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ARTHRITIS & RHEUMATISM
Vol. 56, No. 2, February 2007, pp 639– 646
DOI 10.1002/art.22399
© 2007, American College of Rheumatology
Safety and Efficacy of Meningococcal C Vaccination in
Juvenile Idiopathic Arthritis
Evelien Zonneveld-Huijssoon,
1
Arash Ronaghy,
1
Marion A. J. van Rossum,
2
Ger T. Rijkers,
1
Fiona R. M. van der Klis,
3
Elisabeth A. M. Sanders,
1
Patricia E. Vermeer-de Bondt,
3
Arno W. Hoes,
1
Jan Jaap van der Net,
1
Carla Engels,
1
Wietse Kuis,
1
Berent J. Prakken,
1
Maarten J. D. van Tol,
4
and Nico M. Wulffraat
1
Objective. To determine whether vaccinations ag-
gravate the course of autoimmune diseases such as
juvenile idiopathic arthritis (JIA) and whether the
immune response to vaccinations may be hampered by
immunosuppressive therapy for the underlying disease.
Methods. In this multicenter cohort study, 234
patients with JIA (ages 1–19 years) were vaccinated with
meningococcal serogroup C (MenC) conjugate to pro-
tect against serogroup C disease (caused by Neisseria
meningitidis). Patients were followed up for disease
activity for 1 year, from 6 months before until 6 months
after vaccination. IgG antibody titers against MenC
polysaccharide and the tetanus carrier protein were
determined by enzyme-linked immunosorbent assay and
toxin binding inhibition assay, respectively. A serum
bactericidal assay was performed to determine the
function of the anti-MenC antibodies.
Results. No change in values for any of the 6
components of the core set criteria for juvenile arthritis
disease activity was seen after MenC vaccination. More-
over, no increase in the frequency of disease relapse was
detected. Mean anti-MenC IgG concentrations in JIA
patients rose significantly within 6–12 weeks after vac-
cination. Of 157 patients tested, 153 were able to mount
anti-MenC IgG serum levels >2
g/ml, including pa-
tients receiving highly immunosuppressive medication.
The 4 patients with a lower anti-MenC antibody re-
sponse displayed sufficient bactericidal activity despite
receiving highly immunosuppressive medication.
Conclusion. The MenC conjugate vaccine does
not aggravate JIA disease activity or increase relapse
frequency and results in adequate antibody levels, even
in patients receiving highly immunosuppressive medi-
cation. Therefore, patients with JIA can be vaccinated
safely and effectively with the MenC conjugate.
The induction or worsening of autoimmune dis-
ease by vaccination has been a matter of debate for
many years (1–4). Although most controlled studies fail
to demonstrate any link between vaccination and auto-
immune disease, concerns about possible adverse effects
hamper compliance (5–12). The decreasing herd immu-
nity poses increased risks for patients with chronic
autoimmune diseases (13,14).
Another concern is the potentially diminished
efficacy in patients being treated with immunosuppres-
sive drugs (10). In the UK, physicians were less likely to
vaccinate those children with juvenile idiopathic arthritis
(JIA) who received higher levels of immunosuppressive
drugs (15). Guidelines of the British Society for Rheu-
matology state that the immune response to the menin-
gococcal serogroup C (MenC) conjugate vaccine in
immunosuppressed patients with rheumatic disease may
be suboptimal and therefore they may require boosters
(16).
In 2002, Dutch health authorities initiated a
Supported by the Netherlands Organization for Scientific
Research and the Fifth Framework program of the European Com-
mission.
1
Evelien Zonneveld-Huijssoon, MD, Arash Ronaghy, PhD,
Ger T. Rijkers, PhD, Elisabeth A. M. Sanders, MD, PhD, Arno W.
Hoes, MD, PhD, Jan Jaap van der Net, PhD, Carla Engels, Wietse
Kuis, MD, PhD, Berent J. Prakken, MD, PhD, Nico M. Wulffraat,
MD, PhD: Wilhelmina Children’s Hospital, University Medical Center
Utrecht, Utrecht, The Netherlands;
2
Marion A. J. van Rossum, MD:
Leiden University Medical Center, Emma Children’s Hospital AMC,
Jan van Breemen Institute, Amsterdam, The Netherlands;
3
Fiona
R. M. van der Klis, PhD, Patricia E. Vermeer-de Bondt, MD: RIVM,
Bilthoven, The Netherlands;
4
Maarten J. D. van Tol, PhD: Leiden
University Medical Center, Leiden, The Netherlands.
Drs. Zonneveld-Huijssoon and Ronaghy contributed equally
to this work.
Address correspondence and reprint requests to Nico M.
Wulffraat, MD, PhD, Department of Paediatric Immunology, Wil-
helmina Children’s Hospital, University Medical Center Utrecht,
Room KC 03-063.0, PO Box 85090, 3508 AB Utrecht, The Nether-
lands. E-mail: N.Wulffraat@umcutrecht.nl.
Submitted for publication May 29, 2006; accepted in revised
form November 3, 2006.
639
nationwide campaign in which all children between 1
and 19 years of age were vaccinated against meningo-
coccal serogroup C disease, caused by Neisseria menin-
gitidis (17,18). The guidelines for exclusion were nonspe-
cific with regard to autoimmune diseases or the use of
immunosuppressive drugs. The aim of this study was to
document disease activity and immune responses in JIA
patients before and after MenC vaccination.
