Sara Verazza

Antinuclear antibody–positive patients should be grouped as a separate category in the classification of juvenile idiopathic arthritis

OBJECTIVE We undertook this study to test the hypothesis that in the International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis (JIA), patients with similar characteristics can be classified into different categories. We sought to investigate whether antinuclear antibody (ANA)-positive patients having disease in the ILAR categories of oligoarthritis, rheumatoid factor-negative polyarthritis, psoriatic arthritis, and undifferentiated arthritis share homogeneous features and to compare these features with those of ANA-negative patients having the same categories of disease. METHODS We identified JIA patients who had been followed up during a 22-year period. ANA positivity was defined as ≥2 positive results at a titer of ≥1:160. Demographic and clinical features were recorded retrospectively and compared between ANA-positive and ANA-negative patients. RESULTS Of a total of 971 patients, 711 were ANA positive, 149 were ANA negative, and 111 had an indeterminate ANA status. Patients with indeterminate ANA status were excluded. ANA-positive patients in the different ILAR categories were similar in terms of age at disease presentation, female-to-male ratio, and frequency of asymmetric arthritis and iridocyclitis. Compared with ANA-positive patients, the ANA-negative group was older at disease presentation and had a lower prevalence of females, a lower frequency of iridocyclitis and asymmetric arthritis, a greater number of affected joints over time, and a different pattern of arthritis. The close relationship between the presence of ANAs and younger age at disease presentation, female predominance, asymmetric arthritis, development of iridocyclitis, lower number of affected joints over time, and lack of hip involvement was also confirmed by multivariate and multiple correspondence analysis. CONCLUSION Our findings substantiate the hypothesis that ANA-positive patients classified into different JIA categories by current ILAR criteria constitute a homogeneous patient population.

Parent and child acceptable symptom state in juvenile idiopathic arthritis.

Objective. To explore the parent and child acceptable symptom state in juvenile arthritis (JA-PASS and JA-CASS, respectively) and estimate the JA-PASS and JA-CASS cutoff values for outcome measures. Methods. Children with juvenile idiopathic arthritis (JIA) and their parents completed a multi-dimensional questionnaire that included parent-reported and child-reported outcomes and a question about whether they considered the disease state as satisfactory. Additional assessments included demographic data, physician-reported outcomes, and acute-phase reactant levels. Stepwise logistic regression was used to assess contributors to JA-PASS and JA-CASS. Cutoff values of outcome measures that defined JA-PASS and JA-CASS were determined using both 75th percentile and receiver-operating characteristic (ROC) curve methods. Testing procedures included evaluation of discriminative and construct validity of the satisfaction question and assessment of reliability of JA-PASS and JA-PASS cutoffs. Results. Of 584 parents, 385 (65.9%) considered their child in JA-PASS. Of 343 children, 236 (68.8%) considered themselves in JA-CASS. Significant contributors to being in either JA-PASS or JA-CASS were absence of active joints, better rating of overall well-being, and better physical function or health. Cutoff values yielded by 75th percentile and ROC curve methods were similar. Parent, child, and physician global ratings yielded the lowest percentage of false-positive misclassification and the best tradeoff between sensitivity and specificity. The satisfaction question showed good discriminative and construct validity and the JA-PASS and JA-PASS cutoffs were found to be stable over time. Conclusion. The acceptable symptom state is a relevant concept for children with JIA and their parents and constitutes a valid outcome measure that is potentially applicable in routine practice and clinical trials.

Defining criteria for high disease activity in juvenile idiopathic arthritis based on the Juvenile Arthritis Disease Activity Score

Objective To determine cutoff values for defining the state of high disease activity (HDA) in juvenile idiopathic arthritis (JIA) using the Juvenile Arthritis Disease Activity Score (JADAS). Methods For the selection of cutoff values, data from a clinical database including 609 patients were used. Optimal cutoff values were determined against external criteria by calculating the 25th and 10th centile of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria were based on the therapeutic decision made by the attending doctor. Cross-validation was performed using five patient samples that included 1421 patients. Results The optimal cutoff values were those obtained through the 90% fixed sensitivity method. The selected JADAS cutoff values were the following: 4.2 and 8.5 for JADAS27 in oligoarthritis and polyarthritis, respectively; 4.2 and 10.5 for both JADAS10 and JADAS71 in oligoarthritis and polyarthritis, respectively. In cross-validation analyses, the cutoff values showed strong ability to discriminate between different levels of American College of Rheumatology paediatric response in two clinical trials and could predict worse functional and radiographic outcome. Conclusions Cutoff values for classifying HDA in JIA using the JADAS were developed. In cross-validation analyses, they proved to have good construct and discriminant validity and ability to predict disease outcome.

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial

BACKGROUND Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. METHODS We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. FINDINGS Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. INTERPRETATION Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. FUNDING Italian Agency of Drug Evaluation.

A controlled trial of intra-articular corticosteroids with or without methotrexate in oligoarticular juvenile idiopathic arthritis

In contrast with the numerous controlled trials conducted in polyarticular or systemic juvenile idiopathic arthritis (JIA), little evidence-based information is available for oligoarticular JIA. As a result, the management of children with this subtype, which is the most prevalent in Western countries, is largely empiric. Intra-articular corticosteroid (IAC) injection is the therapy of first choice for oligoarthritis in many pediatric rheumatology centers. However, although IAC injections are usually highly efficacious, relapses of synovitis are common and sometimes occur only a few months after the procedure. It is still unclear whether concomitant administration of methotrexate (MTX) may increase and prolong the effectiveness of IAC injections.

