The adverse effects of corticosteroids are well-known and occur more frequently when corticostero... more The adverse effects of corticosteroids are well-known and occur more frequently when corticosteroids are used perorally or intravenously. The management of uveitis, which normally consists of topical corticosteroids and mydriates, can be challenging. We report a case in which continuous use of topical corticosteroids resulted in adrenal insufficiency and obesity. When topical corticosteroids are used over longer periods, hypophysis-pituitary-adrenal (HPA) function should be carefully monitored.
Etanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile... more Etanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile idiopathic arthritis (JIA) when traditional sDMARD therapy is not su cient. 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 affect ETN serum trough levels in JIA patients and whether concomitant MTX affects clinical response in patients with JIA receiving ETN. Methods This study collected the medical records data of 180 JIA patients from eight Finnish paediatric rheumatological centres. All these patients were treated with ETN monotherapy or combination therapy, with or without sDMARD. 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 signi cant 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, a signi cant correlation was observed between ETN dose and ETN concentration. We also found that concomitant MTX had no effect on serum ETN concentration or on clinical response.
Aim: Corticosteroids have harmful dose-dependent effects on bone metabolism and growth. This stud... more Aim: Corticosteroids have harmful dose-dependent effects on bone metabolism and growth. This study used a new method for volumetric measurements to evaluate the association between inhaled corticosteroids (ICS) for asthma and bone mineral density (BMD) in school-aged children. Methods: We evaluated children hospitalised for wheezing at the age of <24 months at 12.3 years (median). Volumetric BMD (vBMD) was measured using peripheral quantitative computed tomography (pQCT) from the distal tibia and radius in 82 children. Data on ICSs used were collected from hospital records and parent interviews. Cumulative doses and the duration of ICS therapy were calculated. Results: Girls had higher total and cortical vBMD in the tibia than boys. Pubertal children had higher total and cortical vBMD in the radius than prepubertal children. Higher cumulative doses of ICSs were associated with lower total (r = À0.175, adjusted p = 0.016), cortical (r = À0.138, adjusted p = 0.016) and trabecular (r = À0.156, adjusted p = 0.039) vBMD in the radius, but not in the tibia. Age, weight or the cumulative dose of systemic corticosteroids had no significant associations with vBMD. Conclusion: Although correlations between cumulative ICS doses and vBMD were weak, ICS use during childhood may reduce BMD in the radius at school age. Abbreviations BMD, Bone mineral density; BMI-SDS, Body mass index standard deviation score; CI, Confident Intervals; ICS, Inhaled corticosteroid; pQCT, Peripheral quantitative computed tomography; vBMD, Volumetric bone mineral density. Key notes Corticosteroids have harmful dose-dependent effects on bone metabolism and growth. This study used peripheral quantitative computed tomography to evaluate the association between inhaled corticosteroids (ICS) for asthma during childhood and bone mineral density (BMD) in 82 schoolaged children. It provides preliminary evidence that higher cumulative ICS doses during childhood were associated with lower total, cortical and trabecular volumetric BMD in the radius, but not the tibia, before and during puberty.
The aim of our study was to evaluate whether gene polymorphisms in Toll-like receptors (TLR) cons... more The aim of our study was to evaluate whether gene polymorphisms in Toll-like receptors (TLR) constituting TLR2 subfamily are associated with the development of osteitis after Bacillus Calmette-Guerin (BCG) vaccination as newborn. Methods. Blood samples of 132 former BCG osteitis patients now aged 21-49 years were analyzed in a controlled setting for TLR1 T1805G (rs5743618), TLR2 G2258A (rs5743708) and TLR6 C745T (rs5743810) gene single nucleotide polymorphisms (SNPs). The frequencies of the SNPs were compared to those of the 318 Finnish healthy controls. Results. The frequencies of the variant genotypes of TLR2 G2258A (11.4% vs 5.7%, p=0.033) and TLR6 C745T (77.3% vs 61.6%, p=0.001) differed between cases and controls. The TLR2 (aOR 2.154, 95%CI 1.026-4.521) and TLR6 (aOR 1.907, 95%CI 1.183-3.075) variant genotypes were associated with an increased risk of BCG osteitis. The frequency of the TLR1 T1805G variant genotype was 19.7% in cases vs .33.6% in controls (p=0.003). The TLR1 variant genotype was associated with a decreased risk of BCG osteitis (aOR 0.554, 95%CI 0.336-0.911). When different combinations of TLR1, TLR2 and TLR6 wild and variant genotypes were compared with the combination of wild genotypes in all three TLRs, only the combination of TLR1 wild, TLR2 variant and TLR6 variant genotype differed significantly between cases and controls. Conclusions. These results show that there were significant differences in gene polymorphisms of TLR1, TLR2 and TLR6 between the BCG osteitis patients and controls. These results suggest that these polymorphisms play a role in the development of BCG osteitis in vaccinated newborns.
