The feasibility of existing JADAS10 cut-off values in clinical practice: a study of data from The Finnish Rheumatology Quality Register.

BACKGROUND: The ten-joint juvenile arthritis disease activity score (JADAS10) is designed to measure the level of disease activity in non-systemic juvenile idiopathic arthritis by providing a single numeric score. The clinical JADAS10 (cJADAS10) is a modification of the JADAS10 that excludes erythrocyte sedimentation rate (ESR). Three different sets of JADAS10/cJADAS10 cut-offs for disease activity states have been published, i.e., the Backström, Consolaro, and Trincianti cut-offs. The objective of this study was to investigate the performance of existing JADAS10 cut-offs in real-life settings using patient data from The Finnish Rheumatology Quality Register (FinRheuma). METHODS: Data were collected from the FinRheuma register. The proportion of patients with an active joint count (AJC) above zero when classified as being in clinically inactive disease (CID) or low disease activity (LDA) groups according to existing JADAS10/cJADAS10 cut-off levels were analyzed. RESULTS: A significantly larger proportion of the patients classified as being in CID had an AJC > 0 when using the JADAS10/cJADAS10 cut-offs by Trincianti et al. compared to those for the other cut-offs. In the LDA group, a significantly larger proportion of the polyarticular patients (35%/29%) had an AJC of two when Trincianti JADAS10/cJADAS10 cut-offs were used compared with when Backström (11%/10%) and Consolaro (7%/3%) JADAS10/cJADAS10 cut-offs were used. CONCLUSIONS: We found the cut-offs proposed by Consolaro et al. to be the most feasible, since these cut-off levels for CID do not result in the misclassification of active disease as remission, and the proportion of patients with AJC > 1 in the LDA group is lowest using these cut-offs.

Transition to adult care in Finnish adolescents with juvenile idiopathic arthritis.

OBJECTIVE: The symptoms of juvenile idiopathic arthritis (JIA) and the necessity for continuous treatment may persist in adulthood. Therefore, patients with JIA need to be appropriately transferred to adult care. We aimed to analyse the timing of the patients' transition to adult care, and patients' self-management skills with the process and the quality of the transition. METHOD: This study included 161 Finnish participants of the population-based Nordic JIA cohort who attended a 17 year follow-up appointment. Special attention was paid to the three groups: those referred by the paediatric rheumatology outpatient clinic to primary healthcare (PHC), those who were directly transferred to adult rheumatology care, and those who were later referred. RESULTS: A total of 136 patients (84%) were eligible to participate in the study, and 40% of them were directly transferred to an adult rheumatology clinic. Of the patients, 72% eventually ended up being referred to an adult rheumatology outpatient clinic. However, 16% of the patients in the PHC group had active disease during the study appointment and were referred to adult services after the study visit. CONCLUSION: This study reveals the need to improve the transition process from paediatric care to adult care and to find the variables that can indicate the need for immediate transition. Although challenging, it is important to avoid treatment delay in adult patients with JIA who may have active disease but who do not have appropriate access to an adult rheumatological outpatient clinic.

Initiating disease-modifying anti-rheumatic drugs rapidly reduces purchases of analgesic drugs in juvenile idiopathic arthritis.

Objective: To describe the use of analgesics 12 months before and after initiation of the first disease-modifying anti-rheumatic drug (DMARD) in children with juvenile idiopathic arthritis (JIA). Method: A register-based study linked three nationwide registers in Finland: the Register on Reimbursement for Prescription Medicines, the Drug Purchase Register (both maintained by the Finnish Social Insurance Institution), and the Finnish Population Register. The study ran from 1 January 2010 to 31 December 2014. It included 1481 patients aged < 16 years with diagnosed JIA and 4511 matched controls. Index day was the date when reimbursement for JIA medication was approved and treatment was initiated. The study period included 12 months pre- and post-index date, and purchases of prescription drugs were assessed for 3 month periods. Results: Non-steroidal anti-inflammatory drugs (NSAIDs) were purchased for 60% of the patients. Compared to controls, NSAID purchases for JIA patients were at their highest during the last 3 months before the index day [relative rate (RR) 21.2, 95% confidence interval (CI) 17.1-26.2], and they decreased steeply over the 10-12 months post-index (RR 4.0, 95% CI 3.1-5.0). Similar trends were seen with paracetamol and opioid purchases, but only 2% of patients purchased opioids during the 12 months pre-index and 1% during the 12 months post-index. Methotrexate was the most commonly used DMARD (91.9%), biologic DMARDs were used by 2.8% and glucocorticoids by 24.8% in the 3 months after the index day. Conclusion: Initiation of DMARDs rapidly reduces the need for analgesics in patients with JIA.

