Increase in stress contributes to impaired jaw function in juvenile idiopathic arthritis: a two-year prospective study.

BACKGROUND: Stress in patients with Juvenile Idiopathic Arthritis (JIA) has been found to be associated with orofacial pain, psychological distress, jaw dysfunction and loss of daily activities in a cross-sectional study. The aim of this study was to investigate the relations between stress and change of stress over time versus changes in orofacial pain, psychosocial factors and jaw function over a two-year period in patients with JIA. METHODS: This is a two-year prospective follow-up study involving 40 JIA patients. At baseline (2015) the median age was 12 years and at two-year follow up (2018) 14 years. The JIA patients were examined clinically and with questionnaires at baseline and follow-up with the diagnostic criteria for temporomandibular disorders (DC/TMD) and completed the same set of DC/TMD questionnaires regarding orofacial pain symptoms and psychosocial factors. RESULTS: Change in stress was associated with change in catastrophizing, psychological distress as well as limitation in general function and jaw function. CONCLUSIONS: This study emphasizes the importance of maintaining a low stress level in patients with JIA since an increase in stress level over a two-year period seems to impair jaw function as well as psychological distress and catastrophizing.

Infant gut microbiota and environment associate with juvenile idiopathic arthritis many years prior to disease onset, especially in genetically vulnerable children.

BACKGROUND: The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a prospective birth cohort to assess disease risk. METHODS: Data was collected from the All Babies in Southeast Sweden (ABIS) population-based cohort (n = 17,055), 111 of whom later acquired JIA (ABISJIA). Stool samples were collected at one year of age for 10.4%. To determine disease association, 16S rRNA gene sequences were analyzed, with and without confound adjustment. Genetic and environmental risks were assessed. FINDINGS: ABISJIA had higher abundance of Acidaminococcales, Prevotella 9, and Veillonella parvula and lower abundance of Coprococcus, Subdoligranulum, Phascolarctobacterium, Dialister spp., Bifidobacterium breve, Fusicatenibacter saccharivorans, Roseburia intestinalis, and Akkermansia muciniphila (q's < 0.05). Parabacteroides distasonis greatly increased the odds of later contracting JIA (OR = 6.7; 1.81-24.84, p = 0.0045). Shorter breastfeeding duration and increased antibiotic exposure compounded risk in a dose-dependent manner, especially in those with genetic predisposition. INTERPRETATION: Microbial dysregulation in infancy may trigger or accelerate JIA development. Environmental risk factors have a stronger impact on genetically predisposed children. This study is the first to implicate microbial dysregulation in JIA at such an early age, with many bacterial taxa associated with risk factors. These findings provide opportunities for intervention or early screening and offer new insights into JIA pathogenesis. FUNDING: Barndiabetesfonden; Swedish Council for Working Life and Social Research; Swedish Research Council; Östgöta Brandstodsbolag; Medical Research Council of Southeast Sweden; JDRF-Wallenberg Foundation; Linköping.

Normal neonatal TREC and KREC levels in early onset juvenile idiopathic arthritis.

OBJECTIVE: Dysregulated central tolerance predisposes to autoimmune diseases. Reduced thymic output as well as compromised central B cell tolerance checkpoints have been proposed in the pathogenesis of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate neonatal levels of T-cell receptor excision circles (TRECs) and kappa-deleting element excision circles (KRECs), as markers of T- and B-cell output at birth, in patients with early onset JIA. METHODS: TRECs and KRECs were quantitated by multiplex qPCR from dried blood spots (DBS), collected 2-5 days after birth, in 156 children with early onset JIA and in 312 matched controls. RESULTS: When analysed from neonatal dried blood spots, the median TREC level was 78 (IQR 55-113) in JIA cases and 88 (IQR 57-117) copies/well in controls. The median KREC level was 51 (IQR 35-69) and 53 (IQR 35-74) copies/well, in JIA cases and controls, respectively. Stratification by sex and age at disease onset did not reveal any difference in the levels of TRECs and KRECs. CONCLUSION: T- and B-cell output at birth, as measured by TREC and KREC levels in neonatal dried blood spots, does not differ in children with early onset JIA compared to controls.

Infections and antibiotics during fetal life and childhood and their relationship to juvenile idiopathic arthritis: a prospective cohort study.

