ORIGINAL www.jpeds.

com • THE JOURNAL OF PEDIATRICS

ARTICLES
Comorbidity of Type 1 Diabetes Mellitus in Patients with Juvenile
Idiopathic Arthritis
Sandra Schenck, MSc1, Joachim Rosenbauer, MD2,3, Martina Niewerth, MPH1, Jens Klotsche, PhD1,4, Kirsten Minden, MD1,5,
Tobias Schwarz, MD6, Ivan Foeldvari, MD7, Gerd Horneff, MD8, Frank Weller-Heinemann, MD9, Reinhard W. Holl, MD, PhD10,
and Angelika Thon, MD11

Objectives To determine the prevalence of type 1 diabetes mellitus (T1D) in patients with juvenile idiopathic ar-
thritis (JIA) and to characterize patients having both.
Study design Diabetes comorbidity was recorded in the National Pediatric Rheumatologic Database since 2012.
Data from the North Rhine-Westphalian diabetes registry served as the reference population for the prevalence of
diabetes in the general population. The National Pediatric Rheumatologic Database data were indirectly standard-
ized for age and sex for comparison with the general population. The diabetes prevalence ratio was calculated
using the Poisson regression model.
Results The analysis included 12 269 patients with JIA. A total of 58 patients had comorbid T1D, and the dia-
betes prevalence was 0.5%. The mean age was 11.6 years at the time of documentation, and the mean disease
duration was 4.2 years. Compared with the general population, the prevalence of diabetes in patients with JIA was
significantly increased (prevalence ratio 1.76 [95% CI 1.34; 2.28], P < .001). The onset of diabetes in patients with
JIA was earlier than that reported in the reference data. Sixty-three percent of patients developed T1D before JIA.
On average, diabetes onset was 56 months before the onset of JIA. Patients who first developed JIA developed
T1D on average 40 months later. The majority of patients had not received disease-modifying antirheumatic drugs
before diabetes onset.
Conclusions T1D occurs more frequently in patients with JIA than in the general population. The likelihood of
T1D occurrence appears to be slightly higher before JIA manifestation and without disease-modifying antirheu-
matic drug therapy after JIA onset. (J Pediatr 2018;192:196-203).

See editorial, p 6

J
uvenile idiopathic arthritis (JIA) is the most common chronic childhood inflammatory rheumatic disease in Europe,
with an estimated incidence of 2-20 cases per 100 000 children and adolescents.1 JIA comprises a clinically heteroge-
neous group of arthritides characterized by persistent joint inflammation and a disease onset before 16 years of age. Most
of the categories of JIA are related to autoimmunity.2
Twin and family studies have emphasized the importance of genetic predispo-
sition for autoimmune diseases (AIDs).3-5 Genetic analyses have shown an
association between mutations in certain susceptibility gene loci and AIDs. From the 1German Rheumatism Research Center Berlin,
a Leibniz Institute, Berlin, Berlin; 2Institute for Biometrics
Phenotypically different AIDs share genetic susceptibility factors.6,7 Several single and Epidemiology, German Diabetes Center, Leibniz
nucleotide polymorphisms associated with JIA have been identified.7-10 Patients Centre at Heinrich-Heine University Dusseldorf,
Dusseldorf; 3German Center for Diabetes Research
(DZD), Munich-Neuherberg; 4Institute for Social Medicine,
Epidemiology and Health Economics, Charité
Universitätsmedizin, Berlin; 5Department of
Rheumatology and Clinical Immunology, Charité
AID Autoimmune disease Universitätsmedizin Berlin, Berlin; 6Department of
AIT Autoimmune thyroiditis Pediatric Rheumatology, St. Josef-Stift, Sendenhorst;
7Hamburg Centre for Rheumatology for Children and
bDMARD Biological DMARD Adolescents, Clinical Center Eilbek; 8Asklepios Clinic
BMI Body mass index Sankt Augustin, Sankt Augustin, University Hospital of
CD Celiac disease Cologne, Cologne; 9Department of Pediatric
Rheumatology, Prof.-Hess-Kinderklinik, Bremen;
cJADAS Clinical Juvenile Arthritis Disease Activity Score 10Institute of Epidemiology and Medical Biometry, ZIBMT,