Pain interference and associated factors in young adults with juvenile idiopathic arthritis.

Objective: Pain is a common and distressing feature of juvenile idiopathic arthritis (JIA). Pain interference (PI) is underexplored in long-term conditions such as JIA. The aim of this study was to explore the factors associated with PI in young adults with JIA. Methods: All consecutive JIA patients aged 18-30 years in three tertiary rheumatology and rehabilitation centres in Finland between September 2015 and April 2016 were included. The patients completed questionnaires addressing demographics, disability, depressive symptoms, pain anxiety, pain intensity, and PI. PI was measured with a single item from the RAND-36 questionnaire. Five response categories were coded into three groups: patients reporting 'extremely', 'quite a bit' or 'moderate' were classified as having significant PI; 'a little bit' as having minor PI; and 'not at all' as having no PI. A leisure-time physical activity metabolic equivalent of task (LTPA MET) was calculated. Statistical comparisons between PI and categorical variables were made using chi-squared or Fisher-Freeman-Halton tests. Results: Of the total 195 patients, 97 (50%) patients reported PI. PI was associated with a wide spectrum of sociodemographic and disease-related variables. Pain intensity scores were higher in patients expressing greater PI (p < 0.001). Greater PI was associated with higher disability (p < 0.001), higher pain anxiety scores (p < 0.001), lower LTPA MET (p = 0.027), and poorer leisure-time activity (p < 0.001). Conclusions: PI is common in young adults with JIA. We suggest that PI should be taken into account in future outcome studies exploring the impact of pain in children and young adults with JIA.

Disability and health-related quality of life are associated with restricted social participation in young adults with juvenile idiopathic arthritis.

OBJECTIVES: To describe a cohort of Finnish juvenile idiopathic arthritis (JIA) patients, to recognize those young adults who are at risk of becoming socially restricted by their long-term rheumatic disease, and to assess which areas of self-rated health-related quality of life (HRQoL) are associated with the emergence of restricted social participation. METHODS: A total of 195 young adults with JIA completed questionnaires addressing demographics, health behaviour, physical activity, functional ability, HRQoL, depressive symptoms, and self-esteem. Patients were classified as having non-restricted social participation if they were engaged in studying, working, maternity leave, or military service, and restricted social participation if they were unemployed or on disability pension. RESULTS: Of the patients, 162 (83%) were considered as having non-restricted social participation and 33 (16%) restricted social participation. Among patients with restricted social participation, five (15%) were on disability pension and 28 (85%) were unemployed. Patients with restricted social participation participated less in leisure-time non-physical activities (p = 0.033), felt more disturbed during their leisure time (p = 0.010), had lower self-esteem (p = 0.005), and had higher disability scores (p = 0.024). HRQoL scores revealed statistically significant differences between the groups: physical functioning (p = 0.043), social functioning (p = 0.016), and emotional well-being (p = 0.049) were all lower in patients with restricted social participation. CONCLUSIONS: Socially restricted patients showed a higher degree of disability, and lower levels of physical functioning, self-esteem, emotional well-being, and social functioning. These patients should be recognized earlier and interventions provided to enhance their social participation.

Body composition and adipokines in patients with juvenile idiopathic arthritis and systemic glucocorticoids.

