effects and adverse reactions are reported and sent to the Ministry of Health regularly via the online system, and these records are presented on the electronic health record system of the patient. If the parents give consent, physicians following the patient can reach these records. All the records of the patients included in this study were checked from the electronic files carefully with the consent of the parents. Besides this, a questionnaire was built and filled out by the parents and patients with face-to-face interviews by the physician during the study. Vaccine safety was assessed using a structured questionnaire that addressed all potential adverse events, including disease flares and vaccine-related events. In this questionnaire, local reactions (bacterial abscess, sterile abscess, severe local reactions), allergy, anaphylaxis, lymphadenitis, sepsis, rash, fever, encephalopathy, convulsion, acute paralysis, thrombocytopenia, apnea, bradycardia, severe headache, and aseptic meningitis were questioned one by one in detail. Adverse events were categorized as adverse events and serious adverse events. Serious adverse events were defined as events leading to death, life-threatening events, events leading to hospitalization and prolonged hospitalization, and events leading to severe and/ or permanent disability [14]. Patients and their families were questioned on the need to increase their current medication or about any worsening in their self-reported health status, and the patients' files were checked in this regard.
Approval for the study was obtained from the Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (approval number: 816470).

Statistical analysis
Data were analyzed using The SPSS version 21.0 (SPSS, Inc., Chicago, Illinois). The variables were investigated using visual (histogram, probability plots) and analytic methods (Kolmogorov Smirnov/Shapiro-Wilk's test) to determine whether or not they were normally distributed.
Descriptive analysis was presented using proportions, medians, minimum (min), and maximum (max) values as appropriate. Categorical data were statistically analyzed by chi-square analysis. Mann-Whitney U test was used to compare the non-normally distributed variables between the independent two groups. P values < 0.05 were considered statistically significant.

Results
The files of 182 patients were accessed from the Istanbul Medical Faculty pediatric rheumatology biological therapy archive. There were 72 patients treated with bDMARDs or combined therapy, considering the age of 5 to 7 years for initiation of bDMARD therapy. It was determined that 14 of these 72 patients were administered MMR booster dose without interrupting their current treatment and consulting the rheumatologist. The remaining 58 patients were not vaccinated with MMR booster dose while receiving biological therapy in accordance with EULAR recommendations. When investigated in detail, of these 58 patients, 27 patients had completed MMR booster dose before the bDMARD initiation date; 20 patients were on biological therapy, and their parents consulted their rheumatologists at the time of MMR booster dose administration and did not get vaccinated in line with their rheumatologist's suggestion; and parents of 11 patients already knew that live-attenuated vaccines were not recommended while receiving biological treatment from previous visits advice and online information sources and refused vaccination of their children with MMR booster dose (Fig. 1).
Fourteen patients were vaccinated with a booster dose of MMR while receiving bDMARDs or combined therapy. Seven of the patients were girls, and seven were boys. The median age at diagnosis was 43 months (9-73), the median age at MMR booster dose administration was 76 months (70-84). The median follow-up time since the diagnosis was 71 months (40-101), and the median time between

Excluded paƟents (n=58)
PaƟents vaccinated before iniaƟon of bDMARDs(n=27) PaƟents that have not been vaccinated with rheumatologist's suggesƟon(n=20) PaƟents those refuse vaccinaƟon in accordance with their previous knowledge(n=11) bDMARDs initiation and vaccine administration was 14 months (4-45). The median time between completing the questionnaire and getting the MMR booster dose was 24 months (22-60). The demographic and clinical findings of all patients are presented in Table 1. Seven of the patients were followed up with a diagnosis of oligoarticular JIA, three with systemic JIA, two with polyarticular JIA, one with juvenile psoriatic arthritis, and one with colchicine-resistant FMF. Eight patients were receiving bDMARDs at the time of vaccine administration, while six patients were receiving combined bDMARDs and methotrexate (MTX) therapy. Six patients were in remission, five patients had low disease activity, and three had moderate disease activity.
The patients were questioned in terms of local and systemic side effects. One patient from the cohort had rash after vaccination. This patient was under tocilizumab (12 mg/kg/month) and MTX (10 mg/sc/week) treatment with a diagnosis of systemic JIA. In this patient, fever, dry cough, runny nose, redness of the eyes, and small white spots (Koplik spots) on the gums and cheeks were not detected together with the rash. These findings, which were asked retrospectively, were answered by the mother as none. The absence of hospitalization in the information displayed in the electronic system at the time of vaccination suggested that there were no severe side effects and that the patient did not have a severe measles infection. Two more mild adverse events were reported with retrospective family recall. The patient with juvenile psoriatic arthritis had joint pain and fatigue, which was not accompanied by an increase in acute-phase reactants after vaccination. On the other hand, the patient with FMF had angioedema after the MMR booster dose. None of the patients had exacerbation or increase in the activity scores of their disease after vaccination.
All of the patients were receiving their current treatments regularly at the time of vaccination, and the treatments were not interrupted after the vaccination.

