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.

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.

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.

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.

[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.

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.

[Still's disease--juvenile arthritis with systemic onset]. / Stillin tauti--yleisoireinen lastenreuma.

Systemic onset juvenile idiopathic arthritis is a rare form of juvenile arthritis in which, contrary to autoimmune diseases in general, no association with a certain tissue type has been detected. Together with this fact, the lack of autoantibodies and the general symptoms belonging to the diagnostic criteria of the illness such as high fever, rather speak for its classification into autoinflammatory diseases. Treatment is usually started with anti-inflammatory drugs, often requiring combination with a systemic glucocorticoid. Recognition of interleukins 1 and 6 as central mediators in the pathogenesis of the disease has brought new possibilities for its treatment.

Variant MBL2 genotypes producing low mannose-binding lectin may increase risk of Bacillus Calmette-Guerin osteitis in vaccinated newborns.

AIM: The aim of this study was to evaluate whether mannose-binding lectin (MBL) plays a role in the development of osteitis after Bacillus Calmette-Guerin (BCG) vaccination as a newborn. METHODS: Blood samples were obtained from 132 former BCG osteitis patients, now aged 21-49 years, and analysed for MBL concentration and MBL2 genotype in a controlled setting. RESULTS: Variant genotypes in the MBL2 gene were more common in the former BCG osteitis patients (42.4%) than in the population controls (32.3%, p = 0.033). However, MBL concentrations at the age of 21-49 years were not lower in these patients than in the controls in the same age group. The variant MBL2 genotypes were associated with low serum MBL concentrations, and moreover, MBL concentration was not measurable in two of those three patients who were homozygous for the variant MBL2 genotype. Low serum MBL concentrations were not associated with any illnesses in the medical history of the BCG patients, their siblings or children. CONCLUSION: Preliminary evidence was found that variant, low-MBL-producing genotypes may be associated with the increased risk of BCG osteitis in vaccinated newborns.

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.

[Medical treatment of juvenile idiopathic arthritis]. / Lastenreuman hoito kehittyy.

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.

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.

Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial.

OBJECTIVES: In juvenile idiopathic arthritis (JIA), the efficacy of very early disease-modifying drug therapy, synthetic or biological, is not well known. Three alternative strategies were compared for treating recent-onset polyarticular JIA. METHODS: In a 54-week multicentre open-label clinical trial, 60 disease-modifying antirheumatic drug (DMARD)-naive patients aged 4-15 years were randomly assigned into three treatment arms. The efficacy of infliximab plus methotrexate (TNF) was compared to that of two synthetic therapies: methotrexate alone (MTX) and DMARD methotrexate, sulphasalazine and hydroxychloroquine in combination (COMBO). Primary endpoint was American College of Rheumatology paediatric 75% improvement (ACR Pedi 75). Secondary endpoints were inactive disease and safety. RESULTS: In 59 patients, mean (±SE) age at baseline was 9.6±0.4 years, duration of JIA 1.9±0.2 months and number of active joints 18±1. ACR Pedi 75 was achieved in 100% (19/19) of patients receiving TNF, 65% (13/20) on COMBO (95% CI 44% to 86%) and 50% (10/20) on methotrexate (95% CI 28% to 72%) p<0.0001. Thirteen patients receiving TNF (68%; 95% CI 47% to 89%) achieved inactive disease, whereas eight (40%; 95% CI 22% to 63%) on COMBO and five (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002). Patients on TNF spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving COMBO (13 weeks; 95% CI 6 to 20), or methotrexate (6 weeks; 95% CI 2 to 10). Serious adverse events were rare. CONCLUSION: In early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone.

Topical treatment of uveitis resulting in adrenal insufficiency.

UNLABELLED: 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. CONCLUSION: When topical corticosteroids are used over longer periods, hypophysis-pituitary-adrenal (HPA) function should be carefully monitored.

[Loss of mobility in a child with Down syndrome]. / Lastenreuma vei Down-lapsen liikuntakyvyn.

Down syndrome is associated with the risk of various structural abnormalities or functional disturbances of organ systems, and with several abnormalities of the immune system. Screening and monitoring of congenital heart defects or orthopedic problems are managed and the increased risk to develop leukemia, diabetes of hypothyroidism is well known. The 3 to 6-fold incidence of juvenile idiopathic arthritis in Down syndrome compared with the general juvenile population is, however, less known. We describe a patient, for whom the diagnostic delay of juvenile idiopathic arthritis was eight years.

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.