Etanercept for patients with juvenile idiopathic arthritis: drug levels and influence of concomitant methotrexate: observational study.

BACKGROUND: Etanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile idiopathic arthritis (JIA) when traditional synthetic disease modifying antirheumatic drug (sDMARD) therapy is not sufficient. There is limited information about the effects of methotrexate (MTX) on serum ETN concentration in children with JIA. We aimed to investigate whether ETN dose and concomitant MTX would effect ETN serum trough levels in JIA patients, and whether concomitant MTX have an influence on the clinical response in patients with JIA receiving ETN. METHODS: In this study, we collected the medical record data of 180 JIA patients from eight Finnish pediatric rheumatological centres. All these patients were treated with ETN monotherapy or combination therapy with DMARD. To evaluate the ETN concentrations, blood samples of the patients were collected between injections right before the subsequent drug. Free ETN level was measured from serum. RESULTS: Ninety-seven (54%) of the patients used concomitant MTX, and 83 (46%) received either ETN monotherapy or used sDMARDs other than MTX. A significant correlation was noted between ETN dose and drug level [r = 0.45 (95% CI: 0.33-0.56)]. The ETN dose and serum drug level were correlated (p = 0.030) in both subgroups - in MTX group [r = 0.35 (95% CI: 0.14-0.52)] and in non-MTX group [r = 0.54 (95% CI: 0.39-0.67)]. CONCLUSION: In the present study, we found that concomitant MTX had no effect on serum ETN concentration or on clinical response. In addition, a significant correlation was detected between ETN dose and ETN concentration.

Pain-coping scale for children and their parents: a cross-sectional study in children with musculoskeletal pain.

BACKGROUND: In a chronic pain-causing disease such as juvenile idiopathic arthritis, the quality of coping with pain is crucial. Parents have a substantial influence on their children's pain-coping strategies. This study aimed to develop scales for assessing parents' strategies for coping with their children's pain and a shorter improved scale for children usable in clinical practice. METHODS: The number of items in the Finnish version of the pain-coping questionnaire for children was reduced from 39 to 20. A corresponding reduced scale was created for parental use. We recruited consecutive patients from nine hospitals evenly distributed throughout Finland, aged 8-16 years who visited a paediatric rheumatology outpatient clinic and reported musculoskeletal pain during the past week. The patients and parents rated the child's pain on a visual analogue scale from 0 to 100 and completed pain-coping questionnaires and depression inventories. The selection process of pain questionnaire items was performed using factor analyses. RESULTS: The average (standard deviation) age of the 130 patients was 13.0 (2.3) years; 91 (70%) were girls. Four factors were retained in the new, improved Pain-Coping Scales for children and parents. Both scales had 15 items with 2-5 items/factor. The goodness-of-fit statistics and Cronbach's alpha reliability coefficients were satisfactory to good in both scaled. The criterion validity was acceptable as the demographic, disease related, and the depression and stress questionnaires correlated with the subscales. CONCLUSIONS: We created a shorter, feasible pain-coping scale for children and a novel scale for caregivers. In clinical work, the pain coping scales may serve as a visualisation of different types of coping strategies for paediatric patients with pain and their parents and facilitate the identification of families in need of psychological support.

Economic evaluation of infliximab, synthetic triple therapy and methotrexate in the treatment of newly diagnosed juvenile idiopathic arthritis.