BACKGROUND: The aetiology of juvenile idiopathic arthritis (JIA) is poorly understood. It has been shown that use of antibiotics is associated with JIA. However, whether the association is due to increased occurrence of infection in these individuals is unknown. The purpose of this investigation was to measure the association between number of infections and use of antibiotics during childhood with development of JIA. METHODS: In ABIS (All Babies in Southeast Sweden) a population-based prospective birth cohort of 17,055 children, data were collected on infections and antibiotic exposure during pregnancy and childhood. 102 individuals with JIA were identified. Multivariable logistic regression analyses were performed, adjusting for confounding factors. RESULTS: Exposure to antibiotics during the periods 1-12 months, 1-3 years and 5-8 years was significantly associated with increased risk for JIA. The odds of developing JIA were three times higher in those exposed to antibiotics during the first 3 years of life compared with those not exposed (aOR 3.17; 95% CI 1.11-9.03, p = 0.031), and more than twice as high in those exposed to antibiotics during the first 5 years of life compared with those not exposed (aOR 2.18; 95% CI 1.36-3.50, p = 0.001). The odds of developing JIA were 78% higher in those exposed to antibiotics during the first 8 years of life compared with those not exposed (aOR 1.78; 95% CI 1.15-2.73, p = 0.009). Occurrence of infection during fetal life or childhood showed no significant association with the risk of developing JIA, after confounder adjustment. The cumulative number of courses of antibiotics was significantly higher during childhood for the individuals who developed JIA (p < 0.001). Penicillins were more frequently used than non-penicillins, but both had an equal effect on the risk of developing JIA. CONCLUSIONS: Exposure to antibiotics early in life is associated with later onset of JIA in a large birth cohort from the general population. The relationship was dose dependent. These results suggest that further, more restrictive, antibiotic policies during the first years of life would be advisable.

Prevalence of ADHD and Autism Spectrum Disorder in Children with Hypermobility Spectrum Disorders or Hypermobile Ehlers-Danlos Syndrome: A Retrospective Study.

INTRODUCTION: Hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) are both characterized by generalized hypermobility, in combination with pain, affected proprioception, and pronounced fatigue. Clinical observation indicates that behavioral problems, hyperactivity, and autistic traits are overrepresented in children with those conditions. The purpose of this retrospective study was to establish the prevalence of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) among children with HSD and hEDS treated in our clinic since 2012. SUBJECTS AND METHODS: Since Ehlers-Danlos syndrome (EDS) diagnostic criteria and international classification were changed in 2017, we equate the older diagnosis EDS hypermobility type with the newer hEDS and the older hypermobility syndrome with HSD. A registry search from the computerized medical record system found 201 children (88 boys, 113 girls) aged 6-18 years who were treated at our pediatrics department with the diagnoses HSD or EDS. All medical records (113 with HSD, 88 with EDS) were reviewed, and key symptoms such as fatigue and pain, as well as diagnosis of ADHD/ASD, were recorded. RESULTS: All EDS cases could be classified as hEDS. Of the entire study cohort, 16% had a verified ADHD diagnosis and a further 7% were undergoing ADHD diagnostic investigation. Significantly more children with hEDS had ADHD compared to children with HSD (p=0.02). In the age group 15-16 years, 35% of those with hEDS had ADHD and, among those aged 17-18 years, ADHD was present in 46%. Children with coexisting ADHD showed a significantly higher proportion of associated symptoms such as fatigue, sleep-problems, and urinary tract problems. ASD had been verified in 6% of the children. Of those with ASD, 92% had sleep problems. CONCLUSION: This study shows a strong association between HSD or hEDS and ADHD or ASD. Therefore, children with HSD or hEDS may need to be routinely screened for neuropsychiatric symptoms.

Orofacial pain in juvenile idiopathic arthritis is associated with stress as well as psychosocial and functional limitations.

BACKGROUND: The aim of this study was to investigate relations between psychosocial factors, signs and symptoms of orofacial pain and jaw dysfunction in patients with juvenile idiopathic arthritis (JIA). METHODS: Forty-five patients with JIA (median age 12 years) and 16 healthy matched controls (median age 13 years) were examined according to the diagnostic criteria for temporomandibular disorders (DC/TMD). The subjects answered the DC/TMD questionnaires regarding psychosocial factors (pain intensity, pain-related disability, depression, stress, catastrophizing, pain locations and jaw function). RESULTS: JIA patients with orofacial pain had higher degree of stress, depression, catastrophizing and jaw dysfunction compared to subjects without. In turn, these factors were associated with orofacial pain intensity. Also, patients with orofacial pain had higher systemic inflammatory activity. CONCLUSIONS: Orofacial pain in patients with JIA is associated with stress, psychological distress, jaw dysfunction and loss of daily living activities. Pain intensity seems to be the major pain aspect related to these factors. In addition, systemic inflammatory activity appears to be an important factor contributing to orofacial pain in JIA.

Heavy metals in fish and its association with autoimmunity in the development of juvenile idiopathic arthritis: a prospective birth cohort study.

