- Email: [email protected]
Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis Gerhard Hermann, MA1, Angelika Thon, MD2, Kirsten M€onkem€oller, MD3, Eggert Lilienthal, MD4, Christof Klinkert, MD5, Martin Holder, MD6, Thomas H€ortenhuber, MD7, Petra Vogel-Gerlicher, MD8, Holger Haberland, MD9, Martin Schebek, MD10, and Reinhard W. Holl, MD, PhD1, on behalf of the Diabetes Patienten Verlaufsdokumentation-initiative and the Federal Ministry of Education and Research Competence Network Diabetes Mellitus* Objective To analyze the prevalence of juvenile idiopathic arthritis (JIA) and diabetes end points in pediatric patients with type 1 diabetes. Study design Patients with type 1 diabetes, recorded from 1995 up to September 2013 in the Diabetes Patienten Verlaufsdokumentation database (n = 54 911, <16 years of age, 47% girls), were analyzed. The patients’ height, weight, and body mass index SDS, glycosylated hemoglobin A1c (HbA1c); insulin dose; hypertension and dyslipidemia prevalence; rate of hypoglycemic events; and ketoacidosis were compared between patients with and without JIA. To adjust for age, sex, diabetes duration, and migration background, data were analyzed in hierarchic multivariable regression models. Results The prevalence of JIA in type 1 diabetes was 106 of 54 911 patients; 66% were girls. Diabetes onset was earlier in children with JIA (7.2 years vs 8.3 years, P = .04). Children with JIA were smaller (SDS: 0.22 vs 0.09, P = .004). Correspondingly, weight SDS was lower in patients with JIA (0.02 vs 0.22, P = .01). Body mass index SDS did not differ. HbA1c was marginally lower in children with JIA (63 mmol/mol [8.0%] vs 67 mmol/mol [8.3%], P = .06). Insulin requirement was greater in patients with JIA (1.03 vs 0.93 insulin units/weight/day, P = .003). Hypertension and dyslipidemia were comparable in both groups. Conclusions The JIA-prevalence in patients with type 1 diabetes (0.19%) was considerably greater than in the general population (0.05%). Growth is influenced negatively by JIA. Surprisingly, HbA1c was somewhat lower in children with JIA, possibly because of a more intensive treatment or a latent hemolysis caused by the inflammation. (J Pediatr 2015;-:---).
T
ype 1 diabetes mellitus is known to be associated with juvenile idiopathic arthritis (JIA), autoimmune thyroiditis (AIT), and celiac disease (CD).1-3 Reports describing the comorbidity of type 1 diabetes and JIA in larger cohorts are rare.3-5 JIA is the most common chronic arthritis in childhood and encompasses heterogeneous forms of chronic arthritis. Worldwide, the prevalence of JIA varies significantly (7-400 of 100 000 children).6 Reported differences in the prevalence and incidence resulted mainly from different diagnostic and classification criteria, as well as regional variation.6 From the Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm; Department of Fifteen years ago, the prevalence was reported to be 15-20 of 100 000 German Pediatric Pneumology, Allergology & Neonatology, Children’s Hospital, Hanover Medical School, Hanover; children, with girls (18-23 of 100 000) more frequently affected than boys Children’s Hospital, Hospitals of the City of Cologne, (13-17 of 100 000).7,8 Today, the prevalence is estimated up to 100 of 100 000 Cologne; Department of Pediatrics, Ruhr University of 9,10 Bochum, Bochum; Pediatric Practice, Herford; children. Worldwide, AIT was reported to be present in 7%-40% and CD Department of Pediatric Endocrinology and Diabetology, Olgahospital, Stuttgart Clinical Center, in 1%-16% of children and adolescents with type 1 diabetes.11-13 Stuttgart, Germany; Department of Pediatrics and It is known that autoimmune diseases frequently occur in type 1 diabetes Adolescent Medicine, Medical University of Vienna, Vienna, Austria; German Center for Pediatric and patients.1-3,14,15 However, little information on the clinical data and the prevAdolescent Rheumatology with Center for Social Pediatrics, Garmisch-Partenkirchen; Hospital for alence of JIA in subjects with type 1 diabetes based on larger populations are Children and Adolescents, Sana Hospital Lichtenberg, Berlin Lichtenberg; and Department of Pediatrics and available. One goal of the present study was to determine the prevalence of Adolescent Medicine, Kassel Clinical Center, Kassel, JIA in Germany and Austria in a large number of children and adolescents Germany *List of participating centers of the Diabetes Patienten with type 1 diabetes. We hypothesized that in patients with type 1 diabetes Verlaufsdokumentation-initiative and the Federal with JIA, anthropometry is affected by the comorbid rheumatic disease. PaMinistry of Education and Research Competence Network Diabetes Mellitus is available at www.jpeds. tients with JIA may be smaller than patients without JIA. Diabetes treatment com (Appendix 1). also may differ between patients with or without the rheumatic disease. A Supported by the Competence Network for Diabetes mellitus (01GI1106), funded by the Federal Ministry of greater prevalence of JIA in females was reported in studies analyzing smaller Education and Research, by the European Foundation 1
2
3
4
5
6
7
8
9
10
for the Study of Diabetes and the B€ urger-B€ using Foundation. The authors declare no conflicts of interest.
AIT BMI CD HbA1c JIA
Autoimmune thyroiditis Body mass index Celiac disease Glycosylated hemoglobin A1c Juvenile idiopathic arthritis
Portions of the study were presented as a poster at the Congress of the German Society for Rheumatology €r Rheumatologie [DGRh]), (Deutsche Gesellschaft fu September 1, 2011, Munich, Germany. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.12.026
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populations.7,8 On the basis of data from a large registry in the present study, we investigated whether sex differences exist between children and adolescents with and without JIA.
Methods Since 1995 standardized longitudinal data are recorded in the diabetes data acquisition system for prospective surveillance (Diabetes Patienten Verlaufsdokumentation).16 In diabetes health care centers, which used the Diabetes Patienten Verlaufsdokumentation software, all data were entered by physicians, nurses, or other staff members. The centers exported anonymized data and sent them twice a year to the Institute of Epidemiology and Medical Biometry at the University of Ulm, Germany, for aggregated cumulative central analysis. Implausible and inconsistent data were sent back for verification and correction. The ethics committee of the University of Ulm approved analysis of anonymized DPV data. Data of 54 911 patients with type 1 diabetes mellitus, who were younger than 16 years of age, were analyzed. In this observational study, based on information from the Diabetes Patienten Verlaufsdokumentation registry, 330 centers (308 in Germany, 22 in Austria) participated in the prospective data collection from 1995 up to September 2013. The selection of the study population can be seen in a flow chart (Figure 1; available at www.jpeds.com). The measurements herein from each patient’s recent treatment year were extracted from Diabetes Patienten Verlaufsdokumentation. Height and weight were measured, and body mass index (BMI) was calculated. To compare height, weight, and BMI values, the ageand sex-adjusted SDS was determined with contemporary national reference values.17 A patient had a migration background if either the patient or at least one parent was not born in Germany or Austria. Glycemic control was assessed by glycosylated hemoglobin A1c (HbA1c). Each patient’s aggregated HbA1c of the last treatment year was used. To adjust for possible differences between participating centers, HbA1c was standardized to the Diabetes Control and Complication Trial Research Group reference range of 4.05%-6.05% (International Federation of Clinical Chemistry and Laboratory Medicine: 20-42 mmol/mol) by applying the multiple of the mean method.13 Values are displayed in percent and mmol/ mol. The number of blood glucose self-measurements per week and the insulin dose per kilogram and day were self-reported by the children and adolescents, their parents, or caregivers. Blood pressure was measured after current guidelines and hypertension was defined by increased systolic and/or diastolic blood pressure (>95th percentile),18 or when patients used antihypertensive drugs. Blood lipids were evaluated in comparison with national reference values.19 Dyslipidemia was defined by the use of lipid-lowering medication and/or by increased values of one or several blood lipids. Cut-off 2
Vol. -, No. values for blood lipids were as follows: total cholesterol >200 mg/dL, high-density lipoprotein cholesterol <35 mg/ dL, low-density lipoprotein cholesterol >130 mg/dL, and triglycerides >150 mg/dL. Acute metabolic complications, such as severe hypoglycemia (help of another person needed or coma) and ketoacidosis (admission with blood pH less than 7.3), were recorded as number of incidences per year. To select patients with JIA, the Diabetes Patienten Verlaufsdokumentation database was searched for the diagnosis and/or therapy of JIA as comorbidity with search terms and International Classification of Diseases, 10th revision codes according to current guidelines.20 Terms for the diagnosis were “JIA,” “JRA,” “JCA,” “(systemic) idiopathic arthritis,” “SJIA,” “rheumatoid/chronic arthritis,” “Still’s disease,” “oligoarthritis,” “polyarthritis,” “psoriatic arthritis/JIA,” “enthesitis-related arthritis/JIA,” “articular/joint rheumatism,” “ankylosing spondylitis,” “monoarthritis,” and International Classification of Diseases, 10th revision codes M05, M08, and M45. Search terms for disease-modifying antirheumatic drugs or common biologics were additionally applied (Appendix 2: list of drugs). When a patient was found only through treatment search terms, his or her records were reviewed to rule out that the medication was used because of another disease. Such cases were excluded from the analysis. AIT was ascertained when patients were diagnosed with Hashimoto thyroiditis, or if positive thyroid antibodies (thyroid peroxidase antibodies, antithyroglobulin antibodies) greater than 100 U/mL were detected. Patients had CD when confirmed by biopsy. Insulin therapy was classified according to the reported injection frequency per day. Conventional therapy was ascertained when 1-3 injection time points per day were documented. An intensified conventional therapy was determined if more than 3 injection time-points per day were recorded. The documentation of continuous subcutaneous insulin infusion corresponded to pumptherapy. Data were analyzed with SAS 9.3 (SAS Institute Inc, Cary, North Carolina). To compare groups, Kruskal-Wallis test was used for continuous variables and c2; test for dichotomous variables. To compare event rates, a Poisson distribution was assumed. Missing data were not imputed. Data analysis was conducted in regression models (SAS proc glimmix). Regression models were created to adjust for differences in age, sex, diabetes duration, and migration background (in the model for “age at diabetes onset,” diabetes duration was not included; in all sex-stratified models, sex was not included). In additional models for HbA1c and insulin dose per kilogram and day, the confounder “therapy form” was included, to adjust for a possible influence of the applied diabetes therapy. All confounders were fixed effects, and the treatment center was set as random intercept. The models’ estimates were calculated based on observed marginal frequencies. P values <.05 were considered statistically significant. Hermann et al
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ORIGINAL ARTICLES Results
Until September 2013, 54 911 patients with type 1 diabetes up to the age of 16 years were registered in the Diabetes Patienten Verlaufsdokumentation database. The characteristics of patients included (47% girls) are shown in Table I. One hundred six of 54 911 (193 of 100 000) children and adolescents with type 1 diabetes also were diagnosed with JIA and/or treated with antirheumatic drugs (Figure 2). There were significantly more girls among children with JIA (66%), than among children without JIA (47%, P = .0001). Both groups had the same age. In children and adolescents with JIA, 88% had diabetes before the rheumatic disease. Age at diabetes onset (median [Q1; Q3]: 7.2 [4.1; 10.7] years) was 5 years lower than age at first JIA documentation (12.0 [6.3; 13.9] years). In children without JIA, diabetes onset was later (8.3 [4.8; 11.5] years, P = .04). There was no significant difference concerning migration background between subjects with and without JIA. The following results describe the measures after adjustment for possible confounders and are summarized in Table II. The height differed between patients with JIA, and patients without JIA. Patients without JIA were 2.2 cm taller (unadjusted median). Weight also was lower in children and adolescents with JIA. Stratified for sex, only in boys the difference was significant (P = .04; Figure 3). In the whole group, as well as in boys and girls separately,
Table I. Comparison of patients with type 1 diabetes and patients with type 1 diabetes and JIA Diabetes only Study population, n All 54 805 Girls 25 978 Boys 28 827 Sex, % Girls 47.4 Migration background, % All 14.9 Girls 15.2 Boys 14.6 Age at diabetes onset, y All 8.3 (4.8; 11.5) Girls 8.1 (4.8; 11.0) Boys 8.5 (4.8; 11.9) Age at first JIA documentation, y All Girls Boys Current age, y All 14.2 (10.7; 15.4) Girls 14.0 (10.6; 15.4) Boys 14.4 (10.9; 15.4) Current diabetes duration, y All 3.8 (1.4; 6.9) Girls 4.0 (1.5; 7.0) Boys 3.5 (1.3; 6.8)
Diabetes and JIA
P value
106 70 36 66.0
<.001
16.0 17.1 13.9
n.s. n.s. n.s.
