Chris Pruunsild

EULAR/PRINTO/PRES criteria for Henoch–Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria

Objectives To validate the previously proposed classification criteria for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). Methods Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a representative sample of 280 cases. Step 3: statistical (sensitivity, specificity, area under the curve and κ-agreement) and nominal group technique consensus evaluations. Results 827 patients with HSP, 150 with c-PAN, 60 with c-WG, 87 with c-TA and 52 with c-other were compared with each other. A patient was classified as HSP in the presence of purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (1) abdominal pain; (2) histopathology (IgA); (3) arthritis or arthralgia; (4) renal involvement. Classification of c-PAN required a systemic inflammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of five criteria: (1) skin involvement; (2) myalgia/muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classification of c-WG required three of six criteria: (1) histopathological evidence of granulomatous inflammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classification of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of five criteria: (1) pulse deficit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) elevated acute phase reactant. Conclusion European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society propose validated classification criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specificity.

The Ped-APS Registry: the antiphospholipid syndrome in childhood

In recent years, antiphospholipid syndrome (APS) has been increasingly recognised in various paediatric autoimmune and nonautoimmune diseases, but the relatively low prevalence and heterogeneity of APS in childhood made it very difficult to study in a systematic way. The project of an international registry of paediatric patients with APS (the Ped-APS Registry) was initiated in 2004 to foster and conduct multicentre, controlled studies with large number of paediatric APS patients. The Ped-APS Registry is organised as a collaborative project of the European Forum on Antiphospholipid Antibodies and Juvenile Systemic Lupus Erythematosus Working Group of the Paediatric Rheumatology European Society. Currently, it documents a standardised clinical, laboratory and therapeutic data of 133 children with antiphospholipid antibodies (aPL)-related thrombosis from 14 countries. The priority projects for future research of the Ped-APS Registry include prospective enrolment of new patients with aPL-related thrombosis, assessment of differences between the paediatric and adult APS, evaluation of proinflammatory genotype as a risk factor for APS manifestations in childhood and evaluation of patients with isolated nonthrombotic aPL-related manifestations.

Incidence of juvenile idiopathic arthritis in children in Estonia: a prospective population‐based study

Objective: To study the incidence rate of juvenile idiopathic arthritis (JIA) and its clinical subtypes in Estonia, to follow the course of the disease in newly diagnosed patients for 2 years, and to find the frequency of human leucocyte antigens (HLA) B27, DR1 and DR4 in JIA patients. Method: A population‐based study involving prospective registration of new cases of JIA in 1998–2000 and their clinical follow‐up for 2 years. Results: In 1998–2000, 162 new cases of JIA were diagnosed. The mean annual incidence rate of JIA was 21.7 per 100 000 children aged 0–15 years (22.9 in girls and 19.3 in boys). During the investigation period, the incidence rate rose 3.5‐fold. Oligoarthritis was the most frequent subtype (mean annual incidence rate of 11.7 per 100 000), followed by seronegative polyarthritis (4.4 per 100 000). HLA‐DR1, B27 and DR4 were found respectively in 44.4, 28.6 and 11.1% of cases in which the analysis was performed. In HLA‐B27‐positive patients, inflammation markers of blood remained at a high level for a longer period compared with HLA‐B27‐negative patients. Conclusions: This is the first population‐based study on the epidemiology of juvenile arthritis in Estonia in which the new classification criteria defined by the International League of Associations for Rheumatology (ILAR) have been used. In addition to environmental factors, an increase in awareness among family doctors is a probable reason for the rise in incidence during the study period. HLA‐B27 might have predictive value as a marker of chronicity of inflammation.

Inflammatory/oxidative stress during the first week after different types of cardiac surgery

Abstract Objectives. To compare inflammatory and oxidative stress time course during the first week after different types of cardiac surgery. Design. In patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CABG) or on the working heart (OPCAB) and aortic valve replacement (VALVE) blood samples for high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), myeloperoxidase (MPO), asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) were taken preoperatively and for six consecutive postoperative days. Results. Exploitation of cardiopulmonary bypass (CABG, VALVE groups), but not OPCAB, resulted in significant rise of MPO for two postoperative days. ADMA and Hcy changed in parallel fashion, being significantly decreased in the first postoperative morning and rising to the preoperative levels thereafter. In comparison with coronary artery disease patients, VALVE group had lower preoperative levels of ADMA and different postoperative time course. Postoperative concentrations of IL-6 and hsCRP were increased significantly in all groups and remained elevated during the first postoperative week. Conclusions. Cardiac surgery results in extensive and complex inflammatory/oxidative stress reponse regardless of the method or type of surgical procedure used. Myeloperoxidase could be one of the parameters to evaluate the cardiopulmonary bypass-associated inflammatory and oxidative stress response.