PATIENTS AND METHODS
Study design. A multicenter cohort study was per-
formed in which patients served as their own controls. For each
patient, the study period covered 1 year, starting 6 months
before MenC vaccination. Since most autoimmune reactions
reported by others occurred within 1 month of vaccination
(1,3,19–22), we defined this period as the period of exposure.
The remaining 11 months of the study period were defined as
the unexposed period.
Study population. All patients between 1 and 19 years
of age who had been diagnosed as having JIA according to the
criteria of the International League of Associations for Rheu-
matology (23) were eligible. Before the start of the national
vaccination campaign with the MenC conjugate, patients from
pediatric rheumatology outpatient clinics at the University
Medical Centers of Utrecht, Leiden, and Amsterdam, the Jan
van Breemen Institute, and the Juliana Children’s Hospital
(The Hague) were invited by mail to participate in this study.
Written informed consent was obtained from patients or their
parents. Approval by the medical ethics boards of the partici-
pating centers was acquired.
Of 538 invited patients, 277 replied (51.5%). Replying
and nonreplying patients were comparable in age, sex, and JIA
disease type. Twenty of the replying patients attended outpa-
tient clinics elsewhere, 10 patients moved elsewhere, 11 re-
fused to participate, and the vaccination dates of 2 patients
could not be retrieved. Thus, 234 patients from 5 centers in
The Netherlands were enrolled (Figure 1). Sixty-five percent
of the study subjects were female. At the vaccination date, the
mean ⫾SEM age of the patients was 11.1 ⫾4.2 years (range
1.5–18.9 years) and the mean ⫾SEM disease duration was
5.9 ⫾3.5 years (range 0.2–16.0 years). The mean age at onset
of JIA was 5.3 ⫾3.7 years (range 0.5–15.9 years). The group of
patients tested for relapse frequency (n ⫽166) was not
statistically different from the total cohort (n ⫽234) with
respect to demographic, disease, and treatment characteristics.
Definition of medication groups. Postvaccination
blood samples were available from 157 of the patients. The
patients were classified based on medication use at the time of
MenC vaccination. Group 1 (n ⫽47) received no medications,
group 2 (n ⫽41) received nonsteroidal antiinflammatory drug
(NSAID) monotherapy, group 3 received low dosages of
methotrexate (MTX) (⬍10 mg/m
2
/week) (n ⫽36) or sulfasala-
zine (n ⫽7) with or without NSAIDs, and group 4 received
high dosages of MTX (ⱖ10 mg/m
2
/week) (n ⫽15), infliximab
(n ⫽2), etanercept (n ⫽6), cyclosporin A (n ⫽1), or a
combination of MTX and sulfasalazine (n ⫽2) with or without
NSAIDs (Table 1). Patients in the various medication groups
did not differ in age, sex, duration of JIA, or age at onset of
JIA. As expected, medication group 4 contained the most
patients with severe forms of JIA (i.e., extended oligoarticular
JIA and polyarticular JIA), whereas group 1 contained the
most patients with persistent oligoarticular JIA. Consequently,
disease activity before vaccination was highest in medication
group 4.
MenC conjugate vaccination. The NeisVac-C vaccine
(Baxter Healthcare, Vienna, Austria) contains the N meningi-
tidis Z2491 serogroup C polysaccharide (20
g/ml) conjugated
to tetanus toxoid (TT) (20–40
g/ml). Patients received 1
intramuscular dose of 0.5 ml NeisVac-C during the Dutch
national vaccination campaign. All patients were vaccinated,
irrespective of disease activity. Vaccination dates were ob-
tained by questionnaire.
Patients were vaccinated between June 1 and Decem-
ber 26, 2002. In 3 patients, MenC vaccination was postponed
6–12 months because of participation in a drug trial in which
vaccination was not allowed (n ⫽2) or because of severe
uveitis during the national vaccination campaign (n ⫽1). Their
clinical and serologic results were included in the analysis.
Outcome measures. Disease relapse was the primary
outcome measure and was defined using the internationally
validated core set criteria for juvenile arthritis disease activity
(24). Within this core set, a pediatric rheumatologist used a
physician global assessment (PGA) to provide an overall
impression of disease activity. The PGA was measured on a
10-cm visual analog scale and converted to scores on a 0–3
Figure 1. Number of patients with juvenile idiopathic arthritis as-
sessed and enrolled in the study. RF ⫽rheumatoid factor; Pre vac ⫽
prevaccination; MenC ⫽meningococcal serogroup C; ELISA ⫽
enzyme-linked immunosorbent assay; Post vac ⫽postvaccination;
ToBI ⫽toxin-binding inhibition test; SBA ⫽serum bactericidal assay.
640 ZONNEVELD-HUIJSSOON ET AL
scale. The Childhood Health Assessment Questionnaire (C-
HAQ) was used to determine overall well-being (C-HAQ
well-being) and functional ability (C-HAQ disability), both
expressed on a 0–3 scale (25,26). Active joints were defined as
all joints with swelling or with any 2 other signs of inflamma-
tion (heat, limited range of motion, tenderness, or painful
range of motion) (24,27). Limited range of motion was defined
for each joint as a loss of at least 5 degrees in any articular
movement with respect to the normal amplitude. Erythrocyte
sedimentation rate (ESR) completed the core set of 6 criteria.
A disease relapse was defined as a worsening of ⱖ40% in at
least 2 of 6 core set criteria without an improvement of ⬎30%
in more than 1 of the remaining criteria (28).