7.2 (4.1; 10.7) 6.8 (4.7; 10.5) 7.8 (2.7; 11.4)
.038 n.s. n.s.
12.0 (6.3; 13.9) 11.6 (6.1; 13.9) 12.0 (7.3; 13.7)
-
14.1 (10.0; 15.3) 13.8 (9.5; 15.3) 14.2 (11.2; 15.2)
n.s. n.s. n.s.
4.6 (2.4; 7.3) 4.2 (2.4; 6.8) 5.1 (2.5; 8.3)
.031 n.s. n.s.
n.s., not significant. Data are displayed in percent or as median with lower and upper quartile (Q1; Q3).
Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
Figure 2. Prevalence of JIA per 100 000 children and adolescents (<16 years of age). Worldwide, European, and local prevalence of JIA compared with the prevalence of JIA in patients with type 1 diabetes in Germany (*GKJR, 6058 children with JIA in German core documentation in 2010 [http:// www.gkjr.de/381.html]); results are from von Koskull et al8 and Kiessling et al7 are included in the meta data of Thierry et al.21 T1D, type 1 diabetes.
BMI SDS was not significantly different between subjects with and without JIA. Independent of rheumatic disease, BMI SDS was above the reference values of the healthy German population (Table II). CD occurred significantly more often in children with JIA (P = .002), and AIT was not significant (P = .06). Independent of the rheumatic comorbidity, the prevalence of both autoimmune diseases was different in boys and girls. AIT was more frequent in girls than in boys. In contrast, CD was more prevalent in boys (Table II). The number of hypoglycemic events did not differ between children and adolescents with and without JIA. There were no patients with JIA and ketoacidosis (Table II). Patients with and without JIA had similar numbers of days in hospital, inpatient admissions, and outpatient contacts. HbA1c differences between patients with and without JIA were significant only in girls. Independent of sex, HbA1c was a little lower in patients with JIA (63 mmol/mol [8.0%]) compared with 67 mmol/mol (8.3%). The insulin dose was greater in patients with JIA and was less pronounced than in boys P = .008. Diabetes treatment showed small differences between patients with and without JIA (Table II). Pump therapy was applied more often by patients with JIA: every third patient used continuous subcutaneous insulin infusion, compared with every fourth patient without JIA. Conventional or intensified conventional therapy was applied by 67% of the patients with JIA and 76% of children without JIA. For all treatment forms, there were no differences between boys and girls. Concerning JIA medication, disease-modifying antirheumatic drugs, and/or biologics were used by 56%, and 14% also received steroids. 3
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Table II. Confounder adjusted comparison of patients with type 1 diabetes and patients and type 1 diabetes and JIA Diabetes and P JIA (n = 106) value
Diabetes only (n = 54 805) Height (SDS)* All 0.09 (0.01) Girls 0.09 (0.01) Boys 0.08 (0.01) Weight (SDS)* All 0.22 (0.01) Girls 0.29 (0.01) Boys 0.15 (0.01) BMI (SDS)* All 0.24 (0.01) Girls 0.31 (0.01) Boys 0.18 (0.01) HbA1c (aggregated from last treatment year), mmol/mol/% All 67 (1)/8.3 (0.04) Girls 67 (1)/8.3 (0.04) Boys 66 (1)/8.2 (0.04) Self-monitoring of blood glucose, n/wk All 36.6 (0.3) Girls 36.9 (0.3) Boys 36.6 (0.3) Insulin dose, IU/kg/d† All 0.93 (0.01) Girls 0.95 (0.01) Boys 0.92 (0.01)
Conventional therapy All Girls Boys Intensified conventional therapy All Girls Boys Pump therapy (CSII) All Girls Boys Hypertension All Girls Boys Dyslipidemia All Girls Boys AIT (diagnosed and/or antibody confirmed) All Girls Boys CD (biopsy confirmed) All Girls Boys
Hypoglycemia (severe) All Girls Boys Hypoglycemia (coma) All Girls Boys 4
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0.22 (0.10) .004 0.19 (0.13) .032 0.27 (0.18) n.s. 0.02 (0.09) .011 0.11 (0.11) n.s. 0.19 (0.16) .043 0.16 (0.09) n.s. 0.28 (0.11) n.s. 0.01 (0.15) n.s. 63 (2)/8.0 (0.2) n.s 62 (2)/7.9 (0.2) .040 65 (3)/8.1 (0.3) n.s. 37.4 (1.1) 36.9 (1.4) 39.0 (1.8)
n.s. n.s. n.s.
1.03 (0.03) .003 1.02 (0.04) n.s. 1.08 (0.05) .008
%
%
10.4 9.7 10.8
9.5 7.4 12.3
n.s. n.s. n.s.
63.2 60.8 65.3
54.0 56.2 48.0
n.s. n.s. n.s.
23.9 27.2 21.4
33.2 34.4 35.5
.035 n.s. n.s.
24.2 26.1 22.64
16.1 22.1 3.5
n.s. n.s. .030
38.1 41.8 34.7
29.5 37.8 17.1
n.s. n.s. n.s.
12.6 17.5 9.5
18.7 26.4 12.0
n.s. n.s. n.s.
1.5 1.8 1.2
5.2 4.8 8.3
.002 n.s. .001
n/yz
n/yz
0.19 (0.002) 0.19 (0.003) 0.19 (0.003)
0.18 (0.041) 0.15 (0.047) 0.23 (0.076)
0.04 (0.001) 0.04 (0.001) 0.04 (0.001)
0.05 (0.020) n.s. 0.04 (0.025) n.s. 0.05 (0.035) n.s. (continued )
n.s. n.s. n.s.
Table II. Continued n/yz Ketoacidosis All Girls Boys Outpatient appointments All Girls Boys
n/yz
0.05 (0.284) 0.05 (0.263) 0.06 (0.305)
(no cases)
n.s. n.s. n.s.
3.58 (0.09) 3.71 (0.09) 3.67 (0.09)
3.79 (0.24) 4.02 (0.29) 3.68 (0.39)
n.s. n.s. n.s.
CSII, continuous subcutaneous insulin infusion. Data are displayed as least squares means with SE. Confounders in regression models: age, sex, diabetes duration, migration background (in regression models for girls and boys, sex was not included). *Reference values from KIGGS—The German Health Survey for Children and Adolescents (Robert-Koch Institute).17 †Insulin units per body weight and per day. zNumber per patient-year.
Discussion The prevalence of JIA in children and adolescents with type 1 diabetes was significantly greater than in patients without diabetes. Also, it was greater than reported 15 years ago7,8 and greater in girls than in boys. Boys and girls with type 1 diabetes and JIA were smaller and slimmer than their peers without JIA. HbA1c was marginally lower in boys and girls with JIA. AIT and CD were more prevalent in patients with the rheumatic comorbidity. The major strength of the present study was the high number of young patients involved. The study was conducted based on a large, standardized, long-term population-based registry, which allows extensive analysis of routine diabetes care. Our results revealed significantly decreased growth in children and adolescents with JIA. The decreased longitudinal growth suggests that most subjects in the study population had more severe forms of JIA. Different JIA classification criteria over the years and the lack of a specific diagnostic test might be reasons that a bias in the diagnosis of JIA cannot be excluded. The Diabetes Patienten Verlaufsdokumentation register is not a specialized database for rheumatic diseases and cannot provide extensive information on the rheumatic disease. The influence of steroids on glycemic control in patients with JIA was not analyzed because few patients used steroids. The number of children and adolescents with type 1 diabetes and JIA was greater (193 of 100 000) than the prevalence of JIA in the pediatric population ascertained in older German studies (15 and 20 of 100 000)7,8 and compared with the European average (28 of 100 000)21 (Figure 2). To estimate the present JIA prevalence in Germany, the number of children with JIA in the German core documentation22 was related to the national population less than 16 years of age, revealing a prevalence of 52 of 100 000. There is evidence that a significant number of children with undiagnosed JIA exists and the prevalence may be about 100 cases per 100 000.10 In the present study, girls with type 1 diabetes (269 of 100 000) were affected twice as often as boys (125 of 100 000). Female Hermann et al
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ORIGINAL ARTICLES
Figure 3. Weight SDS and height SDS children and adolescents (<16 years) with of type 1 diabetes with and without JIA. Weight and height SDS according to KIGGS—The German Health Survey for Children and Adolescents reference values.17 Error bars show SE.