BACKGROUND: Evaluation of costs and short-term cost-effectiveness of infliximab plus methotrexate (IFX + MTX); triple therapy of hydroxychloquine, sulphasalazine, and methotrexate (TRIPLE); or methotrexate monotherapy (MTX) in patients with new-onset polyarticular juvenile idiopathic arthritis (JIA). METHODS: In a prospective multicenter study (ACUTE-JIA), costs and health outcomes of 60 randomized patients with new-onset disease-modifying anti-rheumatic drug (DMARD)-naïve polyarticular JIA were analyzed during the first year. A mapping algorithm was used to obtain utility values from Child Health Assessment Questionnaire (CHAQ). Wallace criteriae were used to assess clinically inactive disease (CID). Linear regression with non-parametric bootstrapping was used to adjust imbalances at baseline. RESULTS: Using prices for IFX biosimilar, adjusted annual mean (SD) costs of treatment (€) were 21,164 (4158), 12,136 (5286), and 18,300 (8635) on IFX + MTX, TRIPLE, and MTX, respectively. Incremental cost-effectiveness ratio (ICER) for IFX + MTX as compared with TRIPLE or MTX were 3442 € or 678 € per additional month spent in CID. Mean (SD) quality-adjusted life years (QALYs) for IFX + MTX, TRIPLE and MTX were 0.755 (0.065), 0.725 (0.062), and 0.686 (0.124). ICER for IFX + MTX vs TRIPLE was 294,433 €, and for IFX + MTX vs MTX 31,435 € per QALY gained. CONCLUSIONS: In short-term, biosimilar IFX + MTX can be considered cost-effective when compared with MTX alone. TRIPLE was cost-effective when compared with MTX and showed cost advantage when compared with IFX + MTX. Cost per time spent in CID showed similar results than ICER evaluations. TRIAL REGISTRATION: This trial was primarily registered with the Ethical Board of Helsinki District University Hospital ( https://www.hus.fi ), clinical trial number 211864, and later with ClinicalTrials.gov, number NCT01015547.

Short interruptions of TNF-inhibitor treatment can be associated with treatment failure in patients with immune-mediated diseases.

INTRODUCTION: The prevalence of immune-mediated diseases has increased in the past decades and despite the use of biological treatments all patients do not achieve remission. The aim of this study was to characterise the reasons for short interruptions during treatment with two commonly used TNF-inhibitors infliximab and adalimumab and to analyse the possible effects of the interruptions on immunisation and switching the treatment. MATERIAL AND METHODS: This case-control study was based on retrospective analyses of patient records and a questionnaire survey to clinicians. A total of 370 patients (194 immunised cases and 172 non-immunised controls, 4 excluded) were enrolled from eight hospitals around Finland. Eleven different diagnoses were represented, and the largest patient groups were those with inflammatory bowel or rheumatic diseases. RESULTS: Treatment interruptions were associated with immunisation in patients using infliximab (p < .001) or adalimumab (p < .000001). Patients with treatment interruptions were more likely to have been treated with more than one biological agent compared to those without treatment interruptions. This was particularly prominent among patients with a rheumatic disease (p < .00001). The most frequent reason for a treatment interruption among the cases was an infection, whereas among the control patients it was remission. The median length of one interruption was one month (interquartile range 1-3 months). CONCLUSION: Our results suggest that the interruptions of the treatment with TNF-inhibitors expose patients to immunisation and increase the need for drug switching. These findings stress the importance of careful judgement of the need for a short interruption in the biological treatment in clinical work, especially during non-severe infections.

Efficacy and safety of tocilizumab in a real-life observational cohort of patients with polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To evaluate the patterns of usage, efficacy and safety of tocilizumab in polyarticular JIA. METHODS: An observational study of 56 consecutive polyarticular JIA patients was conducted using patient charts and electronic JIA databases. Efficacy was assessed by tocilizumab survival, rates of low disease activity (LDA) and of inactive disease by 10-joint Juvenile Arthritis Disease Activity Score (JADAS-10), and of clinically inactive disease according to Wallace's preliminary criteria. Efficacy and rate of adverse events (AEs) were evaluated during a 24-month period after tocilizumab commencement. RESULTS: Tocilizumab was started on average as third-line biological agent (median, range first- to fourth-line) at a median disease duration of 5.2 years (interquartile range 3.0-7.7). Survival rates were 82% at 12 months and 64% at 24 months. The reasons for discontinuation were inadequate treatment effect in 50%, AE plus inadequate treatment effect in 37.5% and AE alone in 12.5%. LDA (JADAS-10 ⩽3.9) was reached in 58% at 12 months and in 84% at 24 months, inactive disease (JADAS-10 ⩽0.7) in 19% and 44%, and clinically inactive disease in 28% and 46%, respectively. The rate of AEs was 200.9/100 patient years and of serious AEs 12.9/100 patient years. CONCLUSION: Survival of tocilizumab was high and a large proportion of the treatment-resistant patients reached LDA at 12 months of treatment. The LDA rate continued to increase throughout 24 months. The rates of AEs and serious AEs were higher than in register studies but lower than in the originator study of tocilizumab.