Disease activity parameters as assessed by pediatric
rheumatologists during at least 1 visit before and 1 visit after
vaccination were compared. For the detection of disease
relapses in a large subset of patients (n ⫽166, all from the
University Medical Center Utrecht), this assessment of core
set criteria was extended to all available outpatient clinic visits
and hospitalizations during the entire study period. Not every
core set criterion was routinely evaluated, but PGAs and joint
counts were performed in all cases. Patients who did not
consult their physician between scheduled visits were assumed
not to have experienced a disease relapse during that time.
This was always confirmed at the next visit.
Serologic analysis. Blood samples were drawn from
198 patients before and after MenC vaccination. Thirty-three
of the 198 patients were excluded from serologic analysis
because their postvaccination blood sampling was delayed to
⬎12 weeks after vaccination. We analyzed 141 prevaccination
and 157 postvaccination samples, of which 133 were paired.
Anti-MenC total IgG antibodies were quantified in
serum by enzyme-linked immunosorbent assay using the Cen-
ters for Disease Control 1992 reference serum, assigned a
value of 24.1
g/ml anti-MenC IgG (29,30). The lower limit of
antibody detection was 0.24
g/ml. Serum with undetectable
anti-MenC IgG levels was assigned a value of 0.23
g/ml for
mathematical purposes. Low responders were defined based
on postvaccination anti-MenC IgG levels of ⱕ2
g/ml (31,32).
The level of anti-TT antibodies was measured using a
tetanus toxin–binding inhibition assay at the Laboratory of
Vaccine Preventable Diseases, Bilthoven, The Netherlands, as
previously described (33). The lower limit of detection was 0.01
IU/ml.
Serum bactericidal assays (SBAs) against the sero-
group C strain (C11, phenotype C:16:P1.7a,1) were performed
with baby rabbit serum (Pel-Freez, Rogers, AR) as an exoge-
nous complement source. SBA titers were expressed as the
reciprocal of the final serum dilution giving ⱖ50% killing at 60
minutes (34). Postvaccination bactericidal titers ⬍8 were con-
sidered to predict susceptibility to MenC infection (32,35–39).
Both the toxin binding inhibition assay and SBA were
performed on blood samples from the 4 low responders
(anti-MenC IgG ⱕ2
g/ml) and a random sample of 10 of 153
high responders (anti-MenC IgG ⬎2
g/ml).
Statistical analysis. To compare the uniformity of the
subset of 166 patients included in the relapse analysis with the
total cohort (n ⫽234), chi-square tests with expected frequen-
cies of the total cohort for distribution of categorical variables
and 1 sample t-test for means were used. Changes in paired
prevaccination and postvaccination values of core set criteria
components were assessed by Wilcoxon’s signed rank test.
Risk of relapse was quantified by dividing the number
of detected relapses in the exposed or unexposed period by the
number of patient-months within that period. Observed
patient-months were calculated by multiplying the number of
Table 1. Baseline characteristics of the JIA patients*
Total enrolled
(n ⫽234)
Patients tested ⬍12 weeks after MenC vaccination†
Group 1
(n ⫽47)
Group 2
(n ⫽41)
Group 3
(n ⫽43)
Group 4
(n ⫽26)
JIA subtype
Systemic arthritis 34 (14.5) 11 (23.4) 3 (7.3) 5 (11.6) 3 (11.5)
Persistent oligoarthritis 103 (44.0) 26 (55.3) 18 (43.9) 14 (32.6) 2 (7.7)
Extended oligoarthritis 25 (10.7) 2 (4.3) 5 (12.2) 6 (14.0) 7 (26.9)
Polyarthritis 59 (25.2) 5 (10.6) 10 (24.4) 16 (37.2) 14 (53.8)
Rheumatoid factor positive/total typed 5/53 0/3 0/9 0/15 3/13
Psoriatic arthritis 4 (1.7) 0 1 (2.4) 2 (4.7) 0
Enthesitis-related arthritis 7 (3.0) 2 (4.3) 3 (7.3) 0 0
Undifferentiated arthritis 2 (0.9) 1 (2.1) 1 (2.4) 0 0
PGA before vaccination‡
Severely active 8 (3.4) 0 1 (2.4) 4 (9.3) 2 (7.7)
Moderately active 16 (6.8) 1 (2.1) 4 (9.8) 3 (7.0) 5 (19.2)
Mildly active 46 (19.7) 0 13 (31.7) 11 (25.6) 8 (30.8)
Inactive 164 (70.0) 46 (97.9) 23 (56.1) 25 (58.1) 11 (42.3)
Patients taking oral steroids 5 (2.1) 0 0 2 (4.7) 2 (7.7)
Mean ⫾SD dosage, mg/kg/day 0.11 ⫾0.08 – – 0.14 ⫾0.13 0.08 ⫾0.03
Range, mg/kg/day 0.05–0.40 – – – –
* Except where indicated otherwise, values are the number (%). JIA ⫽juvenile idiopathic arthritis; MenC ⫽meningococcal serogroup C.
† Group 1 ⫽no medication; group 2 ⫽nonsteroidal antiinflammatory drug (NSAID) monotherapy; group 3 ⫽low-dosage methotrexate (MTX)
(⬍10 mg/m
2
/week) (n ⫽36) or sulfasalazine (SSZ) (n ⫽7) with or without NSAIDs; group 4 ⫽high-dosage MTX (ⱖ10 mg/m
2
/week) (n ⫽15),
infliximab (n ⫽2), etanercept (n ⫽6), cyclosporin A (n ⫽1), or a combination of MTX and SSZ (n ⫽2) with or without NSAIDs.
‡ Physician’s Global Assessment (PGA) of disease activity (0–3 scale), where 0 ⫽inactive, 0.1–1.4 ⫽mildly active, 1.5–2.4 ⫽moderately active, and
2.5–3.0 ⫽severely active.