preponderance in children with both diseases (2.2 to 1) was thus more pronounced than in children without diabetes (1.4 to 1).7,8 AIT antibodies were found in 13% of children and adolescents with type 1 diabetes, which is slightly greater than the 11% that was reported recently.23 Another survey reported a greater prevalence of 27%, but the authors pointed to the varying prevalence of 8%-50% that was given in other studies.24,25 In the present study, girls with or without JIA had AIT 2 times more frequently than boys. According to a recent study, girls were affected 4 times as often.23 The prevalence of CD in the present population was comparable with results of other studies reporting 4%-11%.15,25 The present study revealed a greater prevalence of CD in children with JIA, and AIT also tended to be more prevalent in these patients. Body weight and especially height differed considerably between patients with and without JIA. Children and adolescents with the rheumatic comorbidity were smaller and slimmer than children and adolescents without JIA (Figure 3). An increased risk of stunted growth in children and adolescents with JIA has been largely documented26 and a comparably decreased height SDS was reported in a study27 with a slightly younger population (11.0 years and height SDS 0.15, compared with 14.1 years and height SDS 0.22 in the present study). The lower weight of children with JIA was probably associated with the lower height of the children. Accordingly, BMI SDS was not significantly different. The present multicenter analysis revealed that the prevalence of JIA in children and adolescents with type 1 diabetes was considerably higher than in children and adolescents without diabetes. The autoimmune diseases JIA and type 1 diabetes in combination influenced growth Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
negatively. To our knowledge, the comorbidity of type 1 diabetes and JIA, in combination with AIT or CD, has not been studied in larger cohorts.28 The seemingly better glycemic control in children with JIA should be analyzed further. Our results confirm the value of a standardized, long-term population-based registry, which allows to record and observe data obtained in routine diabetes care. A more detailed characterization of patients with type 1 diabetes and JIA could be achieved by a combined evaluation of the Diabetes Patienten Verlaufsdokumentation database and the German documentation for children with rheumatic disease (German core documentation22) of the German Society for Pediatric and Adolescent Rheumatology. n The authors would like to thank Esther Bollow (Institute of Epidemiology and Medical Biometry, University of Ulm, Germany) for data processing and statistical analysis. Submitted for publication Jun 4, 2014; last revision received Oct 13, 2014; accepted Dec 11, 2014. Reprint requests: Gerhard Hermann, c/o R. W. Holl, Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Albert-Einstein-Allee 41, 89081 Ulm, Germany. E-mail: [email protected]
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4. Pohjankoski H, Kautiainen H, Korppi M, Savolainen A. Simultaneous juvenile idiopathic arthritis and diabetes mellitus type 1—a Finnish nationwide study. J Rheumatol 2012;39:377-81. 5. Minden K, Niewerth M. Juvenile idiopathic arthritis—clinical subgroups and classification. Z Rheumatol 2008;67:100-10. 6. Manners PJ, Bower C. Worldwide prevalence of juvenile arthritis why does it vary so much? J Rheumatol 2002;29:1520-30. 7. Kiessling U, D€ oring E, Listing J, Meincke J, Sch€ ontube M, Strangfeld A, et al. Incidence and prevalence of juvenile chronic arthritis in East Berlin 1980-88. J Rheumatol 1998;25:1837-43. 8. Von Koskull S, Truckenbrodt H, Holle R, H€ ormann A. Incidence and prevalence of juvenile arthritis in an urban population of southern Germany: a prospective study. Ann Rheum Dis 2001;60:940-5. 9. D€ uckers G, Niehues T. Juvenile idiopathic arthritis (JIA) [in German]. Monatsschr Kinderheilkd 2011;159:25-33. 10. Zink A, Minden K, List SM. Inflammatory rheumatic diseases. Federal Health Monitoring System. Berlin: Robert-Koch-Institute; 2010. 11. Lorini R, d’Annunzio G, Vitali L, Scaramuzza A. IDDM and autoimmune thyroid disease in the pediatric age group. J Pediatr Endocrinol Metab 1996;9(Suppl 1):89-94. 12. Sumnik Z, Cinek O, Bratanic N, Lebl J, Rozsai B, Limbert C, et al. Thyroid autoimmunity in children with coexisting type 1 diabetes mellitus and celiac disease: a multicenter study. J Pediatr Endocrinol Metab 2006;19:517-22. 13. Fr€ ohlich-Reiterer EE, Hofer S, Kaspers S, Herbst A, Kordonouri O, Schwarz H-P, et al. Screening frequency for celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus—data from a German/Austrian multicentre survey. Pediatr Diabetes 2008;9:546-53. 14. Pohjankoski H, Kautiainen H, Kotaniemi K, Korppi M, Savolainen A. Diabetes, coeliac disease, multiple sclerosis and chronic arthritis in first-degree relatives of patients with juvenile idiopathic arthritis. Acta Paediatr 2012;101:767-71. 15. Camarca ME, Mozzillo E, Nugnes R, Zito E, Falco M, Fattorusso V, et al. Celiac disease in type 1 diabetes mellitus. Ital J Pediatr 2012;38:10. 16. Grabert M, Schweiggert F, Holl RW. A framework for diabetes documentation and quality management in Germany: 10 years of experience with DPV. Comput Programs Biomed 2002;69:115-21. 17. Robert-Koch Institute (RKI). KIGGS—The German Health Survey for Children and Adolescents. Reference values for anthropometric mea-
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surements and blood pressure. Report No. 2. Berlin: Robert Koch Institute; 2013. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The Fourth Report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114(Suppl 2): 555-76. Thierfelder W, Dortschy R, Hintzpeter B, Kahl H, Scheidt-Nave C. Biochemical measures in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Bundesgesundheitsbl 2007;50:757-70. Petty 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. Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Joint Bone Spine 2014; 81:112-7. Minden K, Niewerth M. Rheumatic children and adolescents. Core documentation and prognosis [in German]. Monatsschr Kinderheilkd 2012;160:237-43. Ben-Skowronek I, Michalczyk A, Piekarski R, Wysocka-Lukasik B, Banecka B. Type III polyglandular autoimmune syndromes in children with type 1 diabetes mellitus. Ann Agric Environ Med 2013;20:140-6. Burek CL, Rose NR, Guire KE, Hoffman WH. Thyroid autoantibodies in black and in white children and adolescents with type 1 diabetes mellitus and their first degree relatives. Autoimmunity 1990;7:157-67. Hanukoglu A, Mizrachi A, Dalal I, Admoni O, Rakover Y, Bistritzer Z, et al. Extrapancreatic autoimmune manifestations in type 1 diabetes patients and their first-degree relatives. A multicenter study. Diabetes Care 2003;26:1235-40. Giannini C, Mohn A, Chiarelli F. Growth abnormalities in children with type 1 diabetes, juvenile chronic arthritis, and asthma. Int J Endocrinol 2014;2014:265954. Uettwiller F, Perlbarg J, Pinto G, Bader-Meunier B, Mouy R, Compeyrot-Lacassagne S, et al. Effect of biologic treatments on growth in children with juvenile idiopathic arthritis. J Rheumatol 2014;41:128-35. Coulson EJ, Ng W-F, Goff I, Foster HE. Cardiovascular risk in juvenile idiopathic arthritis. Rheumatology (Oxford) 2013;52:1163-71.