DM Diabetes mellitus University of Ulm, Ulm; and 11Department of Pediatric

DMARD Disease-modifying antirheumatic drug Pneumology, Allergology and Neonatology, Children’s
Hospital, Medical School, Hanover, Germany
DPV Diabetes Patienten Verlaufsdokumentation
The NPRD has been funded by the German Children
JIA Juvenile idiopathic arthritis Arthritis Foundation (Deutsche Kinder-Rheumastiftung),
MTX Methotrexate the DPV and METARTHROS (01EC1407D) are funded by
NPRD National Pediatric Rheumatologic Database the Federal Ministry of Education and Research. The
authors declare no conflicts of interest.
PR Prevalence ratio
T1D Type 1 diabetes mellitus 0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights
T2D Type 2 diabetes mellitus reserved.
https://doi.org10.1016/j.jpeds.2017.07.050

196

with 1 AID are at an increased risk for another AID.11 For
example, the genetic association between type 1 diabetes mel-
litus (T1D) and JIA has been described.12,13
Epidemiologic knowledge about the comorbidity of JIA and
T1D is limited. Previous studies are based mostly on case
reports.14-16 A few observational studies have shown an in-
creased frequency of diabetes mellitus (DM) in patients with
JIA compared with the general population.17,18 Detailed in-
formation about the comorbidity of T1D in patients with JIA
has been limited. Two established prospective cohorts in
Germany, the National Pediatric Rheumatologic Database
(NPRD) for JIA and the North Rhine-Westphalian Diabetes
Registry for T1D, provide a unique opportunity to investi-
gate the co-occurrence of JIA and T1D.
In 2015, Hermann et al published data on the prevalence
of JIA in patients with T1D. They showed an increased preva-
lence of JIA compared with the general population and an
earlier onset of diabetes in patients with JIA.19 The present
study, based on the NPRD data, aimed to determine the
prevalence of T1D in patients with JIA and to characterize
the features of patients with JIA with T1D vs patients with
JIA without T1D.
Methods
The NPRD of children and adolescents with rheumatic
diseases was started in 1997 and includes incident and preva-
lent cases of a wide spectrum of juvenile rheumatic diseases.
The majority of enrolled patients (3 of 4 patients) have JIA.
Enrolled patients are followed annually by a physician and
patient questionnaire. For more details, we refer to previous
NPRD publications.20-22 Patients with JIA according to the
International League of Associations for Rheumatology
criteria23,24 who were 20 years of age or younger and re-
corded in the NPRD between 2012 and 2014, were included
in this study.
Information about comorbid DM was recorded from 2012
to 2014. The presence of autoimmune thyroiditis (AIT) and
celiac disease (CD) was documented by physicians only in 2013
and 2014. An additional short questionnaire on DM was used
to confirm the diagnosis of DM and to provide more details
regarding T1D. Patients recorded in multiple years were counted
only once.
The prevalence of T1D in patients with JIA was compared
with the prevalence of T1D in the general population of chil-
dren and adolescents aged 0-20 years in the federal state of
North Rhine-Westphalia on December 31, 2014. Indepen-
dent registries for T1D exist in 4 federal German states. We
chose North Rhine-Westphalia for our comparison because it
comprises 22%-23% of all German children and adoles-
cents. The prevalence data of North Rhine-Westphalia were
derived from the North Rhine-Westphalian diabetes registry
maintained at the German Diabetes Center since 1993. The
prevalence of T1D in North Rhine-Westphalia is higher than
in other parts of Germany.25
