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Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.

https://arctichealth.org/en/permalink/ahliterature291762
Source
Diabetologia. 2017 07; 60(7):1284-1293
Publication Type
Journal Article
Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't
Date
07-2017
Author
Petra M Pöllänen
Johanna Lempainen
Antti-Pekka Laine
Jorma Toppari
Riitta Veijola
Paula Vähäsalo
Jorma Ilonen
Heli Siljander
Mikael Knip
Author Affiliation
Children's Hospital, University of Helsinki and Helsinki University Hospital, P.O. Box 22, FI-00014, Helsinki, Finland.
Source
Diabetologia. 2017 07; 60(7):1284-1293
Date
07-2017
Language
English
Publication Type
Journal Article
Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't
Keywords
Adolescent
Autoantibodies - blood
Autoimmunity
Child
Child, Preschool
Diabetes Mellitus, Type 1 - diagnosis - genetics - physiopathology
Disease Progression
Female
Finland
Genetic Predisposition to Disease
Genotype
Glutamate Decarboxylase - metabolism
HLA Antigens - genetics
HLA-DQ Antigens - genetics
Humans
Infant
Insulin-Secreting Cells - immunology
Longitudinal Studies
Male
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Prevalence
Time Factors
Young Adult
Abstract
In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility.
We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9-21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes.
Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (=2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion.
At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.
Notes
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PubMed ID
28364254 View in PubMed
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Cow's Milk Allergy in Infancy and Later Development of Juvenile Idiopathic Arthritis: A Register-Based Case-Control Study.

https://arctichealth.org/en/permalink/ahliterature285667
Source
Am J Epidemiol. 2017 Jul 15;186(2):237-244
Publication Type
Article
Date
Jul-15-2017
Author
Miika Arvonen
Lauri J Virta
Tytti Pokka
Liisa Kröger
Paula Vähäsalo
Source
Am J Epidemiol. 2017 Jul 15;186(2):237-244
Date
Jul-15-2017
Language
English
Publication Type
Article
Keywords
Adolescent
Animals
Arthritis, Juvenile - epidemiology
Case-Control Studies
Cattle
Child
Child, Preschool
Comorbidity
Female
Finland - epidemiology
Humans
Infant
Logistic Models
Male
Milk Hypersensitivity - epidemiology
Odds Ratio
Registries
Risk factors
Sex Distribution
Abstract
We examined the association between cow's milk allergy (CMA) and juvenile idiopathic arthritis (JIA). The material for this case-control study was collected from national registers of all children born in Finland between 2000 and 2010 and diagnosed with JIA (n = 1,298) and age-, sex-, and place-matched controls (n = 5,179). We identified 235 children with CMA; 66 of these children also had JIA. A conditional logistic regression analysis was performed to evaluate the association between CMA and JIA and to test whether exposure to antibiotics would be a covariate for this association. In boys (but not in girls), a diagnosis of CMA and the use of hypoallergenic formula in infancy were associated with the later development of JIA (odds ratio = 2.4, 95% confidence interval: 1.6, 3.6). The association was most evident in boys who were diagnosed with JIA before age 3 years or diagnosed with CMA with predominantly gastrointestinal symptoms. There was no statistically significant additive interaction between CMA and antibiotic exposure in the later development of JIA. These associations may reflect impaired maturation of intestinal immunity and integrity in boys with a risk of JIA. Predisposing factors related to JIA pathogenesis seem to display a sex-linked disparity.
PubMed ID
28459985 View in PubMed
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Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years.

https://arctichealth.org/en/permalink/ahliterature304817
Source
J Clin Endocrinol Metab. 2020 12 01; 105(12):
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
12-01-2020
Author
Petra M Pöllänen
Samppa J Ryhänen
Jorma Toppari
Jorma Ilonen
Paula Vähäsalo
Riitta Veijola
Heli Siljander
Mikael Knip
Author Affiliation
Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Source
J Clin Endocrinol Metab. 2020 12 01; 105(12):
Date
12-01-2020
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adolescent
Autoantibodies - analysis - blood
Autoimmunity - genetics
Child
Child Development - physiology
Child, Preschool
Diabetes Mellitus, Type 1 - diagnosis - epidemiology - genetics - immunology
Female
Finland - epidemiology
Follow-Up Studies
Genetic Predisposition to Disease
Glutamate Decarboxylase - immunology
HLA Antigens - genetics
Humans
Infant
Infant, Newborn
Insulin Antibodies - analysis - blood
Islets of Langerhans - immunology
Male
Prognosis
Prospective Studies
Receptor-Like Protein Tyrosine Phosphatases, Class 8 - immunology
Time Factors
Zinc Transporter 8 - genetics - immunology
Abstract
We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context.
HLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D.
By age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A- and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01).
In HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.
PubMed ID
32882033 View in PubMed
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Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study.