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- 2015
ORIGINAL ARTICLES Appendix 1
List of Participating Centers Aachen - Uni-Kinderklinik RWTH, Aalen Kinderklinik, Ahlen St. Franziskus Kinderklinik, Aidlingen Praxisgemeinschaft, Alt€ otting Zentrum Inn-Salzach, Alt€ otting-Burghausen Innere Medizin, Amstetten Klinikum Mostviertel Kinderklinik, Arnsberg-H€ usten Karolinenhosp. Kinderabteilung, Aue Helios Kinderklink, Augsburg Innere, Augsburg Kinderklinik Zentralklinikum, Aurich Kinderklinik, Bad Aibling Internist. Praxis, Bad Hersfeld Kinderklinik, Bad Kreuznach-Viktoriastift, Bad K€ osen KinderRehaklinik, Bad Lauterberg Diabeteszentrum Innere, Bad Mergentheim - Diabetesfachklinik, Bad Mergentheim - Gemeinschaftspraxis DM-dorf Althausen, Bad Oeynhausen Herz-und Diabeteszentrum NRW, Bad Orb Spessart Klinik, Bad Orb Spessart Klinik Reha, Bad Reichenhall Kreisklinik Innere Med., Bad Salzungen Kinderklinik, Bad Waldsee Kinderarztpraxis, Bautzen Oberlausitz KK, Bayreuth Innere Medizin, Berchtesgaden CJD, Berchtesgaden MVZ Innere Med, Berlin DRK-Kliniken, Berlin Endokrinologikum, Berlin Klinik St. Hedwig Innere, Berlin Lichtenberg - Kinderklinik, Berlin Virchow-Kinderklinik, Bielefeld Kinderklinik Gilead, Bocholt Kinderklinik, Bochum Universit€atskinderklinik St. Josef, Bonn Uni-Kinderklinik, Bottrop Kinderklinik, Bottrop Knappschaftskrankenhaus Innere, Braunschweig Kinderarztpraxis, Bremen - Kinderklinik Nord, Bremen Zentralkrankenhaus Kinderklinik, Bremerhaven Kinderklinik, B€ oblingen Kinderklinik, Celle Klinik f€ ur Kinder- und Jugendmedizin, Chemnitz Kinderklinik, Coesfeld Kinderklinik, Darmstadt Innere Medizin, Darmstadt Kinderklinik Prinz. Margaret, Datteln Vestische Kinderklinik, Deggendorf Kinderarztpraxis, Deggendorf Kinderklinik, Deggendorf Medizinische Klinik II, Delmenhorst Kinderklinik, Dessau Kinderklinik, Detmold Kinderklinik, Dinslaken Kinderklinik, Dornbirn Kinderklinik, Dortmund Kinderklinik, Dortmund Medizinische Kliniken Nord, Dortmund-St. Josefshospital Innere, Dresden Neustadt Kinderklinik, Dresden Uni-Kinderklinik, Duisburg Evang. und Johanniter Krhs Innere, Duisburg Kinderklinik, Duisburg Malteser St. Anna Innere, Duisburg-Huckingen, Duisburg-St. Johannes Helios, D€ uren-Birkesdorf Kinderklinik, D€ usseldorf Uni-Kinderklinik, Eberswalde Klinikum Barnim Werner Forßmann - Innere, Erfurt Kinderklinik, Erlangen Uni Innere Medizin, Erlangen Uni-Kinderklinik, Essen Diabetes-Schwerpunktpraxis, Essen Elisabeth Kinderklinik, Essen Uni-Kinderklinik, Esslingen Klinik f€ ur Kinder und Jugendliche, Eutin Kinderklinik, Feldkirch Kinderklinik, Forchheim Diabeteszentrum SPP, Frankenthal Kinderarztpraxis, Frankfurt Diabeteszentrum Rhein-MainErwachsenendiabetologie (B€ urgerhospital), Frankfurt UniKinderklinik, Frankfurt Uni-Klinik Innere, Freiburg Kinder-MVZ, Freiburg St. Josef Kinderklinik, Freiburg Uni Innere, Freiburg Uni-Kinderklinik, Freudenstadt Kinderklinik, Friedberg Innere Klinik, Friedrichshafen Kinderklinik, Fulda Innere Medizin, Fulda Kinderklinik, F€ urth Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
Kinderklinik, Gaissach Fachklinik der Deutschen Rentenversicherung Bayern S€ ud, Garmisch-Partenkirchen Kinderklinik, Geislingen Klinik Helfenstein Innere, Gelnhausen Kinderklinik, Gelsenkirchen Kinderklinik Marienhospital, Gera Kinderklinik, Gießen Uni-Kinderklinik, Graz Universit€ats-Kinderklinik, G€ oppingen Kinderklinik am Eichert, G€ orlitz St€adtische Kinderklinik, G€ ottingen UniKinderklinik, Hachenburg Kinderpraxis, Hagen Kinderklinik, Halberstadt Innere Med. St. Salvator AMEOS Klinik, Halberstadt Kinderklinik St. Salvator, Halle UniKinderklinik, Halle-D€ olau St€adtische Kinderklinik, Hamburg Altonaer Kinderklinik, Hamburg Endokrinologikum, Hamburg Kinderklinik Wilhelmstift, Hamburg-Nord Kinder-MVZ, Hameln Kinderklinik, Hamm Kinderklinik, Hanau Kinderklinik, Hannover Henriettenstift - Innere, Hannover Kinderklinik MHH, Hannover Kinderklinik auf der Bult, Haren Kinderarztpraxis, Heide Kinderklinik, Heidelberg Uni-Kinderklinik, Heidenheim Kinderklinik, Heilbronn Innere Klinik, Heilbronn Kinderklinik, Herdecke Kinderklinik, Herford Kinderarztpraxis, Herford Klinikum Kinder & Jugendliche, Heringsdorf Inselklinik, Hermeskeil Kinderpraxis, Herten St. Elisabeth Innere Medizin, Hildesheim GmbH - Innere, Hildesheim Kinderarztpraxis, Hildesheim Kinderklinik, Hinrichsegen-Bruckm€ uhl Diabetikerjugendhaus, Hof Kinderklinik, Homburg UniKinderklinik Saarland, Idar Oberstein Innere, Ingolstadt Klinikum Innere, Innsbruck Universit€atskinderklinik, Iselsberg - Rehazentrum Ederhof, Iserlohn Innere Medizin, Itzehoe Kinderklinik, Jena Uni-Kinderklinik, Kaiserslautern Kinderarztpraxis, Kaiserslautern-Westpfalzklinikum Kinderklinik, Kamen Klinikum Westfalen Hellmig Krankenhaus, Karlsburg Klinik f€ ur Diabetes & Stoffwechsel, Karlsruhe St€adtische Kinderklinik, Kassel Klinikum Kinder-und Jugendmedizin, Kassel St€adtische Kinderklinik, Kaufbeuren Innere Medizin, Kempen Heilig Geist - Innere, Kempten Oberallg€au Kinderklinik, Kiel St€adtische Kinderklinik, Kiel Universit€ats-Kinderklinik, Kirchen DRK Klinikum Westerwald Kinderklinik, Kirchheim-N€ urtingen Innere, Kleve Innere Medizin, Koblenz Kinderklinik Kemperhof, Konstanz Kinderklinik, Krefeld Innere Klinik, Krefeld Kinderklinik, Kreischa-Zscheckwitz Klinik Bavaria, K€ oln Kinderklinik Amsterdamerstrasse, K€ oln Uni-Kinderklinik, Landshut Kinderklink, Lappersdorf Kinderarztpraxis, Leer Kreiskrankenhaus - Kinderabt., Leipzig Uni-Kinderklinik, Leoben LKH Kinderklinik, Leverkusen Kinderklinik, Lienz BKH Kinderklinik, Lienz BKH P€adiatrie, Lilienthal Schwerpunktpraxis, Limburg Innere Medizin, Lindenfels Luisenkrankenhaus Innere, Lingen Kinderklinik St. Bonifatius, Linz Krankenhaus der Barmherzigen Schwestern Kinderklinik, Linz Landes-Kinderklinik, Lippstadt Evangelische Kinderklinik, Ludwigsburg Kinderklinik, Ludwigshafen Kinderklinik St. Anna-Stift, Ludwigshafen diabetol. SPP, L€ ubeck Uni-Kinderklinik, L€ udenscheid Hilfswerk Kinder & Jugendliche, L€ udenscheid M€arkische Kliniken - Kinder & Jugendmedizin, Magdeburg St€adtisches Klinikum Innere, Magdeburg Uni-Kinderklinik, Mainz Uni-Kinderklinik, Mannheim Uni-Kinderklinik, Mannheim Uniklinik Innere 6.e1
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Medizin, Marburg Uni-Kinderklinik, Marktredwitz Innere Medizin, Mechernich Kinderklinik, Memmingen Kinderklinik, Merzig Kinderklinik, Minden Kinderklinik, Moers - St. Josefskrankenhaus Innere, Moers Kinderklinik, Murnau am Staffelsee - diabetol. SPP, Mutterstadt Kinderarztpraxis, M€ odling Kinderklinik, M€ onchengladbach Kinderklinik Rheydt Elisabethkrankenhaus, M€ uhlacker Enzkreiskliniken Innere, M€ uhldorf Gemeinschaftspraxis, M€ unchen 3. Orden Kinderklinik, M€ unchen Diabetes-Zentrum S€ ud, M€ unchen Kinderarztpraxis diabet. SPP, M€ unchen von Haunersche Kinderklinik, M€ unchen-Gauting Kinderarztzentrum, M€ unchen-Harlaching Kinderklinik, M€ unchen-Schwabing Kinderklinik, M€ unster Herz Jesu Innere, M€ unster St. Franziskus Kinderklinik, M€ unster Uni-Kinderklinik, M€ unster p€adiat. Schwerpunktpraxis, Nauen Havellandklinik, Neuburg Kinderklinik, Neumarkt Innere, Neunkirchen Marienhausklinik Kohlhof Kinderklinik, Neuss Lukaskrankenhaus Kinderklinik, Neuwied Kinderklinik Elisabeth, N€ urnberg Cnopfsche Kinderklinik, N€ urnberg Zentrum f Neugeb./Kinder & Jugendl., Oberhausen Kinderklinik, Oberhausen Kinderpraxis, Oberhausen St. Clemens Hospitale Sterkrade, Offenbach/Main Innere Medizin, Offenbach/Main Kinderklinik, Offenburg Kinderklinik, Oldenburg Kinderklinik, Oldenburg Schwerpunktpraxis, Olpe p€adiatrische Gemeinschaftspraxis, Oschersleben MEDIGREIF B€ ordekrankenhaus, Osnabr€ uck Christliches Kinderhospital, Osterkappeln Innere, Oy-Mittelberg Hochgebirgsklinik Kinder-Reha, Paderborn St. Vincenz Kinderklinik, Papenburg Marienkrankenhaus Kinderklinik, Passau Kinderarztpraxis, Passau Kinderklinik, Pforzheim Kinderklinik, Pfullendorf Innere Medizin, Pirmasens St€adtisches Krankenhaus Innere, Plauen Vogtlandklinikum, Prenzlau Krankenhaus Innere, Rastatt Gemeinschaftspraxis, Rastatt Kreiskrankenhaus Innere, Ravensburg Kinderklink St. Nikolaus, Recklinghausen Dialysezentrum Innere, Regensburg Kinderklinik St. Hedwig, Remscheid Kinderklinik, Rendsburg Kinderklinik, Reutlingen Kinderarztpraxis, Reutlingen Kinderklinik, Reutlingen
6.e2
Vol. -, No. Klinikum Steinenberg Innere, Rheine Mathiasspital Kinderklinik, Rosenheim Innere Medizin, Rosenheim Kinderklinik, Rosenheim Schwerpunktpraxis, Rostock Uni-Kinderklinik, Rotenburg/W€ umme Kinderklinik, R€ usselsheim Kinderklinik, Saaldorf-Surheim Diabetespraxis, Saalfeld Th€ uringenklinik Kinderklinik, Saarbr€ ucken Kinderklinik Winterberg, Saarlouis Kinderklinik, Salzburg Kinderklinik, Scheidegg Prinzregent Luitpold, Scheidegg Reha-Kinderklinik Maximilian, Schw. Gm€ und Stauferklinik Kinderklinik, Schweinfurt Kinderklinik, Schwerin Innere Medizin, Schwerin Kinderklinik, Schw€abisch Hall Diakonie Kinderklinik, Siegen Kinderklinik, Singen - Hegauklinik Kinderklinik, Singen Kinderarztpraxis, Sinsheim Innere, Spaichingen Innere, St. Augustin Kinderklinik, St. P€ olten Kinderklinik, Stade Kinderklinik, Stolberg Kinderklinik, Stuttgart Olgahospital Kinderklinik, Suhl Kinderklinik, Sylt Rehaklinik, Tettnang Innere Medizin, Traunstein diabetol. Schwerpunktpraxis, Trier Kinderklinik der Borrom€aerinnen, Trostberg Innere, T€ ubingen Uni-Kinderklinik, Ulm Endokrinologikum, Ulm Schwerpunktpraxis Bahnhofsplatz, Ulm Uni Innere Medizin, Ulm Uni-Kinderklinik, Vechta Kinderklinik, Viersen Kinderkrankenhaus St. Nikolaus, Villach Kinderklinik, Villingen-Schwenningen Diabetesschule, VillingenSchwenningen Schwarzwald-Baar-Klinikum Innere, Waiblingen Kinderklinik, Waldshut Kinderpraxis, Waldshut-Tiengen Kinderpraxis Biberbau, Waren-M€ uritz Kinderklinik, Weiden Kinderklinik, Weingarten Kinderarztpraxis, Weisswasser Kreiskrankenhaus, Wels Klinikum P€adiatrie, Wernberg-K€ oblitz SPP, Wien 3. Med. Hietzing Innere, Wien Preyersches Kinderspital, Wien Rudolfstiftung, Wien SMZ Ost Donauspital, Wien UniKinderklinik, Wien Wilhelminenspital 5. Med. Abteilung, Wiesbaden Horst-Schmidt-Kinderkliniken, Wiesbaden Kinderklinik DKD, Wilhelmshaven Reinhard-NieterKinderklinik, Wilhelmshaven St. Willehad Innere, Wittenberg Kinderklinik, Worms - Weierhof, Worms Kinderklinik, Wuppertal Kinderklinik.