HMGB1 levels are increased in patients with juvenile idiopathic arthritis, correlate with early onset of disease, and are independent of disease duration.

Objective. High mobility group box chromosomal protein 1 (HMGB1) has been implicated as a mediator of inflammation in rheumatoid arthritis (RA), while its role in juvenile idiopathic arthritis (JIA) has not been described. To evaluate the role of HMGB1 in the inflammatory process in JIA and its potential as a therapeutic target, we investigated whether extracellular HMGB1 is detectable in JIA and if so, to correlate the levels with established inflammatory markers and clinical measures. Methods. Matching samples of blood and synovial fluid (SF) were collected from 23 patients with JIA. Levels of HMGB1, soluble receptor for advanced glycation endproducts, S100A12, myeloid-related protein 8/14, and other inflammatory mediators were analyzed. Results. Significantly increased HMGB1 levels were recorded in SF compared to blood samples from patients with JIA. The amount of HMGB1 was highest in patients with early disease onset irrespective of disease duration. In contrast, the proinflammatory S100 protein and interleukin 8 were highest in patients in early phases of disease. Matrix metalloproteinase-3, a marker of cartilage destruction, was higher in patients with late disease onset, indicating similarities with RA in that patient subgroup. Conclusion. Levels of extracellular HMGB1 are increased in the inflamed joints of patients with JIA. This warrants further studies of HMGB1 as a mediator of JIA pathogenesis as well as a biomarker for inflammatory activity and as a target for therapy. The variation in levels of HMGB1 and S100 proteins in relation to disease onset indicates a difference in inflammatory phenotype during disease progression.

Contemporary management of TMJ involvement in JIA patients and its orofacial consequences.

Juvenile idiopathic arthritis is the most common chronic rheumatic condition during childhood. Temporomandibular joint arthritis is frequently asymptomatic. When it takes place during childhood, it may affect condylar growth; therefore, these children are at risk of unfavorable long-term outcomes from the associated joint damage. The etiology is not completely understood, but it is considered as multifactorial with both genetic and environmental factors involved.The standardized examination and imaging protocols serve important purpose to diagnose temporomandibular joint (TMJ) arthritis not only to establish an early interventional strategy but also to assess craniofacial growth and the progression of signs and symptoms in those patients. Although the treatment of juvenile idiopathic arthritis (JIA) has changed dramatically over the last decades due to new therapeutic options, TMJ arthritis still can develop during the course of the disease. In clinical experience, TMJs appear to respond less well to the standard of care used to treat other joints. More individualized approach to the patient’s treatment serves as the main goal of personalized medicine. It could be achieved by adopting new methods of medical imaging such as conebeam computer tomography as well as developing reliable biomarkers which may assist with predicting disease type, course, or severity and predicting response to medication.This article provides an overview of current information on orofacial complications in JIA and its management. Based on information provided in this review, more precise diagnosis, proper tools for recognizing people at risk, and more efficient treatment approaches could be implemented. This may lead to more personalized treatment management strategies of TMJ complications of JIA patients.

Evaluation of the danger signal HMGB1 as a potential biomarker in juvenile idiopathic arthritis (JIA): a preliminary study using the novel biobank jabba

Backgroundand objectives The endogenous danger signal High Mobility Group Box protein 1 (HMGB1) promotes inflammation. HMGB1 has been implicated as a mediator of RA while there are no reports describing its presence in JIA patient samples. HMGB1 is aberrantly expressed in the synovitis of RA patients, intraarticular injection of HMGB1 induces arthritis in mice and HMGB1 blockade has beneficial effects in several different experimental disease models, including arthritis. In this study, the aim was to determine whether HMGB1 is extracellularly increased during JIA and, if so, to correlate the HMGB1 levels both with other more well-described laboratory parameters and with clinical parameters such as age at onset and disease duration. This type of descriptive study forms the basis for the evaluation of HMGB1 as a biomarker of inflammatory activity during JIA and as a potential therapeutic target. The newly established JIA biobank JABBA coupled to a clinical register gives us a unique opportunity to study JIA pathogenesis. Materials and methods Plasma and synovial fluid (SF) was collected from 23 patients with JIA (median age 12 (2–18)) at Astrid Lindgren Childrens hospital, Stockholm, Sweden and at Tartu University Childrens Hospital, Estonia. Samples were analysed by ELISA and Cytometric bead array (CBA) to measure levels of HMGB1, MMP-3, sRAGE, IL-12p70, TNF, IL-10, IL-6, IL-1β, IL-8, MCP-1, IP-10, RANTES, IFNγ, IFNα and IL-17A. Results Increased HMGB1 levels were recorded in SF as compared to plasma from JIA patients. Highest levels of HMGB1 were recorded in patients with a disease onset in early age (before age 10), while no correlation between the HMGB1 levels and disease duration was evident. In contrast, both S100 and IL-8 levels correlated with disease duration being highest during early stages of disease. MMP-3, a marker of cartilage destruction, was higher in patients with late disease onset which indicates similarities with RA. Conclusion The increased levels of HMGB1 in inflamed joints of JIA patients warrants further studies of HMGB1 as a biomarker for inflammatory activity and as a target for therapy. The correlation of HMGB1 levels with age at disease onset and continuously high levels irrespective of disease duration indicates, together with the decreasing levels of S100 and IL-8 during the disease course, that the inflammatory process in JIA evolves over time. Different mediators might thus be of varying importance during the disease progression. The authors conclude that the role of HMGB1 in the pathogenesis of JIA deserves further investigation.