Incident cases between the ages of 0 and 20 years for the
period 2002-2014 were selected from the registry to estimate
Volume 192 • January 2018
the cumulative age distribution of T1D onset in the general
population compared with the distribution of T1D onset in
patients with JIA. This registry ascertains newly diagnosed
cases of T1D from 3 data sources: a prospective hospital-
based active surveillance system (Erhebungseinheit für Seltene
Pädiatrische Erkrankungen in Deutschland [ESPED]), annual
inquiries among medical practices (pediatricians, general
practitioners, and internal specialists), and the diabetes pro-
spective follow-up (Diabetes-Patienten-Verlaufsdokumentation
[DPV]) database. DPV is a computer-based system for lon-
gitudinal documentation of treatment and outcomes in routine
diabetes care.26 The DPV software is used in more than 420
diabetes centers in Germany. Completeness of the North
Rhine-Westphalian diabetes registry is estimated at 99%.
Sociodemographic and clinical characteristics, and patient-
reported outcome measures were annually recorded in the
NPRD. These included age, sex, body height, and weight, JIA
duration, age at JIA onset, JIA category, treatment, and others.
Body mass index (BMI) was calculated by dividing body weight
(in kg) by squared body height (in meters). Categories of un-
derweight, normal weight, overweight, and obesity were defined
according to sex- and age-specific BMI percentile curves for
German children as suggested by Kromeyer-Hauschild et al.27
The physicians recorded treatments with conventional syn-
thetic and biological disease-modifying antirheumatic drugs
(DMARD) as well as glucocorticoids, including low dose
(<0.2 mg/kg), high dose (≥0.2 mg/kg), and pulse therapy. In
addition, physicians recorded comorbidities of DM, AIT, and
CD and their onset dates.
The patient’s JIA disease activity was assessed by the pedi-
atric rheumatologist using a numeric rating scale (0-10, 0-no
disease activity). The clinical Juvenile Arthritis Disease Activ-
ity Score (cJADAS)28 is a composite index for assessment of
JIA disease activity. The cJADAS-10 is the sum of the physi-
cian’s and patient’s/parent’s global assessment and the number
of active joints (maximum = 10). Functional ability was re-
ported by patients or parents using the Childhood Health As-
sessment Questionnaire, calculated as a disability index ranging
between 0 and 3 (0-no disability).29
The DM questionnaire was sent to pediatric rheumatol-
ogy centers that recorded a DM case between 2012 and 2014
and included questions regarding the type of DM (T1D, type
2 diabetes mellitus [T2D], steroid-induced diabetes, maturity-
onset diabetes of the young-type, and others), age at DM di-
agnosis, insulin treatment, diagnosis of other AIDs (including
AIT and CD), and family history of AIDs.
Statistical Analyses
Cross-sectional data from the NPRD for the years 2012, 2013,
and 2014 were used to determine the diabetes rate in pa-
tients with JIA. Descriptive analyses included absolute and rela-
tive frequencies for categorical variables, means and SDs or
median and IQR, if appropriate, for continuously distrib-
uted variables.
The frequency of T1D in patients with JIA was compared
with the population-based data of the North Rhine-Westphalian
diabetes registry.25 Crude diabetes prevalence and respective
197
THE JOURNAL OF PEDIATRICS • www.jpeds.com
95% CIs were estimated assuming a Poisson distribution of
cases. For comparison between the JIA cohort and the general
population, prevalences were indirectly standardized with
respect to sex and/or age (age groups 0-4, 5-9, 10-14, and