Hermann et al
- 2015
ORIGINAL ARTICLES
Appendix 2. In addition to the keywords for the diagnosis, the following treatment search terms were used to screen for JIA in the Diabetes Patienten Verlaufsdokumentation database DMARDs: MTX Methotrexat Metex Lantarel Azathioprin Azafalk Imurek Ciclosporin Sandimmun Leflunomid Azulfidine Chloroquin Hydroxychloroquin
Common biologics: Etanercept Enbrel Adalimumab Humira Anakinra Kineret Abatacept Orencia Canakinumab Ilaris Rilonacept Arcalyst Tozilizumab Roactemra Rituximab Mabthera
DMARD, disease-modifying antirheumatic drug.
Figure 1. Selection of study population from the Diabetes Patienten Verlaufsdokumentation database. Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
6.e3
T
ype 1 diabetes mellitus is known to be associated with juvenile idiopathic arthritis (JIA), autoimmune thyroiditis (AIT), and celiac disease (CD).1-3 Reports describing the comorbidity of type 1 diabetes and JIA in larger cohorts are rare.3-5 JIA is the most common chronic arthritis in childhood and encompasses heterogeneous forms of chronic arthritis. Worldwide, the prevalence of JIA varies significantly (7-400 of 100 000 children).6 Reported differences in the prevalence and incidence resulted mainly from different diagnostic and classification criteria, as well as regional variation.6 From the Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm; Department of Fifteen years ago, the prevalence was reported to be 15-20 of 100 000 German Pediatric Pneumology, Allergology & Neonatology, Children’s Hospital, Hanover Medical School, Hanover; children, with girls (18-23 of 100 000) more frequently affected than boys Children’s Hospital, Hospitals of the City of Cologne, (13-17 of 100 000).7,8 Today, the prevalence is estimated up to 100 of 100 000 Cologne; Department of Pediatrics, Ruhr University of 9,10 Bochum, Bochum; Pediatric Practice, Herford; children. Worldwide, AIT was reported to be present in 7%-40% and CD Department of Pediatric Endocrinology and Diabetology, Olgahospital, Stuttgart Clinical Center, in 1%-16% of children and adolescents with type 1 diabetes.11-13 Stuttgart, Germany; Department of Pediatrics and It is known that autoimmune diseases frequently occur in type 1 diabetes Adolescent Medicine, Medical University of Vienna, Vienna, Austria; German Center for Pediatric and patients.1-3,14,15 However, little information on the clinical data and the prevAdolescent Rheumatology with Center for Social Pediatrics, Garmisch-Partenkirchen; Hospital for alence of JIA in subjects with type 1 diabetes based on larger populations are Children and Adolescents, Sana Hospital Lichtenberg, Berlin Lichtenberg; and Department of Pediatrics and available. One goal of the present study was to determine the prevalence of Adolescent Medicine, Kassel Clinical Center, Kassel, JIA in Germany and Austria in a large number of children and adolescents Germany *List of participating centers of the Diabetes Patienten with type 1 diabetes. We hypothesized that in patients with type 1 diabetes Verlaufsdokumentation-initiative and the Federal with JIA, anthropometry is affected by the comorbid rheumatic disease. PaMinistry of Education and Research Competence Network Diabetes Mellitus is available at www.jpeds. tients with JIA may be smaller than patients without JIA. Diabetes treatment com (Appendix 1). also may differ between patients with or without the rheumatic disease. A Supported by the Competence Network for Diabetes mellitus (01GI1106), funded by the Federal Ministry of greater prevalence of JIA in females was reported in studies analyzing smaller Education and Research, by the European Foundation 1
2
3
4
5
6
7
8
9
10
for the Study of Diabetes and the B€ urger-B€ using Foundation. The authors declare no conflicts of interest.
AIT BMI CD HbA1c JIA
Autoimmune thyroiditis Body mass index Celiac disease Glycosylated hemoglobin A1c Juvenile idiopathic arthritis
Portions of the study were presented as a poster at the Congress of the German Society for Rheumatology €r Rheumatologie [DGRh]), (Deutsche Gesellschaft fu September 1, 2011, Munich, Germany. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.12.026
1
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populations.7,8 On the basis of data from a large registry in the present study, we investigated whether sex differences exist between children and adolescents with and without JIA.
Methods Since 1995 standardized longitudinal data are recorded in the diabetes data acquisition system for prospective surveillance (Diabetes Patienten Verlaufsdokumentation).16 In diabetes health care centers, which used the Diabetes Patienten Verlaufsdokumentation software, all data were entered by physicians, nurses, or other staff members. The centers exported anonymized data and sent them twice a year to the Institute of Epidemiology and Medical Biometry at the University of Ulm, Germany, for aggregated cumulative central analysis. Implausible and inconsistent data were sent back for verification and correction. The ethics committee of the University of Ulm approved analysis of anonymized DPV data. Data of 54 911 patients with type 1 diabetes mellitus, who were younger than 16 years of age, were analyzed. In this observational study, based on information from the Diabetes Patienten Verlaufsdokumentation registry, 330 centers (308 in Germany, 22 in Austria) participated in the prospective data collection from 1995 up to September 2013. The selection of the study population can be seen in a flow chart (Figure 1; available at www.jpeds.com). The measurements herein from each patient’s recent treatment year were extracted from Diabetes Patienten Verlaufsdokumentation. Height and weight were measured, and body mass index (BMI) was calculated. To compare height, weight, and BMI values, the ageand sex-adjusted SDS was determined with contemporary national reference values.17 A patient had a migration background if either the patient or at least one parent was not born in Germany or Austria. Glycemic control was assessed by glycosylated hemoglobin A1c (HbA1c). Each patient’s aggregated HbA1c of the last treatment year was used. To adjust for possible differences between participating centers, HbA1c was standardized to the Diabetes Control and Complication Trial Research Group reference range of 4.05%-6.05% (International Federation of Clinical Chemistry and Laboratory Medicine: 20-42 mmol/mol) by applying the multiple of the mean method.13 Values are displayed in percent and mmol/ mol. The number of blood glucose self-measurements per week and the insulin dose per kilogram and day were self-reported by the children and adolescents, their parents, or caregivers. Blood pressure was measured after current guidelines and hypertension was defined by increased systolic and/or diastolic blood pressure (>95th percentile),18 or when patients used antihypertensive drugs. Blood lipids were evaluated in comparison with national reference values.19 Dyslipidemia was defined by the use of lipid-lowering medication and/or by increased values of one or several blood lipids. Cut-off 2
Vol. -, No. values for blood lipids were as follows: total cholesterol >200 mg/dL, high-density lipoprotein cholesterol <35 mg/ dL, low-density lipoprotein cholesterol >130 mg/dL, and triglycerides >150 mg/dL. Acute metabolic complications, such as severe hypoglycemia (help of another person needed or coma) and ketoacidosis (admission with blood pH less than 7.3), were recorded as number of incidences per year. To select patients with JIA, the Diabetes Patienten Verlaufsdokumentation database was searched for the diagnosis and/or therapy of JIA as comorbidity with search terms and International Classification of Diseases, 10th revision codes according to current guidelines.20 Terms for the diagnosis were “JIA,” “JRA,” “JCA,” “(systemic) idiopathic arthritis,” “SJIA,” “rheumatoid/chronic arthritis,” “Still’s disease,” “oligoarthritis,” “polyarthritis,” “psoriatic arthritis/JIA,” “enthesitis-related arthritis/JIA,” “articular/joint rheumatism,” “ankylosing spondylitis,” “monoarthritis,” and International Classification of Diseases, 10th revision codes M05, M08, and M45. Search terms for disease-modifying antirheumatic drugs or common biologics were additionally applied (Appendix 2: list of drugs). When a patient was found only through treatment search terms, his or her records were reviewed to rule out that the medication was used because of another disease. Such cases were excluded from the analysis. AIT was ascertained when patients were diagnosed with Hashimoto thyroiditis, or if positive thyroid antibodies (thyroid peroxidase antibodies, antithyroglobulin antibodies) greater than 100 U/mL were detected. Patients had CD when confirmed by biopsy. Insulin therapy was classified according to the reported injection frequency per day. Conventional therapy was ascertained when 1-3 injection time points per day were documented. An intensified conventional therapy was determined if more than 3 injection time-points per day were recorded. The documentation of continuous subcutaneous insulin infusion corresponded to pumptherapy. Data were analyzed with SAS 9.3 (SAS Institute Inc, Cary, North Carolina). To compare groups, Kruskal-Wallis test was used for continuous variables and c2; test for dichotomous variables. To compare event rates, a Poisson distribution was assumed. Missing data were not imputed. Data analysis was conducted in regression models (SAS proc glimmix). Regression models were created to adjust for differences in age, sex, diabetes duration, and migration background (in the model for “age at diabetes onset,” diabetes duration was not included; in all sex-stratified models, sex was not included). In additional models for HbA1c and insulin dose per kilogram and day, the confounder “therapy form” was included, to adjust for a possible influence of the applied diabetes therapy. All confounders were fixed effects, and the treatment center was set as random intercept. The models’ estimates were calculated based on observed marginal frequencies. P values <.05 were considered statistically significant. Hermann et al
- 2015
ORIGINAL ARTICLES Results
Until September 2013, 54 911 patients with type 1 diabetes up to the age of 16 years were registered in the Diabetes Patienten Verlaufsdokumentation database. The characteristics of patients included (47% girls) are shown in Table I. One hundred six of 54 911 (193 of 100 000) children and adolescents with type 1 diabetes also were diagnosed with JIA and/or treated with antirheumatic drugs (Figure 2). There were significantly more girls among children with JIA (66%), than among children without JIA (47%, P = .0001). Both groups had the same age. In children and adolescents with JIA, 88% had diabetes before the rheumatic disease. Age at diabetes onset (median [Q1; Q3]: 7.2 [4.1; 10.7] years) was 5 years lower than age at first JIA documentation (12.0 [6.3; 13.9] years). In children without JIA, diabetes onset was later (8.3 [4.8; 11.5] years, P = .04). There was no significant difference concerning migration background between subjects with and without JIA. The following results describe the measures after adjustment for possible confounders and are summarized in Table II. The height differed between patients with JIA, and patients without JIA. Patients without JIA were 2.2 cm taller (unadjusted median). Weight also was lower in children and adolescents with JIA. Stratified for sex, only in boys the difference was significant (P = .04; Figure 3). In the whole group, as well as in boys and girls separately,
Table I. Comparison of patients with type 1 diabetes and patients with type 1 diabetes and JIA Diabetes only Study population, n All 54 805 Girls 25 978 Boys 28 827 Sex, % Girls 47.4 Migration background, % All 14.9 Girls 15.2 Boys 14.6 Age at diabetes onset, y All 8.3 (4.8; 11.5) Girls 8.1 (4.8; 11.0) Boys 8.5 (4.8; 11.9) Age at first JIA documentation, y All Girls Boys Current age, y All 14.2 (10.7; 15.4) Girls 14.0 (10.6; 15.4) Boys 14.4 (10.9; 15.4) Current diabetes duration, y All 3.8 (1.4; 6.9) Girls 4.0 (1.5; 7.0) Boys 3.5 (1.3; 6.8)
Diabetes and JIA
P value
106 70 36 66.0
<.001
16.0 17.1 13.9
n.s. n.s. n.s.