Plasma level of myeloperoxidase in children with juvenile idiopathic arthritis (a pilot study)

To examine the plasma levels of MPO in oligoarthritis and polyarthritis subtypes of JIA in comparison with healthy age-matched controls. Thirty-eight JIA patients (25 girls and 13 boys) aged 9.1–11.8 years and 23 healthy controls (8 girls and 15 boys) participated in the study. Twenty-one patients had oligoarthritis (8 with extended oligoarthritis) and 17 had polyarthritis (among them three were seropositive). The plasma concentration of MPO was measured by the ELISA technique (OxisResearchTM, BIOXYTECH® MPO-EIATM, Portland, OR USA). The mean plasma concentration of MPO in the JIA group was significantly higher than in the control group (76.6±24.8 µg/L versus 62.7±15.6 µg/L; p=0.01). Patients with polyarthritis presented a significantly higher mean plasma MPO level than patients with oligoarthritis (81.3±25.6 µg/L and 62.1±27.1 µg/L, respectively; p=0.02). Different subtypes of JIA may have different MPO-related backgrounds. MPO is a new potent inflammatory marker. Patients with polyarthritis have higher mean plasma MPO levels than patients with oligoarthritis and may therefore have an enhanced risk for subclinical oxidative stress-related atherogenic promotion.

The Estonian 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 Estonian language. The reading comprehension of the questionnaire was tested in 10 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 110 JIA patients (71.8% oligoarticular, 18.2% RF-negative polyarthritis, 10% other categories) and 98 healthy children were enrolled in one paediatric rheumatology centre. Notably, none of the enrolled JIA patients is affected with systemic JIA. The JAMAR components discriminated healthy subjects from JIA patients, except for the Paediatric Rheumatology Quality of Life (HRQoL) Psychosocial Health (PsH) subscales and for the satisfaction with current health status. All JAMAR components revealed good psychometric performances. In conclusion, the Estonian 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.

High mobility group box protein 1—A prognostic marker for structural joint damage in 10-year follow-up of patients with juvenile idiopathic arthritis

OBJECTIVE High mobility group box protein 1 (HMGB1) is an important pro-inflammatory mediator in adult rheumatoid arthritis. The diagnostic utility of HMGB1 in Juvenile Idiopathic Arthritis (JIA) is still unclear. The aim was to examine whether serum HMGB1 levels are associated with inflammation, radiological disease progression, and long-term prognosis in JIA. METHODS We included 131 children with JIA from a population-based prevalence study; 38 of them were prospectively followed up for 10 years. Clinical and laboratory disease characteristics at study entry and after 10 years as well as radiological progression over 10 years were recorded. HMGB1 levels were analyzed by an ELISA. RESULTS The HMGB1 levels were similar in children with different JIA subgroups and in children with established (53%) or newly diagnosed (47%) disease. HMGB1 levels did not differ between groups at entry into the study or at 10 years, by sex, or by the presence or absence of RF or ANA antibodies. HMGB1 levels at the study entry correlated with HMGB1 levels at 10 years and with blood neutrophil count. Most importantly, children with destructive arthritis at 10 years had a tendency toward higher HMGB1 levels at study entry (median 1.2 vs 0.6ng/ml, ns) and displayed 4-fold higher circulating HMGB1 levels (median 3.4 vs 0.8ng/ml, p = 0.0014) than children without radiological destructions. CONCLUSIONS Our results suggest that HMGB1 is a marker of inflammatory activity in children with JIA. Higher serum HMGB1 levels are related to more destructive JIA and could be used as a negative prognostic marker at the disease start. TRIAL REGISTRATION Clinicaltrials.gov NCT01905319. Registered July 16, 2013.