https://arctichealth.org/en/permalink/ahliterature187748
Source
J Med Virol. 2003 Jan;69(1):91-8
Publication Type
Article
Date
Jan-2003
Author
Kimmo Salminen
Karita Sadeharju
Maria Lönnrot
Paula Vähäsalo
Antti Kupila
Sari Korhonen
Jorma Ilonen
Olli Simell
Mikael Knip
Heikki Hyöty
Author Affiliation
Juvenile Diabetes Research Foundation Center for Prevention of Type 1 Diabetes in Finland.
Source
J Med Virol. 2003 Jan;69(1):91-8
Date
Jan-2003
Language
English
Publication Type
Article
Keywords
Adenoviridae Infections - immunology - virology
Antibodies, Viral - blood
Autoantibodies - blood
Autoimmunity
Cohort Studies
Diabetes Mellitus, Type 1 - complications - epidemiology - immunology - virology
Enterovirus Infections - complications - epidemiology
Female
Finland - epidemiology
Humans
Immunoglobulin A - blood
Immunoglobulin G - blood
Infant
Infant, Newborn
Male
Prospective Studies
Reverse Transcriptase Polymerase Chain Reaction
Abstract
Enterovirus infections have been associated with the manifestation of clinical type 1 diabetes in a number of reports, and recent prospective studies have suggested that enterovirus infections may initiate the autoimmune process, leading to the disease. In the present study, we analyzed the role of enterovirus infections in a Finnish birth cohort study, Diabetes Prediction and Prevention (DIPP), in which all newborn infants are screened for diabetes-associated HLA-DQB1 alleles, and those with an increased genetic risk are invited for prospective follow-up. Enterovirus infections were diagnosed by serology and reverse transcriptase-polymerase chain reaction (RT-PCR) from serum samples taken from birth every 3-6 months. Case children included 41 infants who became positive for diabetes-associated autoantibodies during the observation. Control children comprised altogether 196 infants who remained autoantibody negative and were matched for the time of birth, sex, and HLA-DQB1 alleles. Enterovirus infections were more frequent in case children than in control children (P = 0.004), and the average enterovirus antibody levels were also higher in the case children (P = 0.003). Enterovirus infections were particularly frequent during the 6-month period preceding the first detection of autoantibodies: 51% of the case children compared with 28% of the control children had an infection in that time interval (P = 0.003). There was no difference in the frequency of adenovirus infections between the groups (P = 0.9). The present results imply that enterovirus infections are associated with the appearance of beta-cell autoantibodies. A possible causal relationship is supported by the clustering of infections to the time when autoantibodies appeared.
PubMed ID
12436483 View in PubMed
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The Finnish version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

https://arctichealth.org/en/permalink/ahliterature295150
Source
Rheumatol Int. 2018 Apr; 38(Suppl 1):179-186
Publication Type
Journal Article
Multicenter Study
Validation Studies
Date
Apr-2018
Author
Pekka Lahdenne
Kristiina Aalto
Katariina Rebane
Paula Vahasalo
Anne Kristiina Putto-Laurila
Merja Malin
Liisa Kroger
Hanna Saila
Alessandro Consolaro
Francesca Bovis
Nicolino Ruperto
Author Affiliation
Pediatric Rheumatology, Children's Hospital, Helsinki University Central Hospital, Stenbackink, 11, 00290, Helsinki, Finland. pekka.lahdenne@hus.fi.
Source
Rheumatol Int. 2018 Apr; 38(Suppl 1):179-186
Date
Apr-2018
Language
English
Publication Type
Journal Article
Multicenter Study
Validation Studies
Keywords
Adolescent
Age of Onset
Arthritis, Juvenile - diagnosis - physiopathology - psychology - therapy
Case-Control Studies
Child
Child, Preschool
Cultural Characteristics
Disability Evaluation
Female
Finland
Health status
Humans
Male
Parents - psychology
Patient Reported Outcome Measures
Patients - psychology
Predictive value of tests
Prognosis
Psychometrics
Quality of Life
Reproducibility of Results
Rheumatology - methods
Translating
Abstract
The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Finnish language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 173 JIA patients (1.2% systemic, 46.2% oligoarticular, 39.9% RF-negative polyarthritis, 12.7% other categories) and 100 healthy children, were enrolled in five paediatric rheumatology centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Finnish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.
Notes
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PubMed ID
29637332 View in PubMed
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Increased frequency of islet cell antibodies in unaffected brothers of children with type 1 diabetes.