Health-related quality of life during early aggressive treatment in patients with polyarticular juvenile idiopathic arthritis: results from randomized controlled trial.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) may cause significant impairment in health-related quality of life (HrQoL), despite effective therapies. The aim of this study was to assess HrQoL during first-year treatment in patients with new-onset polyarticular JIA, and to compare treatment strategies. METHODS: In ACUTE-JIA Study, 60 patients with new-onset JIA were randomized to receive either infliximab with methotrexate (IFX+MTX); a triple therapy of methotrexate, hydroxychloroquine, and sulfasalazine (Triple); or methotrexate monotherapy (MTX). Efficacy was measured with American College of Rheumatology pediatric (ACRp) score, and juvenile arthritis disease activity score (JADAS). HrQoL was evaluated with Child Health Questionnaire (CHQ), which includes physical and psychosocial summary scores (PhS and PsS). Linear mixed models were utilized to compare groups over time. RESULTS: In the whole group of 60 patients, mean physical summary score (PhS) improved from 26.2 (SD 8.7) at week 0 to 49.7 (SD 13.2) at week 54 (p=0.046). Mean improvement of PhS was 20.3 (95% CI -15.5 to 56.2); 22.6 (-19.5 to 64.7); and 26.6 (-12.1 to 65.3) in IFX+MTX, Triple, and MTX, respectively. Changes in psychosocial summary score (PsS) were smaller: from 51.0 (SD 8.5) to 54.7 (6.3) (p=0.019) in all patients. No differences between the three treatment groups were detected in either of the measures. In multivariate analyses, Child Health Assessment Questionnaire (CHAQ), pain VAS, and time spent in inactive disease contributed to improvement in PhS; gender and CHAQ to PsS. CONCLUSIONS: HrQol improved during the first year on therapy for JIA irrespective of the treatment strategy. The timing of change in the different dimensions of HrQoL varied; improvement occurred earlier in physical than psychosocial domains of HrQol. TRIAL REGISTRATION: This study was registered within the Hospital District of Helsinki and Uusimaa (http://www.hus.fi) clinical trials, number 211864 in October 2002, and later on with ClinicalTrials.gov, number NCT01015547.

A novel mutation in the matrix metallopeptidase 2 coding gene associated with intrafamilial variability of multicentric osteolysis, nodulosis, and arthropathy.

BACKGROUND: MONA, which stands for a spectrum of Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia, is an ultra rare autosomal recessive disorder caused by mutations in the matrix metallopeptidase 2 (MMP2) gene. To date only 44 individuals, carrying 22 different mutations have been reported. Here we report on two brothers with identical homozygous MMP2 gene mutations, but with clearly different phenotypes. METHODS: Genomic DNA was isolated from the affected brothers and the parents. An iliac crest bone biopsy was taken from the younger patient (index case). The level of matrix metallopeptidase 2 enzyme (MMP2) in serum and synovial fluid of the younger patient was analyzed using gelatin zymography. RESULTS: The DNA analysis revealed a homozygous c.1188C>A transversion on exon 8 of the gene. The affected brothers had the same homozygous variant and the parents were heterozygous to this variant. This variant has been reported as a compound heterozygous mutation on one individual resulting in scleroderma like skin thickening. Bone histomorphometry indicated increased trabecular bone remodeling and turnover. The zymography revealed that the level of MMP2 was completely nonmeasurable in the serum and only a minor gelatinolytic protein band of about similar molecular weight as MMP2 was found in the synovial fluid. CONCLUSIONS: Both the age at the onset and the phenotypic severity of the syndrome in these two brothers were different despite identical genotypes. The younger patients had corneal opacities leading to deteriorating visual acuity. For the first time in this disease, opacities were successfully treated with corneal transplantations.

The Finnish version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

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.

Cryopyrin-associated periodic syndrome in early childhood can be successfully treated with interleukin-1 blockades.