MenC VACCINATION IS SAFE AND EFFECTIVE IN JIA 641
patients (n ⫽166) by the duration of the observed period in
months (exposed period ⫽1 month, unexposed period ⫽11
months). Relative risk (RR) of relapse was calculated by
dividing the risk of relapse during the exposed period by the
risk of relapse in the unexposed period. The 95% confidence
interval (95% CI) was calculated using the following equation:
e
lnRR ⫾1.96公1/A1 ⫹1/A0
, in which A
1
represents the number of
relapses in the exposed period and A
0
the number of relapses
in the unexposed period. Chi-square tests were used to analyze
seasonal variability of relapses. The MIXOR program (version
2.0) (40) was used for logistic regression analysis of longitudi-
nal data.
Distribution of geometric mean concentrations and
geometric mean titers was extremely skewed. Therefore, we
used nonparametric tests such as the Mann-Whitney U test or
the Kruskal-Wallis test for comparisons between 2 or multiple
groups, Wilcoxon’s signed rank test for paired variables, and
chi-square test for ordinal variables. For comparison of patient
characteristics and anti-MenC IgG geometric mean concentra-
tions between medication groups, one-way analysis of variance
was performed on natural log–transformed data. The Bonfer-
roni adjustment was applied for multiple comparisons. Pear-
son’s correlation coefficient was calculated for natural log–
transformed titer data.
Statistical analysis was performed using SPSS software,
version 12.0.2 (SPSS, Chicago, IL). Pvalues less than 0.05 were
considered significant.
RESULTS
JIA disease activity. No worsening of disease
activity was seen, based on mean core set criteria values
during the 6 months after MenC vaccination compared
with the 6 months before vaccination as measured in 234
JIA patients (Figure 2). A significant amelioration in
PGA and limited range of motion was observed after
MenC vaccination, but this was too small to be of clinical
significance.
Relapses. We further analyzed data from 747
visits (373 prevaccination and 374 postvaccination) in a
single-center subgroup of 166 patients. A total of 158
relapses was detected in 97 patients (Figure 3). Four
patients did not visit the outpatient clinic at all during
the study period, indicating that they did not experience
any flares. Ten patients experienced a disease relapse
within 1 month after vaccination. The risk of a relapse in
the month after vaccination was 6.0%, whereas the risk
of a relapse in the remaining 11 months was 8.1%. The
resulting RR of relapse in the exposed period was 0.74
(95% CI 0.39–1.41). Relative risks of relapse calculated
with an exposed period of 2, 3, or 6 months after MenC
vaccination were similar (RR 0.81 [95% CI 0.48–1.38],
RR 0.76 [95% CI 0.52–1.12], and RR 0.52 [95% CI
0.37–0.72], respectively). Additional statistical analysis
using a program for logistic regression of longitudinal
data did not reveal any increase in risk of relapse after
vaccination. No seasonal influence on relapse frequency
was seen (P⫽0.09).
Efficacy of vaccination. Before vaccination, anti-
MenC IgG geometric mean concentrations were compa-
rable among medication groups (Table 2). The group as
a whole (n ⫽157) showed a significant rise in anti-MenC
IgG geometric mean concentration, from 0.4
g/ml
before vaccination to 28.9
g/ml after vaccination (range
1.0–1,820.5
g/ml) (P⬍0.0005). Anti-MenC IgG geo-
metric mean concentrations were significantly lower in
patients in medication groups 3 and 4 compared with
those in patients in groups 1 and 2 (Table 2). Four of 157
tested patients (2.5%) had anti-MenC IgG levels ⱕ2
g/ml after vaccination. Three of these low responders
took low-dose MTX, 2 of them in combination with
etanercept. The other low responder was being treated
with sulfasalazine. None of the low responders took
Figure 2. Core set criteria scores 6 months before (Pre) and 6 months
after (Post) vaccination with meningococcal serogroup C conjugate in
234 juvenile idiopathic arthritis patients. Values are the mean and
SEM. C-HAQ ⫽Childhood Health Assessment Questionnaire; PGA
⫽physician’s global assessment; AJ ⫽active joints; LOM ⫽limited
range of motion; ESR ⫽erythrocyte sedimentation rate. ⴱ⫽P⬍0.05;
ⴱⴱ ⫽P⬍0.005, versus before vaccination.
642 ZONNEVELD-HUIJSSOON ET AL
steroids during the study. JIA was inactive in 2 low
responders on the vaccination date, while the other 2
had mild or moderately active disease. Since the ex-
pected relapse frequency in low responders was ⬍5in
each medication group, anti-MenC response ⱕ2
g/ml
does not appear to be associated with an increased risk
of relapse.
The 4 patients who took oral steroids all took
MTX as well, and thus belonged to medication groups 3
and 4. Their mean anti-MenC IgG level did not differ
from that of the other patients in groups 3 and 4 (P⫽
0.63 and P⫽0.73, respectively). Anti-MenC IgG levels
in patients with systemic-onset JIA were comparable
with levels measured in all other patients tested.
Patients with an anti-MenC response of ⬎2
g/ml (high responders) showed a significant mean
17-fold rise in anti-TT antibody titers after MenC vac-
cination (postvaccination geometric mean titer 14.95; P
⬍0.001), whereas low responders (anti-MenC ⱕ2
g/
ml) had only a 1.5-fold rise in anti-TT antibody titers
(postvaccination geometric mean titer 3.19; P⫽0.72).