OBJECTIVES: The aim of this cross-sectional study was to explore body composition, and the relationship of serum adipokines with bone mass and disease activity, in a cohort of JIA patients with at least three months' exposure to systemic glucocorticoids (GC). METHODS: Fifty patients with JIA (34 girls, median age 12.4 years and disease duration 6.3 years) and 88 controls matched for gender and age participated in this study. Bone mineral content (BMC) and areal bone mineral density (BMD) of the lumbar spine and whole body, as well as body composition were assessed with dual-energy x-ray absorptiometry. Fasting serum leptin and adiponectin were measured. RESULTS: Fat and lean mass were similar between patients and controls, but patients had slightly decreased BMD Z-scores. Serum leptin and adiponectin concentrations were similar. Disease activity was low, and no correlation with adipokines was observed. Patients with bone age-corrected lumbar spine BMD Z-score ≤-1.0 ("low BMD") did not show alterations in body composition, GC exposure or current disease activity, but had decreased BMC-to-lean mass ratio (p<0.001) and tendency for increased serum leptin (p=0.064). However, no association of leptin with BMD in multivariate analysis existed in patients or controls. An inverse association between adiponectin and whole body BMD was observed in both groups. CONCLUSIONS: Normal body composition was observed in a JIA cohort with low-dose GC exposure. Patients with "low BMD" tended to have increased serum leptin, but leptin did not associate with BMD. In this cohort with low disease activity, no correlation between adipokines and disease activity was present.

Validity and predictive ability of the juvenile arthritis disease activity score based on CRP versus ESR in a Nordic population-based setting.

OBJECTIVE: To compare the juvenile arthritis disease activity score (JADAS) based on C reactive protein (CRP) (JADAS-CRP) with JADAS based on erythrocyte sedimentation rate (ESR) (JADAS-ESR) and to validate JADAS in a population-based setting. METHODS: The CRP and ESR values and the corresponding JADAS scores (JADAS10/27/71) were compared in a longitudinal cohort study of 389 children newly diagnosed with juvenile idiopathic arthritis (JIA) in the Nordic JIA study. The construct validity and the discriminative and predictive ability of JADAS were assessed during a median disease course of 8 years by comparing JADAS with other measures of disease activity and outcome. RESULTS: At the first study visit the correlation between JADAS27-CRP and JADAS27-ESR was r=0.99 whereas the correlation between CRP and ESR was r=0.57. Children with higher JADAS scores had an increased risk of concomitant pain, physical disability and use of disease-modifying antirheumatic drugs (DMARDs). A higher JADAS score at the first study visit also significantly predicted physical disability, damage and no remission off medication at the final study visit, and also use of DMARDs during the disease course. Sensitivity to change, demonstrated as change in JADAS score compared with the American College of Rheumatology paediatric measures of improvement criteria, mostly showed excellent classification ability. CONCLUSION: The JADAS-CRP and JADAS-ESR correlate closely, show similar test characteristics and are feasible and valid tools for assessing disease activity in JIA.

Prevention of acute adverse events related to infliximab infusions in pediatric patients.

OBJECTIVE: To study whether premedication with an oral antifebrile agent (acetaminophen) and antihistamine (cetirizine) could decrease the frequency of acute infusion reactions in pediatric patients. METHODS: All pediatric patients scheduled for infliximab infusions at the Helsinki University Central Hospital, a tertiary care center, were prospectively introduced to a standard oral premedication of acetaminophen (20 mg/kg) and cetirizine (10 mg) prior to infliximab infusions for a period of 1 year. All acute adverse events related to infliximab infusions given according to the guidelines of pediatric rheumatologists or gastroenterologists were registered for this time period and retrospectively during the preceding year. RESULTS: During the study period, infliximab infusions with premedication were given to 64 pediatric patients (48 with rheumatic disease and l6 with inflammatory bowel disease, mean age 13 years, n = 34 boys, and n = 30 girls). Infliximab was introduced to 14 children; the rest were on maintenance therapy. Twelve infusion reactions, 4 mild and 8 severe, were observed in 8 (12.5%) of the 64 subjects, and in 1 subject 4 times. During the preceding year, 60 pediatric patients had received infliximab infusions without premedication. In this latter group, infusion reactions occurred in 5 children (8.3%; P > 0.05). The presentation of an acute infusion reaction was not related to the sex or diagnosis of the patient. CONCLUSION: In pediatric patients, acute infusion reactions related to infliximab could not be prevented with premedication with oral acetaminophen and cetirizine.

Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis.

OBJECTIVE: To evaluate the efficacy of adalimumab in juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: Retrospective observational study of 20 patients with JIA and chronic uveitis on adalimumab treatment. The ocular inflammation and improvement was assessed according to the Standardization of Uveitis Nomenclature criteria. RESULTS: At the initiation of adalimumab, the mean age of patients was 13.4 yrs and the mean duration of uveitis 8.7 yrs. Seventeen (85%) patients had polyarticular JIA and 19 (95%) had previously been on anti-TNF treatment. The mean duration of adalimumab therapy was 18.7 months. Of the 20 patients, 7 (35%) showed improved activity, 1 (5%) worsening activity and in 12 (60%) no change was observed in the activity of uveitis. Those with improved activity were younger and had shorter disease duration. The mean number of flares/yr decreased from 1.9 to 1.4 during adalimumab treatment. Serious adverse events or side-effects were not observed. Seven patients discontinued adalimumab during the follow-up: six because of inefficacy and one because of inactive uveitis. CONCLUSION: Adalimumab is a potential treatment option in JIA-associated uveitis, even in patients non-responsive to previous other anti-TNF therapy.

Lactate inhibits germ cell apoptosis in the human testis.

Dysregulation of male germ cell apoptosis has been associated with the pathogenesis of male infertility. Therefore, factors involved in the regulation of germ cell death are being actively investigated. Here, we studied the effects of lactate on human male germ cell death, using as a model a testis tissue culture in which physiological contacts are maintained between the germ cells and the supportive somatic Sertoli cells. Apoptosis of spermatocytes, spermatids and a few spermatogonia was induced by culturing segments of seminiferous tubules under serum-free conditions. This germ cell death was inhibited effectively and dose-dependently by lactate, indicating that it plays a crucial role in controlling cell death cascades of male germ cells. Interestingly, the anti-apoptotic role of lactate was not associated with changes in testicular adenine nucleotide (ATP, ADP and AMP) levels. In the seminiferous tubules, the final site of the death-suppressing action of lactate appeared to be downstream along the cell death pathway activated by the Fas receptor of the germ cells. In conclusion, testicular cell death was effectively regulated by lactate, which may be regarded as a potential compound for optimizing in-vitro methods involving male germ cells for assisted reproduction.

Operative versus closed treatment of primary dislocation of the patella. Similar 2-year results in 125 randomized patients.

To assess whether initial surgery is beneficial for patients with primary dislocation of the patella, we carried out a prospective randomized study. Knee stability was examined under anesthesia, and associated injuries were excluded by diagnostic arthroscopy. 55 patients then had closed treatment and 70 patients were operated on with individually adjusted proximal realignment procedures. Surgery gave no benefit based on 2 years of follow-up. The subjective result was better in the non-operative group in respect of mean Houghston VAS knee score (closed 90, operative 87), but similar in terms of the patient's own overall opinion and mean Lysholm II knee score. Recurrent instability episodes (redislocation or recurrent subluxation) occurred in 20 nonoperated and in 18 operated patients. Of these, 15 and 12, respectively, then suffered redislocations. Function was better after closed treatment. Serious complications occurred after surgery in 4 patients. In conclusion, the recurrence of patellar dislocation may be more frequent than reported, whatever the form of treatment. Routine operative management cannot be recommended for primary dislocation of the patella.

The cartilaginous femoral sulcus in children with patellar dislocation: an ultrasonographic study.