Time of onset of iridocyclitis (IC) in children with juvenile idiopathic arthritis (JIA)

Methods 1050 JIA patients seen between 1985 and 2007 were identified. 172 patients (16.4%) had IC. 6 patients with enthesitis-related arthritis with acute IC, 4 patients who developed IC before arthritis onset and 2 patients in whom date of IC onset was unknown were excluded. Of the remaining 160 patients, 108 (67.5%) had oligoarthritis, 36 (22.5%) RF-negative polyarthritis, 9 (5.6%) undifferentiated arthritis, 6 (3.8%) psoriatic arthritis, 1 (0.6%) systemic arthritis. Of the 158 patients who had ANA tested, 144 (91.1%) were positive (≥ 1:160), 8 (5.1%) low-positive (≤ 1:80) or doubtful, 6 (3.8%) negative. Results The cumulative proportion of patients who developed IC over time is shown in figure 1 and table 1.

Chapter 7 – Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is a heterogeneous condition and represents the most common rheumatologic disease in childhood. A variety of cardiac manifestations have been described in JIA. Pericarditis and myocarditis are the most common systemic subset and cardiac failure is a life-threatening complication of macrophage activation syndrome. Valvular heart disease, most frequently aortic insufficiency, has occasionally been seen in rheumatoid factor-positive polyarthritis and juvenile ankylosing spondylitis. The significance of the observed impairment in systolic and diastolic ventricle function is unclear as JIA is not associated with increased prevalence of ischemic heart disease or cardiomyopathy. The risk of premature atherosclerosis is also uncertain. Although some studies have shown endothelial and vascular dysfunction, the carotid intima-media thickness was not found to be consistently thicker than in healthy controls. In spite of decreased anaerobic fitness, the exercise capacity of children with chronic arthritis is preserved irrespective of the stage of disease activity.

AB1020 Evaluation of the Disease Course of Italian Children with Juvenile Idiopathic Arthritis Treated with Etanercept: Preliminary Results in 1019 Patients

Background The advent of biologic medications has considerably increased the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients. Objectives To evaluate the outcome of etanercept (ETN) therapy in Italian children with JIA. Methods This is a multicenter, observational study that includes all children with JIA who were given ETN at Italian pediatric rheumatology centers after January 2000. Patients were classified in 2 groups: patients who were no longer taking ETN at study start (Group 1); patients who were still receiving ETN at study start (Group 2). Patients in Group 1 underwent only retrospective assessments, whereas patients in Group 2 underwent both retrospective and cross-sectional assessments. The primary outcome of the study were reasons for ETN discontinuation in patients in Group 1, and achievement of the states of inactive disease (ID), minimal disease activity (MDA) and parent- and child-acceptable symptom state (PASS, CASS) in patients in Group 2. The above states were assessed through both formal definitions and JADAS cutoffs. The secondary outcome was the evaluation of frequency and characteristics of ETN-related side effects. Results So far, the data of 1019 patients (629 in Group 1 and 390 in Group 2) have been collected. Among the 629 patients in Group 1, reasons for ETN discontinuation evaluated in 460 patients included disease remission (48.5%), lack of efficacy (26.1%), and side effects (14.8%). The results of assessment of disease state through formal definitions in 371 children of the 390 children in Group 2 who had already undergone the cross-sectional evaluation were the following: ID 39.7%, MDA 63.0%, PASS 82.4%, CASS 75.8%. The percentages of patients who reached the same disease states assessed through JADAS cutoffs were: ID 45.9%, MDA 61.6%, PASS 70.0%, CASS 66.2%. Serious adverse events were seen in 17 patients and included inflammatory bowel disease (8 pts), tuberculosis (1 pt), CMV hepatitis (1 pt), recurrent pneumoniae (1 pt), varicella complicated by bronchopneumonia (1 pt), acute pancreatitis (1pt), bacterial osteomyelitis (1 pt), bladder carcinoma (1pt), thyroid carcinoma (1 pt); 1 patient died of sepsis. Conclusions A substantial proportion of children currently receiving ETN were in the states of ID or MDA, or were satisfied with treatment outcome. Half of the patients who had been discontinued from ETN before study start had the medication stopped because of disease remission. Serious adverse events were uncommon. Disclosure of Interest None declared

Evaluation of the disease course of Italian children with juvenile idiopathic arthritis treated with etanercept: preliminary results in 772 patients

The advent of biologic medications has considerably increased the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients.

Is it worth allowing the presence of morning stiffness in the definition of inactive disease in juvenile idiopathic arthritis

Morning stiffness is a major symptom of juvenile idiopathic arthritis (JIA) and it is usually associated with active disease. However, it is common view that children with disease quiescence may have some degrees of residual morning stiffness. The 2004 preliminary criteria for inactive disease (ID) in JIA did not include the assessment of morning stiffness, whereas the 2011 revision of the criteria has allowed the presence of morning stiffness lasting ≤ 15 minutes. However, it is still unknown whether the disease status of children with ID who have or do not have morning stiffness is comparable.