All tested JIA patients, including the 4 with a low
anti-MenC IgG response, were able to mount SBA titers
of ⱖ8 (Figure 4). Although after vaccination a mean
Figure 4. Serum bactericidal antibody titers in patients with juvenile
idiopathic arthritis before and after vaccination with meningococcal
serogroup C (MenC). Low responders (LR) had postvaccination
anti-MenC IgG levels ⱕ2
g/ml; high responders (HR) had postvac-
cination anti-MenC IgG levels ⬎2
g/ml. Broken line indicates the
lower threshold of protection against susceptibility to meningococcal C
infection. Each triangle represents an individual patient (all patients in
the low responder group, and a random sample of 10 patients from the
high responder group). Horizontal lines indicate means.
Figure 3. Distribution of relapses in 97 juvenile idiopathic arthritis
patients before and after meningococcal serogroup C (MenC) vacci-
nation.
Table 2. Anti-MenC IgG geometric mean concentrations and frequency in JIA patients, categorized by medication group*
Group 1 Group 2 Group 3 Group 4
Anti-MenC IgG geometric mean concentration,
g/ml
Before vaccination 0.38 0.41 0.32 0.36
After vaccination 41.00 46.93 17.53 16.28
Low responders (anti-MenC IgG ⱕ2
g/ml), no. (%) 0 0 2 (4.7) 2 (7.7)
* For between-group differences in postvaccination anti-MenC IgG geometric mean concentrations, P⫽0.002, group 1 versus
group 3; P⫽0.01, group 1 versus group 4; P⫽0.003, group 2 versus group 3; P⫽0.012, group 2 versus group 4. There were
no significant differences before vaccination. See Table 1 for definitions and description of the medication groups.
MenC VACCINATION IS SAFE AND EFFECTIVE IN JIA 643
206-fold rise in SBA geometric mean titer was observed
in the 4 low responders, the difference from prevaccina-
tion titers did not reach significance (P⫽0.07) due to
low numbers. The postvaccination SBA titer in the low
responders was not significantly different from that in
the high responders (P⫽0.08).
DISCUSSION
This study shows that MenC vaccination is safe
and effective for use in JIA. In theory, molecular
mimicry of components of the vaccine with self antigens,
combined with specific bystander activation as well as a
loss of regulatory mechanisms, could account for aggra-
vation of autoimmunity after vaccination (1,41). The
occurrence of arthritis in children and adults after
natural infection with N meningitidis indeed suggests
cross-reactivity between nonself and self antigens (42–
44).
In earlier studies, patients with nephrotic syn-
drome seemed to have an increased frequency of relapse
after MenC vaccination (22). Patients with idiopathic
thrombocytopenic purpura also are at a particular risk of
relapse after administration of life-attenuated measles,
mumps, and rubella vaccines (45). Our study in a large
group of JIA patients, however, did not detect any
worsening of disease activity within 6 months after
MenC vaccination. Moreover, the risk of a relapse in the
month after vaccination did not differ from the risk in
the unexposed period. Results remained stable when the
length of the exposed period was varied from 1 to 6
months. This is consistent with previous studies in which
RA and JIA patients tolerated influenza and hepatitis B
vaccinations with no ill effects (8–10,46,47).
Because children could not be included in a
double-blind, placebo-controlled study for ethical rea-
sons, the Dutch vaccination campaign against MenC
yielded a unique study cohort. Because JIA is the most
prevalent autoimmune disease in children, we selected
this patient group. Even though it was possible to
investigate one of the largest cohorts of vaccinated JIA
patients, we realize that statistical power for comparison
of treatment groups is limited.
A large proportion (48.5%) of invited patients
did not reply to the invitation to participate. A low
number of patients agreeing to participate is common in
other vaccination studies. Studies on MenC or influenza
vaccination have yielded participation rates of 47%,
66%, and 53% (22,48,49). Possible explanations for the
low participation rate in this study were the lack of
information provided by the authorities concerning vac-
cination of patients with an autoimmune disease, paren-
tal concerns about a newly introduced vaccine, and the
need for 2 blood draws from the children participating in
the study. Since baseline characteristics of nonreplying
and replying patients were the same, selection bias is
likely to have been minimal.
Since the majority of patients were vaccinated
during the summer, there is a potential influence of
seasonal variability on relapse frequency. In our patient
group, though, a clear seasonality of relapses was absent,
as previously established in other large studies (50,51).
The second aim of our study was to assess the
influence of immunosuppressive medication taken by
JIA patients on the efficacy of MenC vaccines. The
anti-MenC IgG geometric mean concentrations in our
JIA patients overall (28.9
g/ml) was consistent with
anti-MenC IgG values of 29.1–51.6
g/ml observed in 2
separate school cohorts (primary school [age 4.3 years]
and secondary school [age 15.1 years]) and even higher
than those observed by others in healthy adults (17.0
g/ml) or in healthy children ages 12–18 months (13.3
g/ml) 4 weeks after a single dose of the NeisVac-C
vaccine (52–54). Because of this difference in anti-MenC
IgG geometric mean concentrations measured between
our JIA patients and healthy controls in the literature,
we tested 12 healthy volunteers (ages 21–50 years)
before and 6 weeks after vaccination. Their anti-MenC
IgG geometric mean concentration (29.6
g/ml [range
2.1–112.4]) was no different from that in the total group
of JIA patients reported here (P⫽0.631 by Mann-
Whitney U test). Like JIA patients, all healthy controls
showed protective serum bactericidal activity. This fur-
ther supports our conclusion that MenC vaccination in
JIA patients leads to adequate serum antibody levels.