7.2 (4.1; 10.7) 6.8 (4.7; 10.5) 7.8 (2.7; 11.4)
.038 n.s. n.s.
12.0 (6.3; 13.9) 11.6 (6.1; 13.9) 12.0 (7.3; 13.7)
-
14.1 (10.0; 15.3) 13.8 (9.5; 15.3) 14.2 (11.2; 15.2)
n.s. n.s. n.s.
4.6 (2.4; 7.3) 4.2 (2.4; 6.8) 5.1 (2.5; 8.3)
.031 n.s. n.s.
n.s., not significant. Data are displayed in percent or as median with lower and upper quartile (Q1; Q3).
Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
Figure 2. Prevalence of JIA per 100 000 children and adolescents (<16 years of age). Worldwide, European, and local prevalence of JIA compared with the prevalence of JIA in patients with type 1 diabetes in Germany (*GKJR, 6058 children with JIA in German core documentation in 2010 [http:// www.gkjr.de/381.html]); results are from von Koskull et al8 and Kiessling et al7 are included in the meta data of Thierry et al.21 T1D, type 1 diabetes.
BMI SDS was not significantly different between subjects with and without JIA. Independent of rheumatic disease, BMI SDS was above the reference values of the healthy German population (Table II). CD occurred significantly more often in children with JIA (P = .002), and AIT was not significant (P = .06). Independent of the rheumatic comorbidity, the prevalence of both autoimmune diseases was different in boys and girls. AIT was more frequent in girls than in boys. In contrast, CD was more prevalent in boys (Table II). The number of hypoglycemic events did not differ between children and adolescents with and without JIA. There were no patients with JIA and ketoacidosis (Table II). Patients with and without JIA had similar numbers of days in hospital, inpatient admissions, and outpatient contacts. HbA1c differences between patients with and without JIA were significant only in girls. Independent of sex, HbA1c was a little lower in patients with JIA (63 mmol/mol [8.0%]) compared with 67 mmol/mol (8.3%). The insulin dose was greater in patients with JIA and was less pronounced than in boys P = .008. Diabetes treatment showed small differences between patients with and without JIA (Table II). Pump therapy was applied more often by patients with JIA: every third patient used continuous subcutaneous insulin infusion, compared with every fourth patient without JIA. Conventional or intensified conventional therapy was applied by 67% of the patients with JIA and 76% of children without JIA. For all treatment forms, there were no differences between boys and girls. Concerning JIA medication, disease-modifying antirheumatic drugs, and/or biologics were used by 56%, and 14% also received steroids. 3
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Table II. Confounder adjusted comparison of patients with type 1 diabetes and patients and type 1 diabetes and JIA Diabetes and P JIA (n = 106) value
Diabetes only (n = 54 805) Height (SDS)* All 0.09 (0.01) Girls 0.09 (0.01) Boys 0.08 (0.01) Weight (SDS)* All 0.22 (0.01) Girls 0.29 (0.01) Boys 0.15 (0.01) BMI (SDS)* All 0.24 (0.01) Girls 0.31 (0.01) Boys 0.18 (0.01) HbA1c (aggregated from last treatment year), mmol/mol/% All 67 (1)/8.3 (0.04) Girls 67 (1)/8.3 (0.04) Boys 66 (1)/8.2 (0.04) Self-monitoring of blood glucose, n/wk All 36.6 (0.3) Girls 36.9 (0.3) Boys 36.6 (0.3) Insulin dose, IU/kg/d† All 0.93 (0.01) Girls 0.95 (0.01) Boys 0.92 (0.01)
Conventional therapy All Girls Boys Intensified conventional therapy All Girls Boys Pump therapy (CSII) All Girls Boys Hypertension All Girls Boys Dyslipidemia All Girls Boys AIT (diagnosed and/or antibody confirmed) All Girls Boys CD (biopsy confirmed) All Girls Boys
Hypoglycemia (severe) All Girls Boys Hypoglycemia (coma) All Girls Boys 4
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0.22 (0.10) .004 0.19 (0.13) .032 0.27 (0.18) n.s. 0.02 (0.09) .011 0.11 (0.11) n.s. 0.19 (0.16) .043 0.16 (0.09) n.s. 0.28 (0.11) n.s. 0.01 (0.15) n.s. 63 (2)/8.0 (0.2) n.s 62 (2)/7.9 (0.2) .040 65 (3)/8.1 (0.3) n.s. 37.4 (1.1) 36.9 (1.4) 39.0 (1.8)
n.s. n.s. n.s.
1.03 (0.03) .003 1.02 (0.04) n.s. 1.08 (0.05) .008
%
%
10.4 9.7 10.8
9.5 7.4 12.3
n.s. n.s. n.s.
63.2 60.8 65.3
54.0 56.2 48.0
n.s. n.s. n.s.
23.9 27.2 21.4
33.2 34.4 35.5
.035 n.s. n.s.
24.2 26.1 22.64
16.1 22.1 3.5
n.s. n.s. .030
38.1 41.8 34.7
29.5 37.8 17.1
n.s. n.s. n.s.
12.6 17.5 9.5
18.7 26.4 12.0
n.s. n.s. n.s.
1.5 1.8 1.2
5.2 4.8 8.3
.002 n.s. .001
n/yz
n/yz
0.19 (0.002) 0.19 (0.003) 0.19 (0.003)
0.18 (0.041) 0.15 (0.047) 0.23 (0.076)
0.04 (0.001) 0.04 (0.001) 0.04 (0.001)
0.05 (0.020) n.s. 0.04 (0.025) n.s. 0.05 (0.035) n.s. (continued )
n.s. n.s. n.s.
Table II. Continued n/yz Ketoacidosis All Girls Boys Outpatient appointments All Girls Boys
n/yz
0.05 (0.284) 0.05 (0.263) 0.06 (0.305)
(no cases)
n.s. n.s. n.s.
3.58 (0.09) 3.71 (0.09) 3.67 (0.09)
3.79 (0.24) 4.02 (0.29) 3.68 (0.39)
n.s. n.s. n.s.
CSII, continuous subcutaneous insulin infusion. Data are displayed as least squares means with SE. Confounders in regression models: age, sex, diabetes duration, migration background (in regression models for girls and boys, sex was not included). *Reference values from KIGGS—The German Health Survey for Children and Adolescents (Robert-Koch Institute).17 †Insulin units per body weight and per day. zNumber per patient-year.
Discussion The prevalence of JIA in children and adolescents with type 1 diabetes was significantly greater than in patients without diabetes. Also, it was greater than reported 15 years ago7,8 and greater in girls than in boys. Boys and girls with type 1 diabetes and JIA were smaller and slimmer than their peers without JIA. HbA1c was marginally lower in boys and girls with JIA. AIT and CD were more prevalent in patients with the rheumatic comorbidity. The major strength of the present study was the high number of young patients involved. The study was conducted based on a large, standardized, long-term population-based registry, which allows extensive analysis of routine diabetes care. Our results revealed significantly decreased growth in children and adolescents with JIA. The decreased longitudinal growth suggests that most subjects in the study population had more severe forms of JIA. Different JIA classification criteria over the years and the lack of a specific diagnostic test might be reasons that a bias in the diagnosis of JIA cannot be excluded. The Diabetes Patienten Verlaufsdokumentation register is not a specialized database for rheumatic diseases and cannot provide extensive information on the rheumatic disease. The influence of steroids on glycemic control in patients with JIA was not analyzed because few patients used steroids. The number of children and adolescents with type 1 diabetes and JIA was greater (193 of 100 000) than the prevalence of JIA in the pediatric population ascertained in older German studies (15 and 20 of 100 000)7,8 and compared with the European average (28 of 100 000)21 (Figure 2). To estimate the present JIA prevalence in Germany, the number of children with JIA in the German core documentation22 was related to the national population less than 16 years of age, revealing a prevalence of 52 of 100 000. There is evidence that a significant number of children with undiagnosed JIA exists and the prevalence may be about 100 cases per 100 000.10 In the present study, girls with type 1 diabetes (269 of 100 000) were affected twice as often as boys (125 of 100 000). Female Hermann et al
- 2015
ORIGINAL ARTICLES
Figure 3. Weight SDS and height SDS children and adolescents (<16 years) with of type 1 diabetes with and without JIA. Weight and height SDS according to KIGGS—The German Health Survey for Children and Adolescents reference values.17 Error bars show SE.