Background:Etanercept (ETN) is the most used TNF blocker in children with JIA. There is still lim... more Background:Etanercept (ETN) is the most used TNF blocker in children with JIA. There is still limited real-life data of etanercept concentrations in children, especially in association with dosing.Objectives:The aim of the study was to investigate association between ETN dosing and serum trough concentration in children with non-systemic JIA.Methods:We conducted a multicenter retrospective study of 180 Finnish JIA patients (Table 1) receiving ETN either as monotherapy or in combination with one or more DMARDs (Table 2). Prior biologicals were used by 17 % of the patients. Patients were divided into two groups, ETN started before or after one year of diagnosis (Figure 1). ETN concentration samples (collected 2014-2017) were analyzed using validated enzyme-linked immunosorbent assay (ELISA) in Sanquin Diagnostics, Amsterdam, the Netherlands.Results:Demographics at etanercept start and diagnoses are shown in Table 1. Duration of the treatment with ETN, ETN doses, concentrations and concomitant medications at the time of concentration measurement are shown in Table 2.Association between ETN dose and concentration is shown in Figure 1.Those who started medication early (&amp;lt; 1 year from diagnosis) were younger than those who started later (Table 1) and association between ETN dose and concentration was more obvious (Figure 1).Conclusion:There was an association between etanercept dose used and serum trough concentration and it was more evident when medication was started early after diagnosis, when the patients were younger and BSA lower.References:[1]Kneepkens EL et al. Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 2015;74(10):1825-9.[2]Bader-Meunier B et al. Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis. Semin Arthritis Rheum 2019;48(6):1014-1018.Disclosure of Interests:None declared
Skin test reactivity to three mycobacterial sensitins (M. avium, M. fortuitum and M. scrofulaceum... more Skin test reactivity to three mycobacterial sensitins (M. avium, M. fortuitum and M. scrofulaceum) was studied in 353 healthy children vaccinated with the BCG vaccine at birth. A significant waning of reactivity to all of the three sensitins was found to occur with increasing age. Revaccination against measles, parotitis and rubella had been given to 31 (9%) of the children, all aged &gt; 5.5 years. They had significantly larger reactions sizes, which was contrary to what was expected. Children with atopic dermatitis (n=19) had significantly smaller reaction sizes to the M. fortuiturn sensitin. Neither respiratory viral infections during the preceding six months nor contact with pets or farm animals had any influence on reaction sizes. The variation of sensitin reactions was large in preschool children vaccinated with the BCG vaccine at birth. The diagnostic value of sensitin reactions in preschool children needs to be elaborated in clinical studies in children with clinically demonstrable mycobacteriosis.
Aim: Interleukin-17 (IL-17) appears to promote the host`s defense against mycobacterial infection... more Aim: Interleukin-17 (IL-17) appears to promote the host`s defense 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.
Background: Juvenile Idiopathic Arthritis (JIA) may cause significant impairment in health-relate... more 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.
Objectives: To evaluate the patterns of usage, efficacy and safety of tocilizumab in polyarticula... more 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.