We did note lower postvaccination anti-MenC
IgG geometric mean concentrations in patients using
DMARDs. MTX and, less consistently, tumor necrosis
factor
␣
(TNF
␣
) blockade and prednisone have earlier
been associated with lower pneumococcal antibody re-
sponses in adults, but in studies in children with JIA or
asthma this has not been shown (8–10,55–57). Because
in our study, only 1 patient received anti-TNF
␣
mono-
therapy (and this patient did have an antibody response
⬎2
g/ml) and oral steroids were always taken in
combination with MTX, we could not assess the effect of
these drugs separately. No correlation was found be-
tween total IgG levels and anti-MenC IgG levels (r ⫽
0.17), indicating that lower anti-MenC levels could not be
explained by other immunodeficiencies.
The low response to the MenC part of the
vaccine was associated with a low response to the
conjugate protein TT. Using an SBA, we measured the
ability of these low responders to raise sufficient bacte-
644 ZONNEVELD-HUIJSSOON ET AL
ricidal activity after a single dose of the vaccine (58).
Postvaccination SBA titers in low responders (mean
SBA titer 736) were as high as in high responders and
well above the earlier reported SBA titer in healthy chil-
dren ages 12–18 months (mean 564) (53). Importantly, all
SBA titers after vaccination in patients with a low
anti-MenC response were above the level that predicts
protection. Therefore, all tested JIA patients seem to be
adequately protected against meningococcal serogroup
C disease after MenC vaccination, irrespective of the
immunosuppressive treatment given (59).
ACKNOWLEDGMENTS
We thank Erica Roks, Eline van Amerongen, Mark
Klein, Wilco de Jager, Irina Tcherniaeva, Corine Nellestijn,
Rene´e van Soesbergen, Koert Dolman, Rebecca ten Cate,
Yvonne Koopman, and Vincent Zonneveld for patient referral
and technical assistance.
AUTHOR CONTRIBUTIONS
Dr. Zonneveld-Huijssoon had full access to all of the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study design. Drs. van Rossum, Sanders, Vermeer-de Bondt, Hoes,
Kuis, Prakken, van Tol, and Wulffraat.
Acquisition of data. Dr. Zonneveld-Huijssoon, Mr. Ronaghy, Drs. van
Rossum, van der Klis, and van der Net, and Ms Engels.
Analysis and interpretation of data. Dr. Zonneveld-Huijssoon, Mr.
Ronaghy, and Drs. Rijkers, Sanders, and Wulffraat.
Manuscript preparation. Dr. Zonneveld-Huijssoon, Mr. Ronaghy, and
Dr. Wulffraat.
Statistical analysis. Drs. Zonneveld-Huijssoon and Hoes.
REFERENCES
1. Wraith DC, Goldman M, Lambert PH. Vaccination and auto-
immune disease: what is the evidence? [review]. Lancet 2003;362:
1659–66.
2. Ravel G, Christ M, Horand F, Descotes J. Autoimmunit y, envi-
ronmental exposure and vaccination: is there a link? Toxicology
2004;196:211–6.
3. Schattner A. Consequence or coincidence? The occurrence,
pathogenesis and significance of autoimmune manifestations after
viral vaccines [review]. Vaccine 2005;23:3876–86.
4. Gellin BG, Schaffner W. The risk of vaccination: the importance
of “negative” studies. N Engl J Med 2001;344:372–3.
5. Confavreux C, Suissa S, Saddier P, Bourdes V, Vukusic S, for the
Vaccines in Multiple Sclerosis Study Group. Vaccinations and the
risk of relapse in multiple sclerosis. N Engl J Med 2001;344:
319–26.
6. Ascherio A, Zhang SM, Hernan MA, Olek MJ, Coplan PM,
Brodovicz K, et al. Hepatitis B vaccination and the risk of multiple
sclerosis. N Engl J Med 2001;344:327–32.
7. Graves PM, Barriga KJ, Norris JM, Hoffman MR, Yu L, Eisen-
barth GS, et al. Lack of association between early childhood
immunizations and

-cell autoimmunity. Diabetes Care 1999;22:
1694–7.
8. Kanakoudi-Tsakalidou F, Trachana M, Pratsidou-Gertsi P, Tsit-
sami E, Kyriazopoulou-Dalaina V. Influenza vaccination in chil-
dren with chronic rheumatic diseases and long-term immunosup-
pressive therapy. Clin Exp Rheumatol 2001;19:589–94.
9. Malleson PN, Tekano JL, Scheifele DW, Weber JM. Influenza
immunization in children with chronic arthritis: a prospective
study. J Rheumatol 1993;20:1769–73.
10. Kasapcopur O, Cullu F, Kamburoglu-Goksel A, Cam H, Akdenizli
E, Calykan S, et al. Hepatitis B vaccination in children with
juvenile idiopathic arthritis. Ann Rheum Dis 2004;63:1128–30.
11. Offit PA, Hackett CJ. Addressing parents’ concerns: do vaccines
cause allergic or autoimmune diseases? [review]. Pediatrics 2003;
111:653–9.
12. Hak E, Schonbeck Y, De Melker H, Van Essen GA, Sanders EA.
Negative attitude of highly educated parents and health care
workers towards future vaccinations in the Dutch childhood
vaccination program. Vaccine 2005;23:3103–7.
13. Inspectorate for Dutch Health Care. Vaccination situation in the
Netherlands per January 2002 [with abstract in English]. The
Hague, The Netherlands; 2004.
14. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE.
Frequency of infection in patients with rheumatoid arthritis com-
pared with controls: a population-based study. Arthritis Rheum
2002;46:2287–93.