15-20 years) to the general population of North Rhine-
Westphalia. Standardized prevalence ratios (PRs) with 95%
CIs and P values of respective c2 tests were estimated.30 We
analyzed the cumulative distribution of the age at T1D onset
for patients with JIA compared with the general population.
For a descriptive subanalysis of JIA treatment before T1D
onset, longitudinally collected data from 2000 to 2014 were
considered in a subset of patients only, who had been docu-
mented at least once before T1D onset. The overall
redocumentation rate was approximately 60%, which was the
reason longitudinal data were not available for all patients
who developed JIA before T1D. Statistical analysis was
conducted using SPSS Statistics 23, (IBM SPSS; SPSS Inc,
Chicago, Illinois) and SAS v 9.4 (SAS Institute, Cary, North
Carolina).
Results
DM was recorded in 62 of 12 269 patients with JIA. Two pa-
tients were diagnosed with T2D and 2 patients had maturity-
onset diabetes of the young and, therefore, were excluded from
analysis. Therefore, the prevalence of T1D in the NPRD was
0.47% (95% CI 0.36-0.61). T1D prevalences for sex and age
groups are shown in Figure 1. T1D was significantly more
common in patients with JIA than in the general population
(PR 1.76 (CI 1.34; 2.28), P < .001). The T1D PR was 1.72 (CI
1.21; 2.38, P = .003) for female patients and 1.83 (CI 1.15; 2.77,
P = .012) for male patients. There was no statistically signifi-
cant difference in the T1D rate between male and female
Figure 1. Prevalence of T1D in patients with JIA compared with population data stratified by age and sex; reference data from
the North Rhine-Westphalian diabetes register.
198
Volume 192
patients. The T1D prevalence ratio differed among the various
age groups. The T1D rate ratio among male patients differed
with age from 1.73 between 5 and 9 years and 2.18 between
15 and 20 years. Differences between age groups were more
pronounced among female patients from 1.12 between 10 and
14 years and 2.78 between 0 and 4 years. Differences between
the sexes were not statistically significant.
The sociodemographic and clinical characteristics of pa-
tients with JIA with or without T1D are reported in Table I.
The differences in the JIA category distribution were not
statistically significant between the 2 groups. Patients with
JIA without T1D were significantly younger at JIA onset
than patients with T1D (P = .032). There were no significant
differences in the duration of JIA or in the therapy of both
groups. The duration from symptom onset until the first
visit to a rheumatologist did not differ between the patient
groups.
A comparison of sex- and age-adjusted anthropometric SDS
did not reveal differences for height between the groups. Pa-
tients without T1D had a lower weight than patients with T1D
(P = .042). Both groups had a lower weight than the refer-
ence data. The BMI SDS in patients with JIA and T1D (0.17)
were significantly higher than the BMI SDS in patients without
T1D (-0.25, P = .007). The proportion of overweight/obese
patients in the group of patients with JIA and T1D was higher
than in those without T1D (14.3% vs 10.8%, respectively). The
distribution of the outcome variables (functional disability, phy-
sician’s global assessment, and cJADAS-10) was comparable
between the groups.
The mean age at diabetes onset was 7.1 years (SD 4.4
years), and the mean duration of diabetes at documentation
was 6.4 years (SD 4.5 years). Eleven (19%) of the patients
with JIA and T1D were documented with an additional AID.
Comorbid AIT and CD were reported in 6 (10.3%) patients
Schenck et al
January 2018 ORIGINAL ARTICLES