Objectives: To study pJIA-related changes of the cardiovascular, renal and hepatic functions in t... more Objectives: To study pJIA-related changes of the cardiovascular, renal and hepatic functions in the affected children. Methods: This was a prospective cohort study enrolling patients with pJIA. Their cardiovascular system was assessed by ECG, PD-ultrasound and routine arterial blood pressure monitoring. The rate of glomerular filtration, serum creatinine level, serum ALT and AST activity, lipid profile and other specific tests were used to study renal and hepatic functions. Charlson Comorbidity Index (CCI) for children was calculated. It's correlation with various factors have been assessed by regression analysis. Descriptive statistics data are presented as mean ± SD. Results: 118 patients with JIA (78 females) were enrolled. Mean age was 10.27±0.39 years, mean disease duration 132.35±5.26 months. Mean number of affected joints was 6.04±0.3. All patients were treated with NSAIDs. 95.7% patients received MTX, 15.3% MTX+SSZ. 19.5% of patients were treated with GC incl. 5.1% as a puls-therapy. Cardiovascular abnormalities were found in 65.3%, mainly on ECG (low voltage, affected repolarization). 4.2% patients had decreased heart contractility and 1.9% dilated heart compartments. Increased levels of cholesterol were found in 12.8%, β-lipoproteids-in 41.7%. High ALT and AST activity levels were observed in 2.6% and 1.3% of patients accordingly. 19.2% of patients had renal filtration abnormalities: 10.9% low glomerular filtration; 8.3% hyperfiltration. 1.9% had increased serum creatinine level and 2.6% had proteinuria. Total mean CCI was 0.78±0.06. In children with disease duration ≤1 year mean CCI was 0.90±0.28. The highest mean CCI (1.00±0.17) was observed in patients with disease duration 1≤2 years without any significant changes up to 3 (0.86±0.1) and 5 years (0.77±0.08) of observation. In children with disease duration ≤3 years CCI significantly (p<0.05) correlated with age at disease onset, disease activity, disease duration, duration of MTX and GC treatment. Conclusions: Our results show that comorbidities in children with pJIA exist already on the initial stages of disease course and persist in future despite treatment. Organ protectors and immune complex inflammation inhibitors (biologic treatment agents) should be a part of treatment program in this category of patients.
Although etiology of juvenile idiopathic arthritis (JIA) is currently not known, better understan... more Although etiology of juvenile idiopathic arthritis (JIA) is currently not known, better understanding of immunologic pathways of inflammation and the development of new therapies with biologic agents have remarkably improved the treatment of JIA. However, approximately 30% of the patients with JIA do not seem to response adequately to conventional anti-rheumatic drugs but the arthritis runs a continuously active course and may lead to the evolution of erosions. Such patients benefit from biologic agents, of which the longest clinical experience comes from anti-TNF therapies. Molecules targeting IL-1, IL-6 and B- and T-lymphocytes are also used in the treatment of severe JIA.
Bacillus Calmette-Guerin (BCG) osteitis was more common in Finland than elsewhere at the time whe... more 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 multitesting correction). The GTA haplotype of the IL17A SNPs rs4711998, rs8193036 and rs2275913 was associated with osteitis after BCG vaccination. Interleukin-17A (IL-17A) belongs to pro-inflammatory cytokines produced by T helper 17 (Th17) cells 1,2. Th17 cells and Th17-derived cytokines participate in the defense against different pathogens, like Mycobacterium tuberculosis 1. In addition, Th17 cells and Th17-derived cytokines are involved in the pathogenesis of diseases presenting with chronic inflammation, such as asthma and autoimmune diseases 2. Six studies were included in a systematic review on the role of IL-17A in active and latent tuberculosis (TB), and three studies on the role of IL-17A in Bacillus Calmette-Guerin (BCG) vaccination 3. The authors concluded that IL-17A acts as an effector protective molecule in patients with TB and in children after BCG vaccination 3. In a recent meta-analysis, the IL17A rs3748067 single-nucleotide polymorphism (SNP) was associated with the susceptibility to TB in Asian populations 4. There was no significant association between IL17A rs2275913 polymorphism and TB risk, but a significant association was documented in two later studies in Chinese 5 and Brazilian 6 populations. The meta-analysis did not include the IL17A rs8193036 and IL17A rs4711998 SNPs 4 , which we selected in addition to IL17A rs2275913 for the present study. BCG osteitis was more common in Finland than elsewhere at the time when BCG vaccinations were given to all Finnish newborns. During the years 1960-1988, altogether 222 children suffered from BCG osteitis in infancy 7,8 , and in 2008-2009, we collected questionnaire data from 160 of them and blood samples from 132 of them for immunological and genetic studies 9,10 .