https://arctichealth.org/en/permalink/ahliterature186184
Source
Horm Res. 2003;59(4):195-200
Publication Type
Article
Date
2003
Author
Vesa Eskola
Paula Vähäsalo
Hans K Akerblom
Mikael Knip
Author Affiliation
University of Tampere Medical School and Department of Paediatrics, Tampere University Hospital, Tampere, Finland.
Source
Horm Res. 2003;59(4):195-200
Date
2003
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aging - immunology
Autoantibodies - metabolism
Child
Child, Preschool
Demography
Diabetes Mellitus, Type 1 - genetics
Fathers
Female
Finland
Humans
Infant
Male
Mass Screening
Middle Aged
Mothers
Sex Characteristics
Siblings
Abstract
To assess the relation between islet cell antibody (ICA) positivity and demographic characteristics in an extensive series of first-degree relatives of children with type 1 diabetes (T1D).
Family members of children diagnosed with T1D before the age of 16 years and attending one of 27 participating paediatric units in Finland taking care of children with diabetes were invited to volunteer for an ICA screening program aimed at identifying individuals eligible for inclusion in the European Nicotinamide Diabetes Intervention Trial (ENDIT). The final series comprised 2,522 first-degree relatives (1,107 males) with a mean age of 20.4 (range 0.1-51.9) years, out of whom 390 were fathers, 622 mothers, 717 brothers, and 793 sisters of affected cases.
Two hundred and four family members (8.1%) tested positive for ICA with levels ranging from 3 to 564 (median 18) Juvenile Diabetes Foundation (JDF) units. One hundred and five relatives (4.2%) had an ICA level of 18 JDF units or more. Males had detectable ICA more often than females (9.6 vs. 6.9%; p = 0.02). Antibody-positive family members under the age of 20 years had higher ICA levels than the older ones [median 18 (range 3-514) JDF units vs. 10 (range 3-564) JDF units; p = 0.008]. Among the adult relatives (>or=20 years of age) antibody-positive females had higher ICA levels than the males [median 10 (range 5-564) JDF units vs. 9 (range 3-130) JDF units; p = 0.04]. Siblings had an increased frequency of high-titre ICA (>or=18 JDF units) when compared to the parents (4.8 vs. 3.2%; p = 0.05). Among siblings, we found a higher frequency of ICA positivity in brothers than in sisters (10.8 vs. 6.9%; p = 0.01), and this was also true for high-titre ICA (6.0 vs. 3.8 %; p = 0.04). Geographically, the highest ICA prevalence was seen among relatives living in the middle of Finland (10.4 vs. 7.2% in the other parts of Finland; p = 0.01).
These results imply that male gender and young age favour positive ICA reactivity among family members of children with T1D. Siblings test positive for high ICA titres (>or=18 JDF units) more frequently than parents. Accordingly, judged from demographic characteristics, the yield of ICA screening in first-degree relatives would be maximized by targeting young brothers of affected cases.
PubMed ID
12649574 View in PubMed
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The mortality rate and causes of death among juvenile idiopathic arthritis patients in Finland.

https://arctichealth.org/en/permalink/ahliterature300281
Source
Clin Exp Rheumatol. 2019 May-Jun; 37(3):508-511
Publication Type
Journal Article
Author
Minna Susanna Kyllönen
Hannu Kautiainen
Kari Puolakka
Paula Vähäsalo
Author Affiliation
Department of Internal Medicine and Medical Research Centre, University of Oulu and Oulu University Hospital; and PEDEGO Research Unit, University of Oulu, Finland. mikyllon@student.oulu.fi.
Source
Clin Exp Rheumatol. 2019 May-Jun; 37(3):508-511
Language
English
Publication Type
Journal Article
Keywords
Adolescent
Adult
Arthritis, Juvenile - mortality
Case-Control Studies
Cause of Death
Child
Female
Finland
Humans
Male
Proportional Hazards Models
Registries
Young Adult
Abstract
To explore mortality rates and causes of death in juvenile idiopathic arthritis (JIA) patients in Finland compared with the general population.
All incident patients with JIA (age
PubMed ID
30767877 View in PubMed
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Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population.