duration: 80.9 (SD 55.6) months), 4 patients (26.7%) were

Table I. Characteristics and outcomes of patients with
treated at documentation or during the prior year with a
JIA, with and without T1D
combination of methotrexate (MTX) and a biological DMARD
Sociodemographic and Patients with JIA Patients with JIA (bDMARD), 1 patient (6.7%) was treated with a bDMARD,
clinical characteristics without T1D with T1D
and 5 patients (33.3%) were treated with MTX alone. In
No. of patients 12 211 58 (0.5%) contrast, in the group with a higher insulin requirement
Female 8007 (65.6) 36 (62.1)
Age at JIA onset (y) 7.3 (4.6) 8.9 (5.4) (>0.5 IU/kg/day, n = 14, mean T1D duration: 89.6 [SD 54.8]
Duration until first visit at 7.8 (15.7) 9.5 (22.2) months), 2 patients (14.3%) were treated with MTX in com-
rheumatologist (mo) bination with a bDMARD, 1 patient (7.1%) was treated with
JIA duration (y) 4.2 (3.8) 4.8 (4.1)
JIA category a bDMARD, and 6 patients (42.9%) were treated with MTX
RF-positive polyarthritis 275 (2.3) 1 (1.7) alone. Thus, approximately 60% of the patients in both groups
RF-negative polyarthritis 2351 (19.3) 20 (34.5) were treated with MTX. However, patients with a low insulin
Systemic JIA 519 (4.3) 2 (3.4)
Persistent oligoarthritis 5086 (41.7) 17 (29.3) requirement were more often treated with a bDMARD than
Extended oligoarthritis 1141 (9.3) 6 (10.3) patients with a higher insulin requirement (33.3% vs 21.4%,
Psoriatic arthritis 838 (6.9) 5 (8.6) respectively). The duration of T1D was not significantly dif-
Enthesitis-related arthritis 1538 (12.6) 7 (12.1)
Other arthritis 463 (3.8) 0 ferent between the groups (P = .668).
cJADAS-10 4.6 (5.2) 4.0 (5.2) Information about the onset of both diseases was available
JIA disease activity (NRS 0-10) 1.61 (2.0) 1.2 (1.8) for 54 (93.1%) of the 58 T1D cases; for 3 patients the T1D onset
C-HAQ total score 0.26 (0.45) 0.27 (0.6)
Body weight (SDS)* −0.48 (1.2) −0.15 (1.0) was unknown, and in 1 patient both the JIA and diabetes onset
Body height (SDS)* −0.48 (1.4) −0.49 (1.4) was missing. T1D occurred in 63% of the patients before the
BMI (SDS)* −0.25 (1.2) 0.17 (0.8) onset of JIA (mean 56.4 months; SD 42.6 months). In 37%
Treatment†
Systemic glucocorticoids 1526 (12.5) 5 (8.6) of the patients, JIA symptoms preceded the onset of T1D by
cs and bDMARD 6075 (49.8) 28 (48.3) a mean of 40 months (SD 40.9 months).
MTX 4661 (38.2) 22 (37.9) We analyzed the cumulative distribution of the age at T1D
bDMARD 2090 (17.1) 11 (19.0)
onset of patients with JIA compared with the general popu-
cJADAS-10, cJADAS 10-point; NRS, numeric rating scale; C-HAQ, Childhood Health Assess- lation (Figure 2). T1D manifested earlier in patients with JIA
ment Questionnaire; RF, rheumatoid factor.
Data are mean (SD) or n (%). compared with the reference population (means, JIA: 7.1 years;
All characteristics are from the time of documentation. reference: 9.4 years). In the JIA group, 50% developed T1D
*Reference values from KIGGS - The German Health Survey for Children and Adolescents
(Robert-Koch Institute). before the age of 6 years, and in the general population 50%
†Treatment currently and/ or in the year before documentation. of T1D cases developed until the age of 9 years. We observed
an earlier and faster slope for patients with JIA compared with
the general population. However, after the age of 10 years, the
and 2 (3.4%) patients, respectively. One patient had autoim- rate of accumulation of new T1D cases in JIA diminished
mune pancreatitis, and in 2 cases, the additional AID was greatly, although the cumulative incidence in the general popu-
“unknown” or “not confirmed.” Nearly all patients with T1D lation continued to increase with age.
were receiving insulin therapy (94.6%) with a mean daily We divided the patients with JIA with comorbid T1D into
dosage of 0.55 IU/kg (SD 0.29). Among the 15 patients with 2 groups, T1D first (diabetes1st, n = 34) and JIA first (JIA1st,
a low insulin requirement (≤0.5 IU/kg/day, mean T1D n = 20). Patient characteristics for the 2 groups are shown in

Figure 2. Cumulative distribution of age at the onset of T1D in patients with JIA (n = 54) and in the general population (n = 9943);
reference data from the North Rhine-Westphalian diabetes register.