C-reactive protein (CRP) was studied in 209 children treated in hospital due to middle or lower r... more C-reactive protein (CRP) was studied in 209 children treated in hospital due to middle or lower respiratory tract infection with serologically demonstrated viral or bacterial aetiology. Of the 110 patients with serological evidence of bacterial infection, either alone or in association with viral infection, 52% had CRP &gt; 20 mg/l, 35% &gt; 40 mg/l and 15% &gt; 80 mg/l. Of the 99 patients with serological evidence of viral infection alone, 35% had CRP &gt; 20 mg/l, but only 12% &gt; 40 mg/l and 5% &gt; 80 mg/l. Nearly all, 88%, of the 25 patients with CRP &gt; 40 mg/l in association with viral infection had either an infectious focus, specific microbial or non-specific laboratory evidence suggestive of bacterial infection. By calculating diagnostic parameters at 3 cut-off levels of CRP, the level 40 mg/l seemed more useful than 20 mg/l or 80 mg/l for differentiation between viral and bacterial infections. By using a CRP value of 40 mg/l as a screening limit sensitivity was 0.55, specificity 0.88, positive predictive value 0.76, negative predictive value 0.55, and likelihood ratios of a positive and negative test result 2.9 and 0.74, respectively. It is concluded that low CRP values do not rule out bacterial aetiology of respiratory infection in children. On the other hand viral infection without bacterial involvement is very improbable if CRP is &gt; 40 mg/l. Our results suggest that high CRP values rule out viral infection as a sole aetiology of infection; bacterial infection and antibiotic treatment should be considered in these cases.
To evaluate the frequency, clinical features, and prognosis of patients with osteitis caused by b... more To evaluate the frequency, clinical features, and prognosis of patients with osteitis caused by bacille Calmette-Guérin (BCG) vaccination, medical records from Finnish children based on nationwide registration from 1960 to 1988 were retrospectively analyzed. During the study period, three different BCG vaccine preparations were used. In 222 children, diagnostic criteria of BCG osteitis were fulfilled. The age at onset of BCG osteitis varied from 0.25 to 5.7 years. The most common sites of osteitis were metaphyses of the long bones. The lower extremity (58%) was affected more often than the upper (14%). Osteitis was situated in the sternum in 36 patients (15%) and in the ribs in 27 (11%). The frequency of BCG osteitis, but not the clinical parameters, was closely associated with the vaccine preparation used. Only 6 children were left with some sequelae. With adequate treatment, the prognosis for children vaccinated with BCG is good.
The adverse effects of corticosteroids are well-known and occur more frequently when corticostero... more The adverse effects of corticosteroids are well-known and occur more frequently when corticosteroids are used perorally or intravenously. The management of uveitis, which normally consists of topical corticosteroids and mydriates, can be challenging. We report a case in which continuous use of topical corticosteroids resulted in adrenal insufficiency and obesity. When topical corticosteroids are used over longer periods, hypophysis-pituitary-adrenal (HPA) function should be carefully monitored.
Etanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile... more Etanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile idiopathic arthritis (JIA) when traditional sDMARD therapy is not su cient. 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 affect ETN serum trough levels in JIA patients and whether concomitant MTX affects clinical response in patients with JIA receiving ETN. Methods This study collected the medical records data of 180 JIA patients from eight Finnish paediatric rheumatological centres. All these patients were treated with ETN monotherapy or combination therapy, with or without sDMARD. 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 signi cant 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, a signi cant correlation was observed between ETN dose and ETN concentration. We also found that concomitant MTX had no effect on serum ETN concentration or on clinical response.
Aim: Corticosteroids have harmful dose-dependent effects on bone metabolism and growth. This stud... more Aim: Corticosteroids have harmful dose-dependent effects on bone metabolism and growth. This study used a new method for volumetric measurements to evaluate the association between inhaled corticosteroids (ICS) for asthma and bone mineral density (BMD) in school-aged children. Methods: We evaluated children hospitalised for wheezing at the age of <24 months at 12.3 years (median). Volumetric BMD (vBMD) was measured using peripheral quantitative computed tomography (pQCT) from the distal tibia and radius in 82 children. Data on ICSs used were collected from hospital records and parent interviews. Cumulative doses and the duration of ICS therapy were calculated. Results: Girls had higher total and cortical vBMD in the tibia than boys. Pubertal children had higher total and cortical vBMD in the radius than prepubertal children. Higher cumulative doses of ICSs were associated with lower total (r = À0.175, adjusted p = 0.016), cortical (r = À0.138, adjusted p = 0.016) and trabecular (r = À0.156, adjusted p = 0.039) vBMD in the radius, but not in the tibia. Age, weight or the cumulative dose of systemic corticosteroids had no significant associations with vBMD. Conclusion: Although correlations between cumulative ICS doses and vBMD were weak, ICS use during childhood may reduce BMD in the radius at school age. Abbreviations BMD, Bone mineral density; BMI-SDS, Body mass index standard deviation score; CI, Confident Intervals; ICS, Inhaled corticosteroid; pQCT, Peripheral quantitative computed tomography; vBMD, Volumetric bone mineral density. Key notes Corticosteroids have harmful dose-dependent effects on bone metabolism and growth. This study used peripheral quantitative computed tomography to evaluate the association between inhaled corticosteroids (ICS) for asthma during childhood and bone mineral density (BMD) in 82 schoolaged children. It provides preliminary evidence that higher cumulative ICS doses during childhood were associated with lower total, cortical and trabecular volumetric BMD in the radius, but not the tibia, before and during puberty.
