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.

Body composition in children with chronic inflammatory diseases: A systematic review.

BACKGROUND & AIMS: Aberrations in body composition are expected in children suffering from chronic inflammatory conditions. The objective is to examine whether children with inflammatory bowel disease (IBD: Crohn's disease and ulcerative colitis), coeliac disease, asthma and juvenile idiopathic arthritis (JIA) have an altered body composition as compared to healthy children. METHODS: A systematic review, registered in Prospero (registration number: CRD42018107645), was conducted according to PRISMA guidelines. We conducted a search of three databases, Pubmed, Cochrane and Scopus. An assessment of the quality of the study was performed. RESULTS: Data from 50 studies, 32 with IBD, 8 with coeliac disease, 2 with asthma and 8 with JIA, involving 2399 children were selected for review after applying the eligibility criteria. In all but 4 studies, children with Crohn's disease exhibited decreased amounts of fat mass and fat free mass. Reductions in fat mass were also evident in studies in children with coeliac disease. It is uncertain whether body composition is altered in children with asthma or JIA. CONCLUSIONS: Children with Crohn's disease manifest with lowered adiposity and lean mass and therefore are likely to be at risk for suffering malnutrition-related clinical complications. Apart from Crohn's disease, data examining body composition in children with chronic inflammatory conditions are scarce and there is a paucity of reports examining the relationship between inflammation and body composition. Interpretation of the current study results is hampered by the low quality of the studies and due to the fact that the analyses have been habitually secondary outcomes.

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.

Validating 10-joint juvenile arthritis disease activity score cut-offs for disease activity levels in non-systemic juvenile idiopathic arthritis.

Objectives: To validate cut-offs of the Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) and to compare them with other patient cohorts. Methods: In a national multicentre study, cross-sectional data on recent visits of 337 non-systemic patients with juvenile idiopathic arthritis (JIA) were collected from nine paediatric outpatient units. The cut-offs were tested with receiver operating characteristic curve-based methods, and too high, too low and correct classification rates (CCRs) were calculated. Results: Our earlier presented JADAS10 cut-offs seemed feasible based on the CCRs, but the cut-off values between low disease activity (LDA) and moderate disease activity (MDA) were adjusted. When JADAS10 cut-offs for clinically inactive disease (CID) were increased to 1.5 for patients with oligoarticular disease and 2.7 for patients with polyarticular disease, as recently suggested in a large multinational register study, altogether 11 patients classified as CID by the cut-off had one active joint. We suggest JADAS10 cut-off values for oligoarticular/polyarticular disease to be in CID: 0.0-0.5/0.0-0.7, LDA: 0.6-3.8/0.8-5.1 and MDA: >3.8/5.1. Suitable cJADAS10 cut-offs are the same as JADAS10 cut-offs in oligoarticular disease. In polyarticular disease, cJADAS10 cut-offs are 0-0.7 for CID, 0.8-5.0 for LDA and >5.0 for MDA. Conclusion: International consensus on JADAS cut-off values is needed, and such a cut-off for CID should preferably exclude patients with active joints in the CID group.

Defining new clinically derived criteria for high disease activity in non-systemic juvenile idiopathic arthritis: a Finnish multicentre study.

OBJECTIVES: To redefine criteria for high disease activity (HDA) in JIA, to establish HDA cut-off values for the 10-joint Juvenile Arthritis Disease Activity Score (JADAS10) and clinical JADAS10 (cJADAS10) and to describe the distribution of patients' disease activity levels based on the JADAS cut-off values in the literature. METHODS: Data on 305 treatment-naïve JIA patients were collected from nine paediatric units treating JIA. The median parameters of the JADAS were proposed to be the clinical criteria for HDA. The cut-off values were assessed by using two receiver operating characteristics curve-based methods. The patients were divided into disease activity levels based on currently used JADAS cut-off values. RESULTS: We proposed new criteria for HDA. At least three of the following criteria must be satisfied in both disease courses: in oligoarthritis, two or more active joints, ESR above normal, physician global assessment (PGA) of disease activity ≥2 and parent/patient global assessment (PtGA) of well-being ≥2; in polyarthritis, six or more active joints, ESR above normal, PGA of overall disease activity ≥4 and PtGA of well-being ≥2. The HDA cut-off values for JADAS10 (cJADAS) were ≥6.7 (6.7) for oligoarticular and ≥15.3 (14.1) for polyarticular disease. The distribution of the disease activity levels based on the JADAS cut-off values in the literature varied markedly based on which cut-offs were used. CONCLUSION: New clinically derived criteria for HDA in JIA and both JADAS and cJADAS cut-off values for HDA were proposed.

The impact of perinatal probiotic intervention on gut microbiota: double-blind placebo-controlled trials in Finland and Germany.