Comorbidity of Type 1 Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis 199
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 192

nationwide pediatric rheumatologic database. This study in-

Table II. Characteristics and outcomes of patients with
volved a large cohort of patients with JIA with comorbid T1D
JIA and T1D onset before (Diabetes1st) vs after JIA onset
using a cross-sectional design. We found that the T1D preva-
(JIA1st)
lence was nearly twice as high in patients with JIA as in the
Sociodemographic and general population. Comorbid T1D did not seem to affect
clinical characteristics Diabetes1st JIA1st
the outcomes in patients with JIA. T1D onset in patients with
No. of patients 34 20 JIA occurred earlier than in the general population and two-
Female 19 (55.9) 16 (80.0)
Time until second diagnosis (mo) 57 (43) 40 (41) thirds of patients with JIA and T1D developed T1D before
Age at JIA onset (y) 11.8 (4.5) 4.2 (3.2) JIA. No patient with JIA developed T1D after initiating
JIA duration (y) 3.2 (3.4) 7.2 (4.3) bDMARD therapy.
Age at diabetes onset (y) 6.7 (4.7) 7.7 (4.1)
Diabetes duration (y) 7.9 (4.2) 3.9 (3.8) Our results are comparable to findings of previously pub-
JIA category lished studies. An American and a Finnish cohort study also
RF-negative polyarthritis 14 (41.2) 5 (25.0) investigated the occurrence of T1D in patients with JIA com-
Persistent oligoarthritis 9 (26.5) 8 (40.0)
Extended oligoarthritis 2 (5.9) 4 (20.0) pared with population-based data.6,31 T1D prevalence was 1.1%
Other arthritis 9 (26.4) 3 (15.0) (5 of 443 patients) in the American cohort and 2.2% (9 of 417
cJADAS-10 4.3 (6.0) 3.6 (3.2) patients) in the Finnish cohort. Our reported diabetes rate ratio
JIA disease activity (NRS 0-10) 1.20 (1.64) 1.13 (2.11)
Inactive disease* 16 (48.5) 10 (50.0) was lower compared with these cohorts who found a 5- to
C-HAQ total score 0.33 (0.64) 0.18 (0.52) 6-fold increase in the T1D prevalence in patients with JIA com-
No functional limitations† 21 (67.7) 13 (76.5) pared with the reference data. It should be noted that there is
Treatment‡
Systemic glucocorticoids 2 (5.9) 2 (10.0) a north-south gradient of AIDs, and Finland has the world’s
cs and bDMARD 20 (58.8) 8 (40.0) highest T1D prevalence.32 The results of the Finnish cohort were
MTX 15 (44.1) 6 (30.0) similar to our results in that the frequency of an additional
bDMARD 7 (20.6) 4 (20.0)
Duration until first visit at rheumatologist (mo) 9.6 (26.7) 9.2 (13.9) AID (22%), AIT (14.6%), and CD (7%) in patients with JIA
Daily insulin dosage per kg bodyweight (IU/kg) 0.57 (0.32) 0.49 (0.20) was comparable. These results support a genetic association
csDMARD, conventional synthetic DMARD.
of JIA with other AIDs.
Data are mean (SD) or n (%). Although we and others observed a higher prevalence of
All characteristics are from the time of documentation. T1D in patients with JIA, Hermann et al studied comorbid
*Defined by a physician's global assessment score of zero
†Defined as CHAQ = 0. JIA in T1D patients.19,20 Data showed a 4-fold increase in JIA
‡Treatment currently and/ or in the year before documentation. prevalence among 54 911 patients with T1D compared with
the general population. Thus, our results confirmed a higher
Table II. Patients in the JIA1st group were an average of 3.2 years risk for the development of T1D in patients with JIA, and
younger at the time of documentation (P = .01) and 7.6 years the DPV diabetes register data confirmed a higher risk for
younger at JIA onset (P < .001) than patients in the diabetes1st the development of JIA in patients with T1D.19 As in our
group. The age at T1D onset did not differ significantly between data, the majority of patients with T1D and JIA from the
the groups. For the JIA1st group, the mean JIA disease dura- DPV diabetes register developed T1D before the onset of JIA
tion was significantly longer (P < .001), and the mean T1D du- (88%).
ration was significantly shorter (P = .001) than that of the Hermann et al compared patients with T1D and JIA with
diabetes1st group. Differences in the distribution of JIA cat- patients with T1D without JIA and found a decrease in weight
egories, therapy, and anthropometric measurements were not (SDS 0.02 vs 0.22, respectively, P = .01).19 Our data con-