The aim of our study was to evaluate whether gene polymorphisms in Toll-like receptors (TLR) cons... more The aim of our study was to evaluate whether gene polymorphisms in Toll-like receptors (TLR) constituting TLR2 subfamily are associated with the development of osteitis after Bacillus Calmette-Guerin (BCG) vaccination as newborn. Methods. Blood samples of 132 former BCG osteitis patients now aged 21-49 years were analyzed in a controlled setting for TLR1 T1805G (rs5743618), TLR2 G2258A (rs5743708) and TLR6 C745T (rs5743810) gene single nucleotide polymorphisms (SNPs). The frequencies of the SNPs were compared to those of the 318 Finnish healthy controls. Results. The frequencies of the variant genotypes of TLR2 G2258A (11.4% vs 5.7%, p=0.033) and TLR6 C745T (77.3% vs 61.6%, p=0.001) differed between cases and controls. The TLR2 (aOR 2.154, 95%CI 1.026-4.521) and TLR6 (aOR 1.907, 95%CI 1.183-3.075) variant genotypes were associated with an increased risk of BCG osteitis. The frequency of the TLR1 T1805G variant genotype was 19.7% in cases vs .33.6% in controls (p=0.003). The TLR1 variant genotype was associated with a decreased risk of BCG osteitis (aOR 0.554, 95%CI 0.336-0.911). When different combinations of TLR1, TLR2 and TLR6 wild and variant genotypes were compared with the combination of wild genotypes in all three TLRs, only the combination of TLR1 wild, TLR2 variant and TLR6 variant genotype differed significantly between cases and controls. Conclusions. These results show that there were significant differences in gene polymorphisms of TLR1, TLR2 and TLR6 between the BCG osteitis patients and controls. These results suggest that these polymorphisms play a role in the development of BCG osteitis in vaccinated newborns.
Background:Etanercept (ETN) is the most used TNF blocker in children with JIA. There is still lim... more Background:Etanercept (ETN) is the most used TNF blocker in children with JIA. There is still limited real-life data of etanercept concentrations in children, especially in association with dosing.Objectives:The aim of the study was to investigate association between ETN dosing and serum trough concentration in children with non-systemic JIA.Methods:We conducted a multicenter retrospective study of 180 Finnish JIA patients (Table 1) receiving ETN either as monotherapy or in combination with one or more DMARDs (Table 2). Prior biologicals were used by 17 % of the patients. Patients were divided into two groups, ETN started before or after one year of diagnosis (Figure 1). ETN concentration samples (collected 2014-2017) were analyzed using validated enzyme-linked immunosorbent assay (ELISA) in Sanquin Diagnostics, Amsterdam, the Netherlands.Results:Demographics at etanercept start and diagnoses are shown in Table 1. Duration of the treatment with ETN, ETN doses, concentrations and concomitant medications at the time of concentration measurement are shown in Table 2.Association between ETN dose and concentration is shown in Figure 1.Those who started medication early (&amp;lt; 1 year from diagnosis) were younger than those who started later (Table 1) and association between ETN dose and concentration was more obvious (Figure 1).Conclusion:There was an association between etanercept dose used and serum trough concentration and it was more evident when medication was started early after diagnosis, when the patients were younger and BSA lower.References:[1]Kneepkens EL et al. Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 2015;74(10):1825-9.[2]Bader-Meunier B et al. Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis. Semin Arthritis Rheum 2019;48(6):1014-1018.Disclosure of Interests:None declared
Skin test reactivity to three mycobacterial sensitins (M. avium, M. fortuitum and M. scrofulaceum... more Skin test reactivity to three mycobacterial sensitins (M. avium, M. fortuitum and M. scrofulaceum) was studied in 353 healthy children vaccinated with the BCG vaccine at birth. A significant waning of reactivity to all of the three sensitins was found to occur with increasing age. Revaccination against measles, parotitis and rubella had been given to 31 (9%) of the children, all aged &gt; 5.5 years. They had significantly larger reactions sizes, which was contrary to what was expected. Children with atopic dermatitis (n=19) had significantly smaller reaction sizes to the M. fortuiturn sensitin. Neither respiratory viral infections during the preceding six months nor contact with pets or farm animals had any influence on reaction sizes. The variation of sensitin reactions was large in preschool children vaccinated with the BCG vaccine at birth. The diagnostic value of sensitin reactions in preschool children needs to be elaborated in clinical studies in children with clinically demonstrable mycobacteriosis.