Discussion
This retrospective study supports the issue that MMR booster dose may be safe in children with PedRD receiving bDMARDs and combined therapy. The absence of disease exacerbations, serious adverse events, and long-term measles, rubella, or mumps infections in any of the 14 patients, almost all of whom were children diagnosed with JIA, led us to conclude that the live-attenuated MMR vaccine was effective and safe in our cohort. According to Pediatric Rheumatology European Society (PReS) recommendations, administration of live attenuated vaccines should be tailored to the clinical condition of the patient receiving cDMARDs and/or bDMARDs. In children who are in remission with medication, vaccination is recommended, taking into account the balance of profit and loss. The results of our study support this inference. The recommendations were to protect patients from vaccine-preventable infections with immunization; however, studies showed that the vaccination rates of children in the PedRD were lower compared with healthy peers [15]. When the vaccination rates were analyzed according to the treatment alternatives, it was lower in children receiving bDMARDs, and the most frequently missed vaccines were hepatitis B and MMR booster doses [15].
In a multicenter retrospective study of a group of patients diagnosed with PedRD, the booster dose of MMR was found to be safe. Among 71 patients receiving bDMARDs with MTX and 39 patients receiving bDMARDs, no serious side effects and disease flares were observed [16]. Accordingly, in this study, 6 patients receiving bDMARDs and 8 patients receiving both MTX and bDMARDs had no increase in disease activity in the first 6 months after vaccine administration. In a randomized controlled trial in JIA patients, the MMR booster dose was not associated with disease exacerbations in children treated with MTX and bDMARDs, and the rate of development of systemic side effects was similar to that of the healthy controls. However, some of the patients reported joint pain after vaccination; this was thought to be related to the activation of disease due to interruption of therapy before administration of booster dose [13]. There was no exacerbation of the disease in this study, as the current medications of patients were not interrupted during vaccination. In a limited number of studies, the MMR booster dose was found to be safe in children followed up with PedRD and did not cause an increase in disease activity [12,16,17].
As patients under bDMARDs may be more susceptible to bacterial and viral infections, it is crucial to protect them from infections [18]. Vaccines have successfully saved humanity from many infections by controlling disease transmission and consequently reducing morbidity and mortality. Two important objectives in primary immunization are achieving efficacy and safety. The most commonly used way to evaluate efficacy is to monitor postvaccine antibody titers. In studies reporting the MMR vaccine humoral response, the antibody titers were similar between patient groups receiving biologics or other treatment modalities, so the vaccine was considered immunogenic in the biologic group [11,13]. In a study reporting the immunogenicity of the measles vaccine, the humoral antibody response was similar in children diagnosed with jSLE and healthy peers [19]. However, we cannot make an inference about immunogenicity, since the vaccine antibody response was not evaluated in this study.
Our study has some limitations. Since the data were collected retrospectively, some vaccine-related adverse events may have been overlooked; however, we believe that pediatric rheumatologists do not neglect to observe serious adverse events in their patient evaluations, and families give detailed information about patients' clinical status in every visit. In our country, there are penal sanctions in case family physicians do not enter the vaccination records of the patients properly. However, due to the retrospective study design, the severity of symptoms may not be adequately documented, and this may be a bias. A common adverse effect in a small group can easily be overlooked, but it would be fair to discuss, while small contributions to the literature are important for clinicians, as there are many concerns regarding the administration of live-attenuated vaccines to children receiving biologic agents Since the reports concerning administration of live-attenuated vaccines in children with PedRD receiving bDMARDs are limited, we believe that this study may have a contribution to the literature in this aspect.

Conclusions
In summary, the MMR booster dose appears to be safe in children with PedRD receiving bDMARDs or bDMARDs with MTX; however, prospective multicenter studies with larger cohorts are needed to reach a conclusion. Vaccine safety data from our cohort revealed that vaccination seems to be the most appropriate approach to protect PedRD patients from infections.