Specific probiotic combinations during early feeding, via the mother or incorporated in early formula-feeding, mold the intestinal microbiota composition in infants. The objective was to analyze the impact of probiotic administration to mother or infant on gut microbiota composition in 6-month-old Finnish and German infants. In Finland probiotics were given to mothers (n = 79) for 2 months prior to and 2 months after delivery. In Germany probiotics were started in infants (n = 81) at weaning, at the latest at 1 month of age, and continued for 4 months. A breast-fed group of 6-month-old infants (22 from Finland, 8 from Germany) were compared. Gut microbiota were analyzed by FCM-FISH and qPCR methods. In breast-fed infants a trend toward higher counts of bifidobacteria was detected in Finland (p = 0.097) as against Germany, where a more diverse microbiota was reflected in higher Akkermansia (p = 0.003), Clostridium histolyticum (p = 0.035) and Bacteroides-Prevotella (p = 0.027) levels and a higher percentage of Akkermansia (p = 0.004). Finnish LPR + BL999 intervention group (Lactobacillus rhamnosus LPR and Bifidobacterium longum BL999) had higher percentages of fecal Lactobacillus-Enterococcus (9.0% vs. 6.1% placebo, p = 0.003) and lower bifidobacteria levels (10.03 log cells/g vs. 10.68 log cells/g placebo, p = 0.018). Probiotic treatment had different impacts on gut microbiota composition in Finnish and German infants due to differences in mode of feeding and the early commensal microbiota. Probiotic treatment had different impacts on gut microbiota composition in Finnish and German infants due to differences in mode of feeding and the basic commensal microbiota.

Influence of mother's intestinal microbiota on gut colonization in the infant.

The aim here was to elucidate the mother-infant association in the gut colonization of 1-6 month-old infants and to establish whether probiotics can influence this process. Fecal samples from 80 mother-infant pairs were analyzed at 1 month (mothers and infants) and 6 months (infants) by real-time polymerase chain reaction to assess bacterial numbers. This double-blind placebo-controlled trial involved 2 different probiotic combinations (1. Lactobacillus rhamnosus + Bifidobacterium longum and 2. Lactobacillus paracasei + Bifidobacterium longum) given to the mothers 2 months prior to and 2 months after delivery. Bifidobacterium bifidum colonization in the mothers significantly increased the infants' probability of being colonized by B. bifidum and their bifidobacterial diversity indexes (DI) and the mother-infant similarity indexes (SI) both at 1 and 6 months of age. The counts of Bifidobacterium genus (at 1 month) and Bifidobacterium longum (at 6 months) correlated between mothers and infants. At 6 months, a significant effect of the probiotic intervention was found in the mother-infant association of fecal bifidobacterial counts but not in the colonization frequencies, DI or SI. In conclusion, a clear association between mother and infant was found in gut colonization by bifidobacteria. Maternal colonization by B. bifidum had the most consistent effects on the infant's bifidobacterial microbiota. Maternal probiotic treatment had little effect on this mother-infant association.

Mode of delivery and asthma -- is there a connection?

Genetic factors cannot explain the recent rapid increase in the incidence of atopic diseases. The phenomenon has been explained by environmental factors, and there are data for and against the hypothesis that a decline in the pressure of microbial stimulation early in life could be behind the allergy epidemic. Changes have also occurred in maternity care, among them a rise in the caesarean section rate, which could diminish initial microbial exposure and thereby alter T helper 1 cell/T helper-2 cell development and affect the risk of developing atopy. In this study, we sought to establish whether mode of delivery does influence the development of atopic asthma. Finnish 1987 Medical Birth Register (n = 59,927 live births) information was linked between several national health registers to obtain information on asthma and mode of delivery in children registered. The data were adjusted for maternal age, previous deliveries, child's sex, and birth size. Atopy was evaluated in the second study (Turku Birth Cohort), which involved 219 children born by vaginal delivery (n = 106) or caesarean section (n = 113); history of atopic symptoms was established by questionnaire and a clinical examination was conducted, including skin prick testing and determination of total and allergen-specific IgE in serum. The register study showed the cumulative incidence of asthma at the age of seven to be significantly higher in children born by caesarean section (4.2%) than in those vaginally delivered (3.3%), the adjusted odds ratio (OR) for confounding variables being 1.21 (1.08-1.36), p < 0.01. In the second study, significantly more positive allergy tests were reported in questionnaires in the caesarean (22%) than in the vaginal delivery group (11%), OR 2.22 (1.06-4.64), p < 0.01, and a trend toward more positive skin prick reactions was documented at clinical examination; 41% versus 29%, OR 1.31 (0.65-2.65), p = 0.11. In conclusion, these results suggest that caesarean section delivery may be associated with an increased prevalence of atopic asthma.