Aim: Interleukin-17 (IL-17) appears to promote the host`s defense against mycobacterial infection... more Aim: Interleukin-17 (IL-17) appears to promote the host`s defense 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.
Background: Juvenile Idiopathic Arthritis (JIA) may cause significant impairment in health-relate... more 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.
Objectives: To evaluate the patterns of usage, efficacy and safety of tocilizumab in polyarticula... more 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.
Objectives: To study pJIA-related changes of the cardiovascular, renal and hepatic functions in t... more Objectives: To study pJIA-related changes of the cardiovascular, renal and hepatic functions in the affected children. Methods: This was a prospective cohort study enrolling patients with pJIA. Their cardiovascular system was assessed by ECG, PD-ultrasound and routine arterial blood pressure monitoring. The rate of glomerular filtration, serum creatinine level, serum ALT and AST activity, lipid profile and other specific tests were used to study renal and hepatic functions. Charlson Comorbidity Index (CCI) for children was calculated. It's correlation with various factors have been assessed by regression analysis. Descriptive statistics data are presented as mean ± SD. Results: 118 patients with JIA (78 females) were enrolled. Mean age was 10.27±0.39 years, mean disease duration 132.35±5.26 months. Mean number of affected joints was 6.04±0.3. All patients were treated with NSAIDs. 95.7% patients received MTX, 15.3% MTX+SSZ. 19.5% of patients were treated with GC incl. 5.1% as a puls-therapy. Cardiovascular abnormalities were found in 65.3%, mainly on ECG (low voltage, affected repolarization). 4.2% patients had decreased heart contractility and 1.9% dilated heart compartments. Increased levels of cholesterol were found in 12.8%, β-lipoproteids-in 41.7%. High ALT and AST activity levels were observed in 2.6% and 1.3% of patients accordingly. 19.2% of patients had renal filtration abnormalities: 10.9% low glomerular filtration; 8.3% hyperfiltration. 1.9% had increased serum creatinine level and 2.6% had proteinuria. Total mean CCI was 0.78±0.06. In children with disease duration ≤1 year mean CCI was 0.90±0.28. The highest mean CCI (1.00±0.17) was observed in patients with disease duration 1≤2 years without any significant changes up to 3 (0.86±0.1) and 5 years (0.77±0.08) of observation. In children with disease duration ≤3 years CCI significantly (p<0.05) correlated with age at disease onset, disease activity, disease duration, duration of MTX and GC treatment. Conclusions: Our results show that comorbidities in children with pJIA exist already on the initial stages of disease course and persist in future despite treatment. Organ protectors and immune complex inflammation inhibitors (biologic treatment agents) should be a part of treatment program in this category of patients.
Although etiology of juvenile idiopathic arthritis (JIA) is currently not known, better understan... more Although etiology of juvenile idiopathic arthritis (JIA) is currently not known, better understanding of immunologic pathways of inflammation and the development of new therapies with biologic agents have remarkably improved the treatment of JIA. However, approximately 30% of the patients with JIA do not seem to response adequately to conventional anti-rheumatic drugs but the arthritis runs a continuously active course and may lead to the evolution of erosions. Such patients benefit from biologic agents, of which the longest clinical experience comes from anti-TNF therapies. Molecules targeting IL-1, IL-6 and B- and T-lymphocytes are also used in the treatment of severe JIA.