Cryopyrin-associated periodic syndrome (CAPS) is caused by a mutation in the NLRP3 gene encoding cryopyrin production. Overproduction of interleukin-1 (IL-1) leads to symptoms that are associated with elevated inflammatory markers, including periodic fever and a rash. We provide a clinical overview of CAPS in children, including three Finnish case studies. CONCLUSION: When CAPS has been diagnosed, an IL-1 blockade with biological should be introduced to lessen the symptoms and to prevent the progression of organ damage.

Body fat mass, lean body mass and associated biomarkers as determinants of bone mineral density in children 6-8years of age - The Physical Activity and Nutrition in Children (PANIC) study.

Lean body mass (LM) has been positively associated with bone mineral density (BMD) in children and adolescents, but the relationship between body fat mass (FM) and BMD remains controversial. Several biomarkers secreted by adipose tissue, skeletal muscle, or bone may affect bone metabolism and BMD. We investigated the associations of LM, FM, and such biomarkers with BMD in children. We studied a population sample of 472 prepubertal Finnish children (227 girls, 245 boys) aged 6-8years. We assessed BMD, LM, and FM using whole-body dual-energy x-ray absorptiometry and analysed several biomarkers from fasting blood samples. We studied the associations of LM, FM, and the biomarkers with BMD of the whole body excluding the head using linear regression analysis. LM (standardized regression coefficient ß=0.708, p<0.001), FM (ß=0.358, p<0.001), and irisin (ß=0.079, p=0.048) were positive correlates for BMD adjusted for age, sex, and height in all children. These associations remained statistically significant after further adjustment for LM or FM. The positive associations of dehydroepiandrosterone sulphate (DHEAS), insulin, homeostatic model assessment for insulin resistance (HOMA-IR), leptin, free leptin index, and high-sensitivity C-reactive protein and the negative association of leptin receptor with BMD were explained by FM. The positive associations of DHEAS and HOMA-IR with BMD were also explained by LM. Serum 25-hydroxyvitamin D was a positive correlate for BMD adjusted for age, sex, and height and after further adjustment for FM but not for LM. LM and FM were positive correlates for BMD also in girls and boys separately. In girls, insulin, HOMA-IR, leptin, and free leptin index were positively and leptin receptor was negatively associated with BMD adjusted for age, height, and LM. After adjustment for age, height, and FM, none of the biomarkers was associated with BMD. In boys, leptin and free leptin index were positively and leptin receptor was negatively associated with BMD adjusted for age, height, and LM. After adjustment for age, height and FM, 25(OH)D was positively and IGF-1 and leptin were negatively associated with BMD. FM strongly modified the association between leptin and BMD. LM but also FM were strong, independent positive correlates for BMD in all children, girls, and boys. Irisin was positively and independently associated with BMD in all children. The associations of other biomarkers with BMD were explained by LM or FM.

Haplotype of the Interleukin 17A gene is associated with osteitis after Bacillus Calmette-Guerin vaccination.

Bacillus Calmette-Guerin (BCG) osteitis was more common in Finland than elsewhere at the time when universal BCG vaccinations were given to Finnish newborns. There is evidence that IL-17 plays a role in the defense against tuberculosis. The aim of this study was to evaluate the associations of IL17A rs4711998, IL17A rs8193036 and IL17A rs2275913 single-nucleotide polymorphisms (SNPs) with the risk of BCG osteitis after newborn vaccination. IL17A rs4711998, rs8193036 and rs2275913 SNPs were determined in 131 adults had presented with BCG osteitis after newborn BCG vaccination. We analyzed, using the HaploView and PLINK programs, whether allele or haplotype frequencies of these SNPs differ between the former BCG osteitis patients and Finnish population controls. Of the three IL17A SNPs studied, rs4711998 associated nominally with BCG osteitis; minor allele frequency was 0.215 in 130 BCG osteitis cases and 0.298 in 99 controls (p = 0.034). Frequency of the second common haplotype (GTA) differed significantly between BCG osteitis cases and controls (0.296 vs. 0.184, p = 0.040 after multi-testing correction). The GTA haplotype of the IL17A SNPs rs4711998, rs8193036 and rs2275913 was associated with osteitis after BCG vaccination.