BACKGROUND: The etiology of Juvenile Idiopathic Arthritis (JIA) is poorly understood. The purpose of this study was to examine the possible influence of early nutrition on later development of JIA. METHODS: In a population-based prospective birth cohort of 15,740 children we collected nutritional data, including fish consumption, and biological samples during pregnancy, at birth and at different ages. 16 years after study inclusion we identified 42 children with JIA, of whom 11 were positive for Antinuclear Antibodies (ANA). Heavy metals were analysed in cord blood of all 42 JIA patients and 40 age and sex-matched controls. A multivariable logistic regression model, adjusted for relevant factors, was used as well as Mann-Whitney U-test. RESULTS: Fish consumption more than once a week during pregnancy as well as during the child's first year of life was associated with an increased risk of JIA (aOR 4.5 (1.95-10.4); p < 0.001 and aOR 5.1 (2.1-12.4) p < 0.001) and of ANA-positivity (aOR 2.2 (1.4-3.6); p = 0.002 and p < 0.001). Concentrations of Al, Cd, Hg and Li in cord blood were significantly higher in the JIA-group than in controls. The ANA-positive, all of whom had consumed fish >once/week their first year, had significantly higher concentrations of Al (p < 0.001), Cd (p = 0.003), and Li (p < 0.001) in cord blood than controls. Frequency of fish consumption correlated with concentrations of Cd (p = 0.003), Li (p = 0.015) and Hg (p = 0.011). CONCLUSIONS: Moderate exposure to heavy metals, associated with fish consumption, during pregnancy and early childhood may cause effects on the immune system of the offspring, resulting in ANA positivity and JIA.

Early feeding and risk of Juvenile idiopathic arthritis: a case control study in a prospective birth cohort.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is considered to be an autoimmune disease, but the etiology is unknown. We decided to study the influence of early nutrition on later development of JIA. METHODS: All parents with children born between October 1, 1997 and October 1, 1999 in Southeast Sweden were asked to participate in the ABIS prospective cohort study (All Babies in Southeast Sweden), At 1 year, questionnaires with information on breastfeeding and introduction of foods were completed by 10,565 families. We identified 32 children with JIA and 111 children with non-chronic arthritis with completed questionnaires after delivery and after 1 year. A multivariable logistic regression model, adjusted for relevant factors, was performed to calculate the association between JIA and feeding during the first year of life. RESULTS: An increased risk for JIA was found in children who had breast fed for less than 4 months, as opposed to those who were continued on breast milk beyond 4 months of age (aOR 3.5, 95% CI 1.4-8,5; p = 0.006). A short duration of exclusive as well as total breastfeeding was associated with an increased risk of JIA (aOR 1.3, 95% CI 1.1-1.6; p = 0.008 and aOR 1.2, 95% CI 1.1-1.3; p < 0.001). All associations between breastfeeding and JIA persisted after adjustment. There was no relationship between early nutrition and non-chronic arthritis. CONCLUSIONS: Our results indicate that there are different disease mechanisms for different types of arthritis in childhood. Longer duration of breastfeeding (both total and exclusive) may protect against development of JIA. Mothers should be encouraged to breast-feed their babies exclusively, if at all possible, for 4 months and continue partial breastfeeding for an extended time when foreign proteins are introduced.

Development of abdominal fat and incipient metabolic syndrome in young healthy men exposed to long-term stress.

BACKGROUND AND AIM: The sympathetic nervous system may be involved in the pathophysiology of insulin resistance and metabolic cardiovascular syndrome in young men. The aim was to study the effects of long-term stress on different features of the metabolic syndrome (MES) in formerly non-obese healthy young males during 5 months of defined conditions. METHODS AND RESULTS: Sixteen healthy male sailors (mean age 36.5 (SD)+/-7 years) participating in a sailing race around the world were recruited for the study. Investigations were done before the start and at stop overs after finishing laps 1, 2 and 4 (1, 2(1/2) and 5 months, respectively). Anthropometric and blood pressure data as well as biochemical data associated with MES were substantiated. Food intake and exercise were chartered and largely controlled. A mean weight loss of 4.5+/-2 kg (P<0.005), comprising both fat and lean body mass, was recorded during the first lap. Subsequently after 5 months, a weight gain, mainly consisting of 1.2+/-1.1 kg body fat (P<0.05), took place, concomitantly with a protein mass drop of 0.6+/-1.1 kg (P<0.05). The body fat gain accumulated on the abdominal region. Elevated blood levels of HbA1c, insulin and the triglycerides/high-density lipoprotein ratio were also observed during the race. Likewise heart rate and systolic blood pressure increased slightly but to a statistically significant extent. CONCLUSIONS: Non-obese healthy young men exposed to long-term stress developed abdominal obesity and signs of a metabolic syndrome in embryo, also emphasized by biochemical and blood pressure alterations. It is suggested that long-term and sustained stress activation might be an additional risk factor for the development of MES, even after control of dietary and exercise habits.