https://arctichealth.org/en/permalink/ahliterature148540
Source
Diabetes. 2009 Dec;58(12):2835-42
Publication Type
Article
Date
Dec-2009
Author
Heli T A Siljander
Satu Simell
Anne Hekkala
Jyrki Lähde
Tuula Simell
Paula Vähäsalo
Riitta Veijola
Jorma Ilonen
Olli Simell
Mikael Knip
Author Affiliation
Hospital for Children and Adolescents and Folkhälsan Research Center, University of Helsinki, Helsinki, Finland.
Source
Diabetes. 2009 Dec;58(12):2835-42
Date
Dec-2009
Language
English
Publication Type
Article
Keywords
Adolescent
Autoantibodies - blood
Biological Markers - blood
Child
Cohort Studies
Diabetes Mellitus, Type 1 - epidemiology - immunology
Disease Progression
Disease Susceptibility
Female
Finland - epidemiology
Genotype
HLA-DQ Antigens - immunology
HLA-DQ beta-Chains
Humans
Male
Membrane Glycoproteins - immunology
Prediabetic State - immunology
Predictive value of tests
Sensitivity and specificity
Abstract
As data on the predictive characteristics of diabetes-associated autoantibodies for type 1 diabetes in the general population are scarce, we assessed the predictive performance of islet cell autoantibodies (ICAs) in combination with autoantibodies against insulin (IAAs), autoantibodies against GAD, and/or islet antigen 2 for type 1 diabetes in children with HLA-defined disease predisposition recruited from the general population.
We observed 7,410 children from birth (median 9.2 years) for beta-cell autoimmunity and diabetes. If a child developed ICA positivity or diabetes, the three other antibodies were measured in all samples available from that individual. Persistent autoantibody positivity was defined as continued positivity in at least two sequential samples including the last available sample.
Pre-diabetic ICA positivity was observed in 1,173 subjects (15.8%), 155 of whom developed type 1 diabetes. With ICA screening, 86% of 180 progressors (median age at diagnosis 5.0 years) were identified. Positivity for four antibodies was associated with the highest disease sensitivity (54.4%) and negative predictive values (98.3%) and the lowest negative likelihood ratio (0.5). The combination of persistent ICA and IAA positivity resulted in the highest positive predictive value (91.7%), positive likelihood ratio (441.8), cumulative disease risk (100%), and specificity (100%). Young age at seroconversion, high ICA level, multipositivity, and persistent positivity for IAA were significant risk markers for type 1 diabetes.
Within the general population, the combination of HLA and autoantibody screening resulted in disease risks that are likely to be as high as those reported among autoantibody-positive siblings of children with type 1 diabetes.
Notes
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PubMed ID
19755526 View in PubMed
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Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group's greater susceptibility to infections?

https://arctichealth.org/en/permalink/ahliterature271210
Source
J Rheumatol. 2015 Mar;42(3):521-6
Publication Type
Article
Date
Mar-2015
Author
Miika Arvonen
Lauri J Virta
Tytti Pokka
Liisa Kröger
Paula Vähäsalo
Source
J Rheumatol. 2015 Mar;42(3):521-6
Date
Mar-2015
Language
English
Publication Type
Article
Keywords
Anti-Bacterial Agents - adverse effects - therapeutic use
Arthritis, Juvenile - diagnosis - etiology
Bacterial Infections - drug therapy
Case-Control Studies
Child
Child, Preschool
Disease Susceptibility
Female
Finland
Humans
Infant
Male
Registries
Risk factors
Abstract
Previous exposure to antibiotics has been associated with the pathogenesis of several autoimmune diseases. Our objective was to explore whether childhood exposure to antibiotics would be associated with the risk of developing juvenile idiopathic arthritis (JIA).
The material was collected from national registers containing all children born in 2000-2010 in Finland and diagnosed with JIA by the end of December 2012 (n = 1298) and appropriate controls (n = 5179) matched for age, sex, and place of birth. All purchases of antibiotics were collected from birth until the index date (i.e., the date of special reimbursement for JIA medications). A conditional logistic regression was performed to evaluate the association between the exposure to antibiotics and the risk of JIA.
The risk of JIA increased with the number of antibiotic purchases from birth to the index date: for = 1 purchases versus none, OR 1.6, 95% CI 1.3-1.9 with an upward trend in OR (p
Notes
Comment In: J Rheumatol. 2015 Mar;42(3):355-725729039
PubMed ID
25320218 View in PubMed
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