preponderance in children with both diseases (2.2 to 1) was thus more pronounced than in children without diabetes (1.4 to 1).7,8 AIT antibodies were found in 13% of children and adolescents with type 1 diabetes, which is slightly greater than the 11% that was reported recently.23 Another survey reported a greater prevalence of 27%, but the authors pointed to the varying prevalence of 8%-50% that was given in other studies.24,25 In the present study, girls with or without JIA had AIT 2 times more frequently than boys. According to a recent study, girls were affected 4 times as often.23 The prevalence of CD in the present population was comparable with results of other studies reporting 4%-11%.15,25 The present study revealed a greater prevalence of CD in children with JIA, and AIT also tended to be more prevalent in these patients. Body weight and especially height differed considerably between patients with and without JIA. Children and adolescents with the rheumatic comorbidity were smaller and slimmer than children and adolescents without JIA (Figure 3). An increased risk of stunted growth in children and adolescents with JIA has been largely documented26 and a comparably decreased height SDS was reported in a study27 with a slightly younger population (11.0 years and height SDS 0.15, compared with 14.1 years and height SDS 0.22 in the present study). The lower weight of children with JIA was probably associated with the lower height of the children. Accordingly, BMI SDS was not significantly different. The present multicenter analysis revealed that the prevalence of JIA in children and adolescents with type 1 diabetes was considerably higher than in children and adolescents without diabetes. The autoimmune diseases JIA and type 1 diabetes in combination influenced growth Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
negatively. To our knowledge, the comorbidity of type 1 diabetes and JIA, in combination with AIT or CD, has not been studied in larger cohorts.28 The seemingly better glycemic control in children with JIA should be analyzed further. Our results confirm the value of a standardized, long-term population-based registry, which allows to record and observe data obtained in routine diabetes care. A more detailed characterization of patients with type 1 diabetes and JIA could be achieved by a combined evaluation of the Diabetes Patienten Verlaufsdokumentation database and the German documentation for children with rheumatic disease (German core documentation22) of the German Society for Pediatric and Adolescent Rheumatology. n The authors would like to thank Esther Bollow (Institute of Epidemiology and Medical Biometry, University of Ulm, Germany) for data processing and statistical analysis. Submitted for publication Jun 4, 2014; last revision received Oct 13, 2014; accepted Dec 11, 2014. Reprint requests: Gerhard Hermann, c/o R. W. Holl, Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Albert-Einstein-Allee 41, 89081 Ulm, Germany. E-mail: [email protected]
References 1. Barker JM. Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab 2006;91: 1210-7. 2. Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JHM, et al. Shared and distinct genetic variants in Type 1 diabetes and celiac disease. N Engl J Med 2008;359:2767-77. 3. Stagi S, Giani T, Simonini G, Falcini F. Thyroid function, autoimmune thyroiditis and coeliac disease in juvenile idiopathic arthritis. Rheumatology 2005;44:517-20. 5
THE JOURNAL OF PEDIATRICS
4. Pohjankoski H, Kautiainen H, Korppi M, Savolainen A. Simultaneous juvenile idiopathic arthritis and diabetes mellitus type 1—a Finnish nationwide study. J Rheumatol 2012;39:377-81. 5. Minden K, Niewerth M. Juvenile idiopathic arthritis—clinical subgroups and classification. Z Rheumatol 2008;67:100-10. 6. Manners PJ, Bower C. Worldwide prevalence of juvenile arthritis why does it vary so much? J Rheumatol 2002;29:1520-30. 7. Kiessling U, D€ oring E, Listing J, Meincke J, Sch€ ontube M, Strangfeld A, et al. Incidence and prevalence of juvenile chronic arthritis in East Berlin 1980-88. J Rheumatol 1998;25:1837-43. 8. Von Koskull S, Truckenbrodt H, Holle R, H€ ormann A. Incidence and prevalence of juvenile arthritis in an urban population of southern Germany: a prospective study. Ann Rheum Dis 2001;60:940-5. 9. D€ uckers G, Niehues T. Juvenile idiopathic arthritis (JIA) [in German]. Monatsschr Kinderheilkd 2011;159:25-33. 10. Zink A, Minden K, List SM. Inflammatory rheumatic diseases. Federal Health Monitoring System. Berlin: Robert-Koch-Institute; 2010. 11. Lorini R, d’Annunzio G, Vitali L, Scaramuzza A. IDDM and autoimmune thyroid disease in the pediatric age group. J Pediatr Endocrinol Metab 1996;9(Suppl 1):89-94. 12. Sumnik Z, Cinek O, Bratanic N, Lebl J, Rozsai B, Limbert C, et al. Thyroid autoimmunity in children with coexisting type 1 diabetes mellitus and celiac disease: a multicenter study. J Pediatr Endocrinol Metab 2006;19:517-22. 13. Fr€ ohlich-Reiterer EE, Hofer S, Kaspers S, Herbst A, Kordonouri O, Schwarz H-P, et al. Screening frequency for celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus—data from a German/Austrian multicentre survey. Pediatr Diabetes 2008;9:546-53. 14. Pohjankoski H, Kautiainen H, Kotaniemi K, Korppi M, Savolainen A. Diabetes, coeliac disease, multiple sclerosis and chronic arthritis in first-degree relatives of patients with juvenile idiopathic arthritis. Acta Paediatr 2012;101:767-71. 15. Camarca ME, Mozzillo E, Nugnes R, Zito E, Falco M, Fattorusso V, et al. Celiac disease in type 1 diabetes mellitus. Ital J Pediatr 2012;38:10. 16. Grabert M, Schweiggert F, Holl RW. A framework for diabetes documentation and quality management in Germany: 10 years of experience with DPV. Comput Programs Biomed 2002;69:115-21. 17. Robert-Koch Institute (RKI). KIGGS—The German Health Survey for Children and Adolescents. Reference values for anthropometric mea-
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Hermann et al
- 2015
ORIGINAL ARTICLES Appendix 1
List of Participating Centers Aachen - Uni-Kinderklinik RWTH, Aalen Kinderklinik, Ahlen St. Franziskus Kinderklinik, Aidlingen Praxisgemeinschaft, Alt€ otting Zentrum Inn-Salzach, Alt€ otting-Burghausen Innere Medizin, Amstetten Klinikum Mostviertel Kinderklinik, Arnsberg-H€ usten Karolinenhosp. Kinderabteilung, Aue Helios Kinderklink, Augsburg Innere, Augsburg Kinderklinik Zentralklinikum, Aurich Kinderklinik, Bad Aibling Internist. Praxis, Bad Hersfeld Kinderklinik, Bad Kreuznach-Viktoriastift, Bad K€ osen KinderRehaklinik, Bad Lauterberg Diabeteszentrum Innere, Bad Mergentheim - Diabetesfachklinik, Bad Mergentheim - Gemeinschaftspraxis DM-dorf Althausen, Bad Oeynhausen Herz-und Diabeteszentrum NRW, Bad Orb Spessart Klinik, Bad Orb Spessart Klinik Reha, Bad Reichenhall Kreisklinik Innere Med., Bad Salzungen Kinderklinik, Bad Waldsee Kinderarztpraxis, Bautzen Oberlausitz KK, Bayreuth Innere Medizin, Berchtesgaden CJD, Berchtesgaden MVZ Innere Med, Berlin DRK-Kliniken, Berlin Endokrinologikum, Berlin Klinik St. Hedwig Innere, Berlin Lichtenberg - Kinderklinik, Berlin Virchow-Kinderklinik, Bielefeld Kinderklinik Gilead, Bocholt Kinderklinik, Bochum Universit€atskinderklinik St. Josef, Bonn Uni-Kinderklinik, Bottrop Kinderklinik, Bottrop Knappschaftskrankenhaus Innere, Braunschweig Kinderarztpraxis, Bremen - Kinderklinik Nord, Bremen Zentralkrankenhaus Kinderklinik, Bremerhaven Kinderklinik, B€ oblingen Kinderklinik, Celle Klinik f€ ur Kinder- und Jugendmedizin, Chemnitz Kinderklinik, Coesfeld Kinderklinik, Darmstadt Innere Medizin, Darmstadt Kinderklinik Prinz. Margaret, Datteln Vestische Kinderklinik, Deggendorf Kinderarztpraxis, Deggendorf Kinderklinik, Deggendorf Medizinische Klinik II, Delmenhorst Kinderklinik, Dessau Kinderklinik, Detmold Kinderklinik, Dinslaken Kinderklinik, Dornbirn Kinderklinik, Dortmund Kinderklinik, Dortmund Medizinische Kliniken Nord, Dortmund-St. Josefshospital Innere, Dresden Neustadt Kinderklinik, Dresden Uni-Kinderklinik, Duisburg Evang. und Johanniter Krhs Innere, Duisburg Kinderklinik, Duisburg Malteser St. Anna Innere, Duisburg-Huckingen, Duisburg-St. Johannes Helios, D€ uren-Birkesdorf Kinderklinik, D€ usseldorf Uni-Kinderklinik, Eberswalde Klinikum Barnim Werner Forßmann - Innere, Erfurt Kinderklinik, Erlangen Uni Innere Medizin, Erlangen Uni-Kinderklinik, Essen Diabetes-Schwerpunktpraxis, Essen Elisabeth Kinderklinik, Essen Uni-Kinderklinik, Esslingen Klinik f€ ur Kinder und Jugendliche, Eutin Kinderklinik, Feldkirch Kinderklinik, Forchheim Diabeteszentrum SPP, Frankenthal Kinderarztpraxis, Frankfurt Diabeteszentrum Rhein-MainErwachsenendiabetologie (B€ urgerhospital), Frankfurt UniKinderklinik, Frankfurt Uni-Klinik Innere, Freiburg Kinder-MVZ, Freiburg St. Josef Kinderklinik, Freiburg Uni Innere, Freiburg Uni-Kinderklinik, Freudenstadt Kinderklinik, Friedberg Innere Klinik, Friedrichshafen Kinderklinik, Fulda Innere Medizin, Fulda Kinderklinik, F€ urth Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