statistically significant between the groups. Both groups did firmed the results of the DPV diabetes register. Patients with
not differ significantly in functional disability, in the cJADAS- JIA without T1D had a significantly lower body weight than
10 or in the physician’s global assessment. patients with JIA and T1D, who had less negative body weight
Information about DMARD treatment before T1D onset was SDS, which translates to less of a decrease in body weight.
available for 10 (50%) of 20 JIA1st patients. Among those pa- The higher body weight of patients with JIA and T1D re-
tients, 7 (70.0%) had not received any DMARD therapy. Three sulted in higher BMI SDS. A previous NPRD analysis of BMI
patients (30.0%) were treated with MTX before T1D onset, 2 in patients with JIA compared with population-based data
of whom were also treated with systemic glucocorticoids. No in Germany did not reveal significant differences in general,21
patients were treated with a bDMARD before T1D onset. The but the study showed an increased prevalence of a higher
patients with available data from previous years did not differ BMI in patients with systemic JIA and enthesitis-related ar-
in the JIA category distribution, sex, age, disease duration, and thritis. These categories are not distributed differently between
age of onset of JIA and T1D from those patients with T1D patients with JIA with and without T1D; thus, the underly-
without previous documentation. ing cause for a higher BMI might be related to T1D-
indicated insulin therapy, which is associated with weight
Discussion gain.34
Several studies have shown that DMARD use is associated
We analyzed the T1D occurrence in patients with JIA and with a significantly lower frequency of comorbid DM in
characterized patients having JIA and T1D using data from a patients with rheumatoid arthritis.35 Hydroxychloroquine35,36
200 Schenck et al
January 2018
and antitumor necrosis factor therapy37 also decreased the
risk for development of DM in patients with rheumatoid
arthritis. The investigations included patients with all DM
diagnoses (International Classification of Diseases, Ninth Revision,
Clinical Modification 250) including T1D. However, the ma-
jority of patients in these studies probably had T2D. The key
mechanism in T1D pathogenesis is inflammation of pancre-
atic b cells and a linked expression of proinflammatory
cytokines.38,39 The immunomodulatory effect of several medi-
cations was found to improve T1D outcomes37,40 and may
potentially prevent T1D.41-45 Asseldonk et al observed im-
proved insulin sensitivity and a reduced insulin requirement
in 14 patients with T1D who were treated with the interleukin-1
receptor antagonist anakinra for 1 week.46 The effect lasted 4
weeks after the final application, which may be an explana-
tion for the low insulin requirement of patients with JIA in
our study cohort. The insulin requirement in patients with
comorbidity of T1D and JIA was lower in the NPRD data
than in the diabetes registry (0.55 IU/kg/day vs 1.03 IU/kg/
day, respectively). The subanalysis of our data revealed that
patients with JIA with T1D and low insulin requirement
were more frequently treated with bDMARDs, and patients
with JIA and a higher insulin requirement were less often
treated with bDMARDs (33.0% vs 21.4%, respectively). Un-
fortunately, we did not have information on the treatment
of patients with JIA in the diabetes registry. Thus, the com-
parison of DMARD therapy between the registries remains
open.
Compared with reference data from the general popula-
tion, patients in our study with JIA and T1D had an earlier
onset of diabetes. Hermann et al 19 found significantly
earlier T1D manifestations in patients with comorbid JIA vs
patients without JIA (median: 7.2 vs 8.3 years, respectively,
P = .04). Regarding the age distribution of the cumulative T1D
incidence (Figure 2), we observed that the peak incidence
of diabetes cases in the older age groups found in the general
population data was absent in the JIA data. We speculate that
the decreased occurrence of T1D in older patients with JIA may
be associated with JIA-indicated DMARD therapy. Alterna-
tively, the decreased T1D incidence may also be caused by
“depletion of susceptibles.” Predisposed patients may develop