One hundred and sixteen knees of 33 patients with patellar dislocation and 25 normal children 12-18 years of age were examined by ultrasonography to measure the cartilaginous sulcus angle on the patellar surface of the femur. In knees with patellar dislocation, the cartilaginous sulcus angle measured between 154 and 195 degrees, exceeding the corresponding values of normal knees (134-153 degrees). In patient knees, the cartilaginous sulcus was also consistently wider than the underlying osseous sulcus. This suggests that in pediatric patients with patellar dislocation, the actual patella-stabilizing ability of the femoral sulcus is weaker than the osseous outline in axial radiographs would lead one to suppose. It would appear also that by measuring the cartilaginous sulcus angle of the femur, a clear distinction can be made between normal knee joints and joints displaying patellar instability.

Intracellular high energy metabolite depletion and cell membrane injury with antioxidant enzymes during oxidant exposure in vitro.

We compared oxidant-induced intracellular adenine nucleotide catabolism and cell membrane injury in 4 different human cell types. Responses to oxidant exposure were correlated with endogenous antioxidant enzyme activities in these cells. Blood monocytes, amniotic fibroblasts, umbilical vein endothelial cells in primary culture, and transformed bronchial epithelial cells (BEAS 2B) were exposed to 0.1-5 mM hydrogen peroxide (H2O2) for 4 h. Some experiments were conducted in cells pretreated with 3-amino 1:2,4-triazole (ATZ) to inactivate catalase or with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to inactivate glutathione (GSH) reductase. Depletion of adenine nucleotides and accumulation of their catabolic products (hypoxanthine, xanthine and uric acid) occurred to varying extent, monocytes being the most resistant. There was a mutual relationship between catalase and GSH reductase activities and maintenance of cellular adenine nucleotide levels during H2O2 exposure. GSH reductase inhibition rendered BEAS 2B cells susceptible to lytic injury by H2O2, assessed by release of lactate dehydrogenase and intact nucleotides into the medium, there was no correlation between these markers of such injury and endogenous antioxidant enzymes. We conclude that adenine nucleotide depletion and nucleotide catabolite accumulation relate closely with the antioxidant enzyme activities, whereas the lack of a similar correlation between the enzyme levels and markers of lytic cell injury suggest that intracellular antioxidant enzymes do not protect cells from membrane damage due to extracellular oxidants.

Mitochondrial superoxide dismutase induction does not protect epithelial cells during oxidant exposure in vitro.

The significance of manganese superoxide dismutase (MnSOD) induction in cells and tissues during oxidant stress is still poorly understood. In this study, transformed human bronchial epithelial cells (BEAS 2B) were treated with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or with combination of these cytokines (10 ng/ml concentrations) for 48 or 72 h and exposed to selected oxidants. TNF-alpha and IFN-gamma + TNF-alpha combination resulted in a marked increase of MnSOD protein and MnSOD activity. When cells pretreated with the cytokines were exposed to hyperoxia (95% O2, 72 h), menadione (5-50 microM, 4 h), or H2O2 (0.5 and 5 mM, 4 h), in all cases IFN-gamma and TNF-alpha enhanced oxidant-related cell injury. The effect was most significant with cells pretreated with a combination of IFN-gamma and TNF-alpha. Antioxidant enzymes such as total SOD, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase did not change significantly during the cytokine treatment. Catalase activity was not changed by IFN-gamma or TNF-alpha but it decreased significantly (34%) in IFN-gamma + TNF-alpha-treated cells. Free radical generation was not changed by these cytokines in acute (30 min) experimental conditions or after 48-h treatment. These results suggest that cytokine-induced MnSOD does not protect bronchial epithelial cells against endogenously or exogenously generated oxidants in vitro. In fact, cells that contained the highest MnSOD activity were the most sensitive to subsequent oxidant damage.

High hydrostatic pressures in traumatic joints require elevated synovial capillary pressure probably associated with arteriolar vasodilatation.