Interleukin 17A gene polymorphism rs2275913 is associated with osteitis after the Bacillus Calmette-Guérin vaccination.

AIM: Interleukin-17 (IL-17) appears to promote the host's defence against mycobacterial infections. This study evaluated the association between IL17A gene polymorphism and the risk of Bacillus Calmette-Guérin (BCG) osteitis after newborn vaccination and between IL17A gene polymorphism and IL-17A concentrations in serum. METHODS: IL17A rs2275913 gene polymorphisms and serum IL-17A concentrations were studied in 132 adults aged 21-49 years from across Finland, who had BCG osteitis in infancy after a newborn BCG vaccination. The subjects were recruited in 2007-2008, and their whole-blood samples were sent to the National Institute for Health and Welfare, Turku, Finland. Their genotypes and minor allele frequencies were compared with 405 population-based unvaccinated controls aged two to three months from a prospective birth cohort study. RESULTS: The genotypes and allele frequencies of IL17A rs2275913 differed significantly between the former BCG osteitis patients and controls. The genotype was variant in 75.8% of cases and 64.0% of controls (p = 0.012), and the minor allele frequency was 50.0% in the cases and 41.6% of the controls (p = 0.009). Serum IL-17 concentrations did not differ significantly between the cases with wild or variant genotypes. CONCLUSION: IL17A rs2275913 gene polymorphism was associated with a risk of BCG osteitis after vaccination.

Cow's Milk Allergy in Infancy and Later Development of Juvenile Idiopathic Arthritis: A Register-Based Case-Control Study.

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.

Association of MBL2, TLR1, TLR2 and TLR6 Polymorphisms With Production of IFN-γ and IL-12 in BCG Osteitis Survivors R1.

BACKGROUND: Interferon-gamma (IFN-γ) is a key cytokine in defense against mycobacteria, including Bacillus Calmette-Guérin (BCG). Mannose-binding lectin (MBL) and toll-like receptors (TLRs) are pattern-recognizing molecules of innate immunity. The aim of the present study was to investigate the relationship between polymorphisms in MBL, TLR1, TLR2 and TLR6 encoding genes and stimulated IFN-γ and interleukin-12 (IL-12) ex vivo production in BCG osteitis survivors. METHODS: Data on single nucleotide polymorphisms in the MBL2 gene and TLR1, TLR2 and TLR6 genes were available from 132 former BCG osteitis patients, and data on ex vivo IFN-γ and IL-12 production were available from 115 and 118 patients, respectively. The present study is a secondary analysis of these available data. In an earlier study, we were able to characterize low IFN-γ and low IL-12 producers after BCG+IL-12 or BCG+IFN-γ stimulations, respectively. RESULTS: Three patients had the homozygous variant MBL2 genotype, and one of them was a low IFN-γ producer (both concentration and response <5th percentile). The heterozygous variant MBL2 genotype showed no association with IFN-γ or IL-12 production. The TLR2 variant genotype was present in 14 subjects; 28.6% of them were low IFN-γ producers versus 7.8% of those 103 with the TLR2 wild genotype (P = 0.037). TLR1 or TLR6 polymorphisms had no significant associations with stimulated ex vivo IFN-γ or IL-12 production. CONCLUSIONS: Preliminary evidence was found that variant genotypes of the MBL2 gene (if homozygous) and variant genotypes of the TLR2 gene (only heterozygotes present) are associated with low IFN-γ production.

Interferon-gamma-dependent Immunity in Bacillus Calmette-Guérin Vaccine Osteitis Survivors.