15. Davies K, Woo P. Immunization in rheumatic diseases of child-
hood: an audit of the clinical practice of British Paediatric
Rheumatology Group members and a review of the evidence.
Rheumatology (Oxford) 2002;41:937–41.
16. BSR Clinical Affairs Committee. Vaccinations in the immunocom-
promised person: guidelines for the patient taking immunosup-
pressants, steroids and the new biologic therapies. London: British
Society for Rheumatology; 2002.
17. Conyn-van Spaendonck MA, Reintjes R, Spanjaard L, van
Kregten E, Kraaijeveld AG, Jacobs PH. Meningococcal carriage in
relation to an outbreak of invasive disease due to Neisseria
meningitidis serogroup C in the Netherlands. J Infect 1999;39:
42–8.
18. Van Furth AM, Vandenbroucke-Grauls CM. Universal vaccina-
tion against group C meningococci and pneumococci; advice from
the Health Council of the Netherlands. Ned Tijdschr Geneeskd
2002;146:932–3.
19. World Health Organization. Causalit y assessment of adverse
events following immunization. Wkly Epidemiol Rec 2001;76:
85–9.
20. Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Taylor B.
Idiopathic thrombocytopenic purpura and MMR vaccine. Arch
Dis Child 2001;84:227–9.
21. Benjamin CM, Chew GC, Silman AJ. Joint and limb symptoms in
children after immunisation with measles, mumps, and rubella
vaccine. BMJ 1992;304:1075–8.
22. Abeyagunawardena AS, Goldblatt D, Andrews N, Trompeter RS.
Risk of relapse after meningococcal C conjugate vaccine in
nephrotic syndrome. Lancet 2003;362:449–50.
23. Pett y RE, Southwood TR, Manners P, Baum J, Glass DN,
Goldenberg J, et al. International League of Associations for
Rheumatology classification of juvenile idiopathic arthritis: second
revision, Edmonton, 2001. J Rheumatol 2004;31:390–2.
24. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT,
Martini A. Preliminary definition of improvement in juvenile
arthritis. Arthritis Rheum 1997;40:1202–9.
25. Ruperto N, Ravelli A, Pistorio A, Malattia C, Cavuto S, Gado-
West L, et al. Cross-cultural adaptation and psychometric evalu-
ation of the Childhood Health Assessment Questionnaire
(CHAQ) and the Child Health Questionnaire (CHQ) in 32
countries: review of the general methodology. Clin Exp Rheuma-
tol 2001;19(4 Suppl 23):S1–9.
26. Wulffraat N, van der Net JJ, Ruperto N, Kamphuis S, Prakken BJ,
Ten Cate R, et al. The Dutch version of the Childhood Health
Assessment Questionnaire (CHAQ) and the Child Health Ques-
tionnaire (CHQ). Clin Exp Rheumatol 2001;19(4 Suppl 23):
S111–5.
MenC VACCINATION IS SAFE AND EFFECTIVE IN JIA 645
27. Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Dalakos TG,
Grieveson P, et al. Clinical studies with an articular index for the
assessment of joint tenderness in patients with rheumatoid arthri-
tis. Q J Med 1968;37:393–406.
28. Brunner HI, Lovell DJ, Finck BK, Giannini EH. Preliminary
definition of disease flare in juvenile rheumatoid arthritis. J Rheu-
matol 2002;29:1058–64.
29. Gheesling LL, Carlone GM, Pais LB, Holder PF, Maslanka SE,
Plikaytis BD, et al. Multicenter comparison of Neisseria meningi-
tidis serogroup C anti-capsular polysaccharide antibody levels
measured by a standardized enzyme-linked immunosorbent assay.
J Clin Microbiol 1994;32:1475–82.
30. Holder PK, Maslanka SE, Pais LB, Dykes J, Plikaytis BD, Carlone
GM. Assignment of Neisseria meningitidis serogroup A and C
class-specific anticapsular antibody concentrations to the new
standard reference serum CDC1992. Clin Diagn Lab Immunol
1995;2:132–7.
31. Maslanka SE, Tappero JW, Plikaytis BD, Brumberg RS, Dykes
JK, Gheesling LL, et al. Age-dependent Neisseria meningitidis
serogroup C class-specific antibody concentrations and bacteri-
cidal titers in sera from young children from Montana immunized
with a licensed polysaccharide vaccine. Infect Immun 1998;66:
2453–9.
32. Gold R, Lepow ML, Goldschneider I, Draper TF, Gotshlich EC.
Kinetics of antibody production to group A and group C menin-
gococcal polysaccharide vaccines administered during the first six
years of life: prospects for routine immunization of infants and
children. J Infect Dis 1979;140:690–7.
33. Hendriksen CF, van der Gun JW, Kreeftenberg JG. Combined
estimation of tetanus and diphtheria antitoxin in human sera by
the in vitro toxin-binding inhibition (ToBI) test. J Biol Stand
1989;17:191–200.
34. Maslanka SE, Gheesling LL, Libutti DE, Donaldson KB, Harakeh
HS, Dykes JK, et al, for the Multilaboratory Study Group.
Standardization and a multilaboratory comparison of Neisseria
meningitidis serogroup A and C serum bactericidal assays. Clin
Diagn Lab Immunol 1997;4:156–67.
35. Borrow R, Andrews N, Goldblatt D, Miller E. Serological basis for
use of meningococcal serogroup C conjugate vaccines in the
United Kingdom: reevaluation of correlates of protection. Infect
Immun 2001;69:1568–73.