Kinderklinik, Gaissach Fachklinik der Deutschen Rentenversicherung Bayern S€ ud, Garmisch-Partenkirchen Kinderklinik, Geislingen Klinik Helfenstein Innere, Gelnhausen Kinderklinik, Gelsenkirchen Kinderklinik Marienhospital, Gera Kinderklinik, Gießen Uni-Kinderklinik, Graz Universit€ats-Kinderklinik, G€ oppingen Kinderklinik am Eichert, G€ orlitz St€adtische Kinderklinik, G€ ottingen UniKinderklinik, Hachenburg Kinderpraxis, Hagen Kinderklinik, Halberstadt Innere Med. St. Salvator AMEOS Klinik, Halberstadt Kinderklinik St. Salvator, Halle UniKinderklinik, Halle-D€ olau St€adtische Kinderklinik, Hamburg Altonaer Kinderklinik, Hamburg Endokrinologikum, Hamburg Kinderklinik Wilhelmstift, Hamburg-Nord Kinder-MVZ, Hameln Kinderklinik, Hamm Kinderklinik, Hanau Kinderklinik, Hannover Henriettenstift - Innere, Hannover Kinderklinik MHH, Hannover Kinderklinik auf der Bult, Haren Kinderarztpraxis, Heide Kinderklinik, Heidelberg Uni-Kinderklinik, Heidenheim Kinderklinik, Heilbronn Innere Klinik, Heilbronn Kinderklinik, Herdecke Kinderklinik, Herford Kinderarztpraxis, Herford Klinikum Kinder & Jugendliche, Heringsdorf Inselklinik, Hermeskeil Kinderpraxis, Herten St. Elisabeth Innere Medizin, Hildesheim GmbH - Innere, Hildesheim Kinderarztpraxis, Hildesheim Kinderklinik, Hinrichsegen-Bruckm€ uhl Diabetikerjugendhaus, Hof Kinderklinik, Homburg UniKinderklinik Saarland, Idar Oberstein Innere, Ingolstadt Klinikum Innere, Innsbruck Universit€atskinderklinik, Iselsberg - Rehazentrum Ederhof, Iserlohn Innere Medizin, Itzehoe Kinderklinik, Jena Uni-Kinderklinik, Kaiserslautern Kinderarztpraxis, Kaiserslautern-Westpfalzklinikum Kinderklinik, Kamen Klinikum Westfalen Hellmig Krankenhaus, Karlsburg Klinik f€ ur Diabetes & Stoffwechsel, Karlsruhe St€adtische Kinderklinik, Kassel Klinikum Kinder-und Jugendmedizin, Kassel St€adtische Kinderklinik, Kaufbeuren Innere Medizin, Kempen Heilig Geist - Innere, Kempten Oberallg€au Kinderklinik, Kiel St€adtische Kinderklinik, Kiel Universit€ats-Kinderklinik, Kirchen DRK Klinikum Westerwald Kinderklinik, Kirchheim-N€ urtingen Innere, Kleve Innere Medizin, Koblenz Kinderklinik Kemperhof, Konstanz Kinderklinik, Krefeld Innere Klinik, Krefeld Kinderklinik, Kreischa-Zscheckwitz Klinik Bavaria, K€ oln Kinderklinik Amsterdamerstrasse, K€ oln Uni-Kinderklinik, Landshut Kinderklink, Lappersdorf Kinderarztpraxis, Leer Kreiskrankenhaus - Kinderabt., Leipzig Uni-Kinderklinik, Leoben LKH Kinderklinik, Leverkusen Kinderklinik, Lienz BKH Kinderklinik, Lienz BKH P€adiatrie, Lilienthal Schwerpunktpraxis, Limburg Innere Medizin, Lindenfels Luisenkrankenhaus Innere, Lingen Kinderklinik St. Bonifatius, Linz Krankenhaus der Barmherzigen Schwestern Kinderklinik, Linz Landes-Kinderklinik, Lippstadt Evangelische Kinderklinik, Ludwigsburg Kinderklinik, Ludwigshafen Kinderklinik St. Anna-Stift, Ludwigshafen diabetol. SPP, L€ ubeck Uni-Kinderklinik, L€ udenscheid Hilfswerk Kinder & Jugendliche, L€ udenscheid M€arkische Kliniken - Kinder & Jugendmedizin, Magdeburg St€adtisches Klinikum Innere, Magdeburg Uni-Kinderklinik, Mainz Uni-Kinderklinik, Mannheim Uni-Kinderklinik, Mannheim Uniklinik Innere 6.e1
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Medizin, Marburg Uni-Kinderklinik, Marktredwitz Innere Medizin, Mechernich Kinderklinik, Memmingen Kinderklinik, Merzig Kinderklinik, Minden Kinderklinik, Moers - St. Josefskrankenhaus Innere, Moers Kinderklinik, Murnau am Staffelsee - diabetol. SPP, Mutterstadt Kinderarztpraxis, M€ odling Kinderklinik, M€ onchengladbach Kinderklinik Rheydt Elisabethkrankenhaus, M€ uhlacker Enzkreiskliniken Innere, M€ uhldorf Gemeinschaftspraxis, M€ unchen 3. Orden Kinderklinik, M€ unchen Diabetes-Zentrum S€ ud, M€ unchen Kinderarztpraxis diabet. SPP, M€ unchen von Haunersche Kinderklinik, M€ unchen-Gauting Kinderarztzentrum, M€ unchen-Harlaching Kinderklinik, M€ unchen-Schwabing Kinderklinik, M€ unster Herz Jesu Innere, M€ unster St. Franziskus Kinderklinik, M€ unster Uni-Kinderklinik, M€ unster p€adiat. Schwerpunktpraxis, Nauen Havellandklinik, Neuburg Kinderklinik, Neumarkt Innere, Neunkirchen Marienhausklinik Kohlhof Kinderklinik, Neuss Lukaskrankenhaus Kinderklinik, Neuwied Kinderklinik Elisabeth, N€ urnberg Cnopfsche Kinderklinik, N€ urnberg Zentrum f Neugeb./Kinder & Jugendl., Oberhausen Kinderklinik, Oberhausen Kinderpraxis, Oberhausen St. Clemens Hospitale Sterkrade, Offenbach/Main Innere Medizin, Offenbach/Main Kinderklinik, Offenburg Kinderklinik, Oldenburg Kinderklinik, Oldenburg Schwerpunktpraxis, Olpe p€adiatrische Gemeinschaftspraxis, Oschersleben MEDIGREIF B€ ordekrankenhaus, Osnabr€ uck Christliches Kinderhospital, Osterkappeln Innere, Oy-Mittelberg Hochgebirgsklinik Kinder-Reha, Paderborn St. Vincenz Kinderklinik, Papenburg Marienkrankenhaus Kinderklinik, Passau Kinderarztpraxis, Passau Kinderklinik, Pforzheim Kinderklinik, Pfullendorf Innere Medizin, Pirmasens St€adtisches Krankenhaus Innere, Plauen Vogtlandklinikum, Prenzlau Krankenhaus Innere, Rastatt Gemeinschaftspraxis, Rastatt Kreiskrankenhaus Innere, Ravensburg Kinderklink St. Nikolaus, Recklinghausen Dialysezentrum Innere, Regensburg Kinderklinik St. Hedwig, Remscheid Kinderklinik, Rendsburg Kinderklinik, Reutlingen Kinderarztpraxis, Reutlingen Kinderklinik, Reutlingen
6.e2
Vol. -, No. Klinikum Steinenberg Innere, Rheine Mathiasspital Kinderklinik, Rosenheim Innere Medizin, Rosenheim Kinderklinik, Rosenheim Schwerpunktpraxis, Rostock Uni-Kinderklinik, Rotenburg/W€ umme Kinderklinik, R€ usselsheim Kinderklinik, Saaldorf-Surheim Diabetespraxis, Saalfeld Th€ uringenklinik Kinderklinik, Saarbr€ ucken Kinderklinik Winterberg, Saarlouis Kinderklinik, Salzburg Kinderklinik, Scheidegg Prinzregent Luitpold, Scheidegg Reha-Kinderklinik Maximilian, Schw. Gm€ und Stauferklinik Kinderklinik, Schweinfurt Kinderklinik, Schwerin Innere Medizin, Schwerin Kinderklinik, Schw€abisch Hall Diakonie Kinderklinik, Siegen Kinderklinik, Singen - Hegauklinik Kinderklinik, Singen Kinderarztpraxis, Sinsheim Innere, Spaichingen Innere, St. Augustin Kinderklinik, St. P€ olten Kinderklinik, Stade Kinderklinik, Stolberg Kinderklinik, Stuttgart Olgahospital Kinderklinik, Suhl Kinderklinik, Sylt Rehaklinik, Tettnang Innere Medizin, Traunstein diabetol. Schwerpunktpraxis, Trier Kinderklinik der Borrom€aerinnen, Trostberg Innere, T€ ubingen Uni-Kinderklinik, Ulm Endokrinologikum, Ulm Schwerpunktpraxis Bahnhofsplatz, Ulm Uni Innere Medizin, Ulm Uni-Kinderklinik, Vechta Kinderklinik, Viersen Kinderkrankenhaus St. Nikolaus, Villach Kinderklinik, Villingen-Schwenningen Diabetesschule, VillingenSchwenningen Schwarzwald-Baar-Klinikum Innere, Waiblingen Kinderklinik, Waldshut Kinderpraxis, Waldshut-Tiengen Kinderpraxis Biberbau, Waren-M€ uritz Kinderklinik, Weiden Kinderklinik, Weingarten Kinderarztpraxis, Weisswasser Kreiskrankenhaus, Wels Klinikum P€adiatrie, Wernberg-K€ oblitz SPP, Wien 3. Med. Hietzing Innere, Wien Preyersches Kinderspital, Wien Rudolfstiftung, Wien SMZ Ost Donauspital, Wien UniKinderklinik, Wien Wilhelminenspital 5. Med. Abteilung, Wiesbaden Horst-Schmidt-Kinderkliniken, Wiesbaden Kinderklinik DKD, Wilhelmshaven Reinhard-NieterKinderklinik, Wilhelmshaven St. Willehad Innere, Wittenberg Kinderklinik, Worms - Weierhof, Worms Kinderklinik, Wuppertal Kinderklinik.
Hermann et al
- 2015
ORIGINAL ARTICLES
Appendix 2. In addition to the keywords for the diagnosis, the following treatment search terms were used to screen for JIA in the Diabetes Patienten Verlaufsdokumentation database DMARDs: MTX Methotrexat Metex Lantarel Azathioprin Azafalk Imurek Ciclosporin Sandimmun Leflunomid Azulfidine Chloroquin Hydroxychloroquin
Common biologics: Etanercept Enbrel Adalimumab Humira Anakinra Kineret Abatacept Orencia Canakinumab Ilaris Rilonacept Arcalyst Tozilizumab Roactemra Rituximab Mabthera
DMARD, disease-modifying antirheumatic drug.
Figure 1. Selection of study population from the Diabetes Patienten Verlaufsdokumentation database. Comorbidity of Type 1 Diabetes and Juvenile Idiopathic Arthritis
6.e3