BACKGROUND: Inborn errors of interferon-gamma (IFN-γ)-mediated immunity underlie disseminated disease caused by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) live vaccines. We hypothesized that some patients with osteitis after BCG vaccination may have an impaired IFN-γ immunity. Our aim was to investigate interleukin (IL)-12 and IFN-γ ex vivo production stimulated with BCG and BCG + IFN-γ or BCG + IL-12, respectively, in BCG osteitis survivors. METHODS: Fresh blood samples were collected from 132 former BCG osteitis Finnish patients now aged 21-49 years, and IL-12 and IFN-γ were measured in cell cultures with and without stimulation with BCG and with BCG + IFN-γ or BCG + IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-γ immunity (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB) were investigated in 20 selected patients by whole exome sequencing. RESULTS: By the limit of <5th percentile, ex vivo IL-12 concentration and increase in concentration was low in 5 and ex vivo IFN-γ concentration and increase in concentration was low in 6 patients (including 2 samples with both IL-12 and IFN-γ findings). By the limit of <10th percentile, an additional 6 and 4 patients were, respectively, detected (including 2 samples with both findings). With 2 exceptions, low concentrations and low increases in concentrations picked-up the same cases. Mutations in known disease-causing IFN-γ-related genes were not found in any of these patients. CONCLUSION: These findings call for searching of mutations in new genes governing IFN-γ-dependent immunity to live BCG vaccine.

[Chronic nonbacterial osteomyelitis]. / Krooninen-ei-bakteeriperäinen osteomyeliitti.

Chronic nonbacterial osteomyelitis is an autoinflammatory disease occurring mainly in children and adolescents, typically involving recurrent or persistent osteitic foci. The symptom is bone pain, possibly accompanied by soft tissue tenderness. Some patients exhibit symptoms of systemic inflammation. The. precise etiology of the disease is not known, but an imbalance of inflammatory and anti-inflammatory cytokines is presumed to play a role in the development of the disease. While an anti-inflammatory analgesic is in most cases sufficient to calm down the osteitis, the use of corticosteroids, anti- TNF-a inhibitors or bisphosphonates is required in some cases.

Orthopedic Complications in Former Bacillus Calmette-Guérin Osteitis Patients.

In 160 Finnish former Bacillus Calmette-Guérin osteitis patients, a questionnaire revealed that later in life, 22 (13.8%) had mild orthopedic complications as a consequence of the infection.

Toll-like receptor 2 subfamily gene polymorphisms are associated with Bacillus Calmette-Guérin osteitis following newborn vaccination.

AIM: Toll-like receptor (TLR) 1, 2, 6 and 10, the TLR2 subfamily, are known to be associated with immunity against tuberculosis. We evaluated whether polymorphisms in genes encoding TLR1, TLR2 and TLR6 were associated with osteitis in infants who received the Bacillus Calmette-Guérin (BCG) vaccination soon after birth. METHODS: Blood samples from 132 adults aged 21-49 who had BCG osteitis in early childhood were analysed in a controlled study for TLR1 T1805G (rs5743618), TLR2 G2258A (rs5743708) and TLR6 C745T (rs5743810) gene single nucleotide polymorphisms. RESULTS: The frequencies of the variant genotypes differed between the cases and controls: 11.4% versus 5.7% for TLR2 G2258A (p = 0.033) and 77.3% versus 61.6% for TLR6 C745T (p = 0.001). The TLR2 and TLR6 variant genotypes were associated with a higher risk of BCG osteitis, with adjusted odds ratios (aOR) of 2.154 (95%CI 1.026-4.521) and 1.907 (95%CI 1.183-3.075), respectively. The frequency of the TLR1 T1805G variant genotype was 19.7% in the cases and 33.6% in the controls (p = 0.003). The TLR1 variant genotype was associated with a lower risk of BCG osteitis (aOR 0.554, 95%CI 0.336-0.911). CONCLUSION: Gene polymorphisms that regulate the function of the TLR2 subfamily play a role in the development of BCG osteitis in vaccinated infants.

Repeated exposure to antibiotics in infancy: a predisposing factor for juvenile idiopathic arthritis or a sign of this group's greater susceptibility to infections?

OBJECTIVE: 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). METHODS: 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. RESULTS: 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 < 0.001). Antibiotic groups lincosamides and cephalosporins showed the strongest association with JIA (OR 6.6, 95% CI 3.7-11.7, and OR 1.6, 95% CI 1.4-1.8, respectively). Overall exposure to antibiotics before 2 years of age was associated with an increased risk of JIA (OR 1.4, 95% CI 1.2-1.6), with the trend test of OR (p < 0.001). CONCLUSION: Previous early and repeated exposure to antibiotics may predispose individuals to develop JIA. Alternatively, the apparent association may reflect shared susceptibility to infections and JIA.