36. Fairley CK, Begg N, Borrow R, Fox AJ, Jones DM, Cartwright K.
Conjugate meningococcal serogroup A and C vaccine: reactoge-
nicity and immunogenicity in United Kingdom infants. J Infect Dis
1996;174:1360–3.
37. King WJ, MacDonald NE, Wells G, Huang J, Allen U, Chan F, et
al. Total and functional antibody response to a quadrivalent
meningococcal polysaccharide vaccine among children. J Pediatr
1996;128:196–202.
38. Mitchell LA, Ochnio JJ, Glover C, Lee AY, Ho MK, Bell A.
Analysis of meningococcal serogroup C-specific antibody levels in
British Columbian children and adolescents. J Infect Dis 1996;173:
1009–13.
39. Lepow ML, Beeler J, Randolph M, Samuelson JS, Hankins WA.
Reactogenicity and immunogenicity of a quadrivalent combined
meningococcal polysaccharide vaccine in children. J Infect Dis
1986;154:1033–6.
40. Hedeker D, Gibbons RD. MIXOR: a computer program for
mixed-effects ordinal regression analysis. Comput Methods Pro-
grams Biomed 1996;49:157–76.
41. Wucherpfennig KW. Mechanisms for the induction of autoimmu-
nity by infectious agents [review]. J Clin Invest 2001;108:1097–104.
42. Schaad UB. Arthritis in disease due to Neisseria meningitidis
[review]. Rev Infect Dis 1980;2:880–8.
43. Likitnukul S, McCracken GH Jr, Nelson JD. Arthritis in children
with bacterial meningitis. Am J Dis Child 1986;140:424–7.
44. Edwards MS, Baker CJ. Complications and sequelae of meningo-
coccal infections in children. J Pediatr 1981;99:540–5.
45. Vlacha V, Forman EN, Miron D, Peter G. Recurrent thrombocy-
topenic purpura after repeated measles-mumps-rubella vaccina-
tion. Pediatrics 1996;97:738–9.
46. Chalmers A, Scheifele D, Patterson C, Williams D, Weber J,
Shuckett R, et al. Immunization of patients with rheumatoid
arthritis against influenza: a study of vaccine safety and immuno-
genicity. J Rheumatol 1994;21:1203–6.
47. Elkayam O, Yaron M, Caspi D. Safet y and efficacy of vaccination
against hepatitis B in patients with rheumatoid arthritis. Ann
Rheum Dis 2002;61:623–5.
48. Lasky T, Terracciano GJ, Magder L, Koski CL, Ballesteros M,
Nash D, et al. The Guillain-Barre syndrome and the 1992-1993
and 1993-1994 influenza vaccines. N Engl J Med 1998;339:
1797–802.
49. Mutsch M, Zhou W, Rhodes P, Bopp M, Chen RT, Linder T, et al.
Use of the inactivated intranasal influenza vaccine and the risk of
Bell’s palsy in Switzerland. N Engl J Med 2004;350:896–903.
50. Uziel Y, Pomeranz A, Brik R, Navon P, Mukamel M, Press J, et al.
Seasonal variation in systemic onset juvenile rheumatoid arthritis
in Israel. J Rheumatol 1999;26:1187–9.
51. Feldman BM, Birdi N, Boone JE, Dent PB, Duffy CM, Ellsworth
JE, et al. Seasonal onset of systemic-onset juvenile rheumatoid
arthritis. J Pediatr 1996;129:513–8.
52. Burrage M, Robinson A, Borrow R, Andrews N, Southern J,
Findlow J, et al. Effect of vaccination with carrier protein on
response to meningococcal C conjugate vaccines and value of
different immunoassays as predictors of protection. Infect Immun
2002;70:4946–54.
53. Richmond P, Borrow R, Goldblatt D, Findlow J, Martin S, Morris
R, et al. Ability of 3 different meningococcal C conjugate vaccines
to induce immunologic memory after a single dose in UK toddlers.
J Infect Dis 2001;183:160–3.
54. Richmond P, Goldblatt D, Fusco PC, Fusco JD, Heron I, Clark S,
et al. Safety and immunogenicity of a new Neisseria meningitidis
serogroup C-tetanus toxoid conjugate vaccine in healthy adults.
Vaccine 1999;18:641–6.
55. Kapetanovic MC, Saxne T, Sjoholm A, Truedsson L, Jonsson G,
Geborek P. Influence of methotrexate, TNF blockers and pred-
nisolone on antibody responses to pneumococcal polysaccharide
vaccine in patients with rheumatoid arthritis. Rheumatology (Ox-
ford) 2006;45:106–11.
56. Mease PJ, Ritchlin CT, Martin RW, Gottlieb AB, Baumgartner
SW, Burge DJ, et al. Pneumococcal vaccine response in psoriatic
arthritis patients during treatment with etanercept. J Rheumatol
2004;31:1356–61.
57. Park CL, Frank AL, Sullivan M, Jindal P, Baxter BD. Influenza
vaccination of children during acute asthma exacerbation and
concurrent prednisone therapy. Pediatrics 1996;98:196–200.
58. Nicholson A, Lepow IH. Host defense against Neisseria meningi-
tidis requires a complement-dependent bactericidal activity. Sci-
ence 1979;205:298–9.
59. Andrews N, Borrow R, Miller E. Validation of serological corre-
late of protection for meningococcal C conjugate vaccine by using
efficacy estimates from postlicensure surveillance in England. Clin
Diagn Lab Immunol 2003;10:780–6.
646 ZONNEVELD-HUIJSSOON ET AL