T1D at an early age because of a strong autoimmune
phenotype.
Furthermore, we analyzed the treatment with glucocorti-
coids and DMARDs in patients with JIA diagnosed before
T1D onset. Although the number of patients was small
(n = 10), we observed that no patient in our cohort received
bDMARD therapy before T1D onset, which may be linked to
an association between DMARD therapy and the risk of
T1D. Three patients were documented as previously being
treated with MTX therapy; MTX alone does not seem to be
associated with a reduced risk for DM in patients with JIA.35
Bongartz et al hypothesized that the risk-reducing effect of
DMARDs for DM is not based only on an anti-inflammatory
effect but may be amplified by pathway-specific effects of
immunosuppressive agents that induce an anti-hyperglycemic
impact.47
Comorbidity of Type 1 Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis
ORIGINAL ARTICLES
In summary, several findings in our study support the
hypothesis, that bDMARD therapy may be associated with a
lower incidence of T1D in patients with JIA. Patients with
JIA with T1D who had a low insulin requirement were more
often treated with bDMARD than patients with JIA with
T1D who had a higher insulin requirement. The majority of
T1D cases occurred before the onset of JIA and therefore,
before JIA-indicated therapy. None of the cases of diabetes
in our cohort (with available therapy data) were treated with
a bDMARD before the onset of diabetes. The association
between DMARD therapy in general, and bDMARD in par-
ticular, and a reduced risk for T1D should further be
investigated in longitudinal analysis of a large, long-term
prospective cohorts.
A limitation of our study is the small number of patients
with T1D, especially for subgroup analysis such as insulin re-
quirement. We may have underestimated the number of pa-
tients with T1D because we required validation of the DM
diagnosis by a positive response to that item in the physi-
cian’s questionnaire. Information on comorbid DM was not
provided in one-fourth of the patients with JIA. Further-
more, the nationwide JIA data were compared with the ref-
erence data of the federal state of North Rhine-Westphalia. The
T1D prevalence in North Rhine-Westphalia is higher than the
estimated nationwide T1D prevalence,25 which would result
in a lower prevalence ratio.
Our analyses were based on diabetes data that were col-
lected in the NPRD only from 2012 to 2014. Cross-sectional
data do not allow many assertions about the disease course
and other factors. Moreover, because of the NPRD study
design, patients were documented at an arbitrary time
during the disease course, which may have led to a variation
in the time between the onset of JIA and outcome
assessments at documentation. Nevertheless, most of our
findings are supported by results of previous international
studies.
In conclusion, our study in the NPRD and the study of
Hermann et al in the diabetes registry confirm the clustering
of JIA, T1D, AIT, and CD in large populations.19 If a child or
adolescent has developed JIA or T1D, the treating pediatri-
cian should be aware of the increased risk for the develop-
ment of the other AID. ■
We thank the participating patients and sites and the following pedi-
atric rheumatologists, who enrolled at least 200 patients: Ralf Trauzeddel
(Berlin), Tilmann Kallinich (Berlin), Rolf-Michael Küster (Wedel,
current address: Hamburg), Gerd Ganser (Sendenhorst), Christoph
Rietschel (Frankfurt), Markus Hufnagel (Freiburg), Johannes-Peter Haas
(Garmisch-Partenkirchen), Rainer Berendes (Landshut), Anton Hospach
(Stuttgart), Thomas Lutz (Heidelberg), and Hans-Iko Huppertz
(Bremen).
The support of Tobias Schwarz, Ivan Foeldvari, Gerd Horneff, Frank
Weller-Heinemann in the NPRD is gratefully acknowledged.
Submitted for publication Apr 26, 2017; last revision received Jun 2, 2017;
accepted Jul 26, 2017
Reprint requests: Sandra Schenck, MSc, German Rheumatism Research
Centre Berlin, a Leibniz Institute, Berlin, Charitéplatz 1, 10117 Berlin, UK.
E-mail: Sandra.Schenck@drfz.de
201
THE JOURNAL OF PEDIATRICS • www.jpeds.com
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Comorbidity of Type 1 Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis 203