Bacillus Calmette-Guerin (BCG) osteitis was more common in Finland than elsewhere at the time whe... more 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 multitesting correction). The GTA haplotype of the IL17A SNPs rs4711998, rs8193036 and rs2275913 was associated with osteitis after BCG vaccination. Interleukin-17A (IL-17A) belongs to pro-inflammatory cytokines produced by T helper 17 (Th17) cells 1,2. Th17 cells and Th17-derived cytokines participate in the defense against different pathogens, like Mycobacterium tuberculosis 1. In addition, Th17 cells and Th17-derived cytokines are involved in the pathogenesis of diseases presenting with chronic inflammation, such as asthma and autoimmune diseases 2. Six studies were included in a systematic review on the role of IL-17A in active and latent tuberculosis (TB), and three studies on the role of IL-17A in Bacillus Calmette-Guerin (BCG) vaccination 3. The authors concluded that IL-17A acts as an effector protective molecule in patients with TB and in children after BCG vaccination 3. In a recent meta-analysis, the IL17A rs3748067 single-nucleotide polymorphism (SNP) was associated with the susceptibility to TB in Asian populations 4. There was no significant association between IL17A rs2275913 polymorphism and TB risk, but a significant association was documented in two later studies in Chinese 5 and Brazilian 6 populations. The meta-analysis did not include the IL17A rs8193036 and IL17A rs4711998 SNPs 4 , which we selected in addition to IL17A rs2275913 for the present study. BCG osteitis was more common in Finland than elsewhere at the time when BCG vaccinations were given to all Finnish newborns. During the years 1960-1988, altogether 222 children suffered from BCG osteitis in infancy 7,8 , and in 2008-2009, we collected questionnaire data from 160 of them and blood samples from 132 of them for immunological and genetic studies 9,10 .
C-reactive protein (CRP) was studied in 209 children treated in hospital due to middle or lower r... more C-reactive protein (CRP) was studied in 209 children treated in hospital due to middle or lower respiratory tract infection with serologically demonstrated viral or bacterial aetiology. Of the 110 patients with serological evidence of bacterial infection, either alone or in association with viral infection, 52% had CRP &gt; 20 mg/l, 35% &gt; 40 mg/l and 15% &gt; 80 mg/l. Of the 99 patients with serological evidence of viral infection alone, 35% had CRP &gt; 20 mg/l, but only 12% &gt; 40 mg/l and 5% &gt; 80 mg/l. Nearly all, 88%, of the 25 patients with CRP &gt; 40 mg/l in association with viral infection had either an infectious focus, specific microbial or non-specific laboratory evidence suggestive of bacterial infection. By calculating diagnostic parameters at 3 cut-off levels of CRP, the level 40 mg/l seemed more useful than 20 mg/l or 80 mg/l for differentiation between viral and bacterial infections. By using a CRP value of 40 mg/l as a screening limit sensitivity was 0.55, specificity 0.88, positive predictive value 0.76, negative predictive value 0.55, and likelihood ratios of a positive and negative test result 2.9 and 0.74, respectively. It is concluded that low CRP values do not rule out bacterial aetiology of respiratory infection in children. On the other hand viral infection without bacterial involvement is very improbable if CRP is &gt; 40 mg/l. Our results suggest that high CRP values rule out viral infection as a sole aetiology of infection; bacterial infection and antibiotic treatment should be considered in these cases.
To evaluate the frequency, clinical features, and prognosis of patients with osteitis caused by b... more To evaluate the frequency, clinical features, and prognosis of patients with osteitis caused by bacille Calmette-Guérin (BCG) vaccination, medical records from Finnish children based on nationwide registration from 1960 to 1988 were retrospectively analyzed. During the study period, three different BCG vaccine preparations were used. In 222 children, diagnostic criteria of BCG osteitis were fulfilled. The age at onset of BCG osteitis varied from 0.25 to 5.7 years. The most common sites of osteitis were metaphyses of the long bones. The lower extremity (58%) was affected more often than the upper (14%). Osteitis was situated in the sternum in 36 patients (15%) and in the ribs in 27 (11%). The frequency of BCG osteitis, but not the clinical parameters, was closely associated with the vaccine preparation used. Only 6 children were left with some sequelae. With adequate treatment, the prognosis for children vaccinated with BCG is good.
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