Three out of the four Starling pressures were determined at arthroscopy of traumatic effusions of the knee. The range of the joint fluid hydrostatic pressure Pjoint was 5-83 cmH2O (0.5-8.1 kPa, 4-61 mmHg), that of the colloid osmotic pressure difference COPplasma-COPjoint 0-21.7 cmH2O. In 11 of 15 cases the sum Pjoint+COP difference exceeded 32.6 cmH2O (3.19 kPa, 24 mmHg), a high estimate of average capillary pressure at the level of the heart. The number of 'exceeding' cases was 8/15 if only 80% of the COP difference was considered effective. Pjoint and the COP difference oppose filtration of fluid from plasma into joints, indicating that mean capillary pressure, the only Starling pressure not determined, was elevated unless the effusions were being resorbed back into the blood. The findings can be explained by tamponade compensated by arteriolar vasodilatation, suspected to be metabolically mediated.

Acute patellar dislocation in children: incidence and associated osteochondral fractures.

In a prospective two-year study on urban (city of Helsinki) Finnish children, 72 acute patellar dislocations were observed. The calculated annual incidence rate was 43/100,000 in children under 16 years. A total of 28 knees (39%) had associated osteochondral fractures. These fractures comprised 15 capsular avulsions of the medial patellar margin and 15 loose intra-articular fragments detached from the patella and/or lateral femoral condyle. The intra-articular fragments were found only after spontaneous relocation of the patella. The femoral fracture constantly involved the edge of the articular surface in the middle third of the condylar arc.

Cytotoxicity of oxidants and asbestos fibers in cultured human mesothelial cells.

The authors investigated the mechanisms caused by oxidants (superoxide and hydrogen peroxide) and asbestos (amosite) fibers in human mesothelial cells. Immortalized human pleural mesothelial cells (MET 5A) were exposed in vitro to one of the following: hypoxanthine (100-200 microM) plus xanthine oxidase (10-20 mU/ml) as a superoxide-generating system, H2O2 (50 microM-5 mM); or amosite (1-100 micrograms/cm2). Cellular adenine nucleotide depletion, DNA single strand breaks, extracellular release of nucleotides, and their catabolites and lactate dehydrogenase (LDH) were assessed as markers of cell damage after 4-6 h exposure to the oxidants or fibers. The effect of intracellular antioxidant enzymes and exogenous antioxidants on cell damage were investigated during oxidant and amosite exposure. Superoxide radical and H2O2 exposure resulted in the depletion of adenine nucleotides, accumulation of the products of nucleotide catabolism, induction of DNA single strand breaks, and extracellular LDH release. Amosite exposure did not cause nucleotide depletion or induction of DNA single strand breaks. Inactivation of the intracellular antioxidant enzymes glutathione reductase or catalase augmented cell damage during H2O2 exposure but not during amosite exposure.

Distraction bone healing.

Bone formation by distraction was studied using three different experimental models: (1) Physeal distraction of the sheep radius was performed in 20 animals. (2) Distraction after osteotomy of the radius was carried out in 39 sheep. (3) Mandibular distraction after osteotomy was performed in 17 sheep. Formation of the organic matrix and osteogenesis were studied by radiographic, histologic, and biochemical methods as well as by electron microscopy. The mode of osteogenesis was essentially similar in all of these distraction models. Bone formation was preceded by organization of the collagenous matrix in the distraction area. In the beginning of the distraction, the gap was composed of a heterogeneous cell population, with large polymorphic fibroblast-like cells. The cells in the central part differentiated into fibroblasts, which remained functionally active as long as distraction proceeded. During physeal distraction, bone formed from the epiphyseal and metaphyseal sides as well as from the surrounding perichondrium. Also, in osteotomy distraction of both tubular bone and mandible, bone formed centripetally from the osteotomized bone ends toward the center of the gap. The organic matrix was composed almost solely of Type I collagen in the earliest stages, suggesting that the mode of osteogenesis differs from bone repair by fracture callus. The structure of the distracted segment was mainly lamellar trabecular. Corticalization of the lengthened bone segment occurred gradually after several months.