CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is considered a complex genetic autoimmune disease. We investigated the association of genetic variants previously implicated in JIA, autoimmunity and/or immunoregulation, with susceptibility to JIA. METHODS: A genetic association study was performed in 639 JIA patients and 1613 healthy controls of northwest European descent. Ninety-three single nucleotide polymorphisms (SNP) were genotyped in a candidate gene approach. Results of the entire JIA patient group (all subtypes) were compared with results obtained, alternatively, with a clinically homogeneous patient group including only oligoarticular and rheumatoid factor (RF) negative polyarticular JIA patients (n=493). Meta-analyses were performed for all SNPs that have been typed in other Caucasian JIA cohorts before. RESULTS: SNPs in or near PTPN22, VTCN1, the IL2-IL21 region, ANKRD55 and TNFA were confirmed to be associated with JIA (p<0.05), strengthening the evidence for involvement of these genes in JIA. In the majority of these replicated SNPs, effect sizes were larger when analysing a homogeneous patient cohort than when analysing all subtypes. We identified two novel associations with oligoarticular and RF-negative polyarticular JIA: CD226 rs763361 (OR 1.30, 95% CI 1.12 to 1.51, p=0.0006) and CD28 rs1980422 (OR 1.29, 95% CI 1.07 to 1.55, p=0.008). Meta-analyses including reported studies confirmed the association of both SNPs with susceptibility to JIA (OR 1.16, p=0.001 and OR 1.18, p=0.001, for rs763361 and rs1980422, respectively). CONCLUSIONS: The CD226 gene has been identified as novel association with JIA, and a SNP near CD28 as a suggestive association. Both genes are probable candidate risk factors, since they are involved in costimulation of T cells.

Genetic variation in VTCN1 (B7-H4) is associated with course of disease in juvenile idiopathic arthritis.

OBJECTIVE: The course of disease in juvenile idiopathic arthritis (JIA) is unpredictable with episodes of activity and remission. In order to identify predictive factors, 93 SNPs, JIA subtype, age at onset and ANA status were studied in relation to disease course. METHODS: Genetic and clinical parameters were analysed in a cohort of 272 Caucasian patients with persistent oligoarthritis (n=129), extended oligoarthritis (n=57) and rheumatoid factor negative polyarthritis (n=86). Categories of disease course (remitting (n=65), intermediate (n=96) and unremitting (n=111)) were designed based on the cumulative time spent in active disease in the first 2 years. RESULTS: Univariate analysis revealed association of the course of disease with JIA subtype (p=5.7*10(-5)) and three SNPs; VTCN1 rs10 923 223 (p=4.4*10(-5)), VTCN1 rs12 046 117 (p=0.017) and CDK6 rs42 041 (p=0.038). In a subsequent multivariate ordinal logistic regression analysis, VTCN1 rs10 923 223 (OR 0.41, 95%-CI 0.26 to 0.63) and JIA subtype (OR 3.8, 95%-CI 2.0 to 7.2; OR 2.5, 95%-CI 1.4 to 4.2, for extended oligoarthritis and RF-negative polyarthritis vs persistent oligoarthritis, respectively) were the strongest independent factors for course of disease. CONCLUSIONS: This study provides evidence that VTCN1, encoding B7-H4, is associated with course of disease in selected subtypes of JIA. VTCN1 might be useful in predicting the course of disease.

Major improvements in health-related quality of life during the use of etanercept in patients with previously refractory juvenile idiopathic arthritis.

OBJECTIVE: To evaluate changes in health-related quality of life (HRQoL) in patients with refractory juvenile idiopathic arthritis (JIA) who are being treated with etanercept. METHODS: 53 patients with JIA from seven Dutch centres were included. HRQoL was measured by the Childhood Health Assessment Questionnaire (CHAQ), Child Health Questionnaire (CHQ) and Health Utilities Index mark 3 (HUI3) at the start and after 3, 15 and 27 months of treatment. At the same time points the following JIA disease activity variables were collected; physician's global assessment through the visual analogue scale (VAS), number of active and limited joints and erythrocyte sedimentation rate. A statistical method linear mixed models was used to assess outcomes over time. RESULTS: During etanercept treatment both disease-specific and generic HRQoL outcomes improved dramatically. Significant improvements were shown after 3 months and these improvements continued at least up to 27 months of treatment. The disease-specific CHAQ, including VAS pain and wellbeing, showed a significant improvement in all domains. The generic health-profile measure CHQ improved for all the health concepts except for "family cohesion", which was normal. The generic preference-based HUI3 showed impairment and, subsequently, significant improvement in the more specific domains ("pain", "ambulatory", "dexterity"). In accordance disease activity variables also improved significantly over time. CONCLUSION: This study shows that the HRQoL of patients with refractory JIA can be substantially improved by the use of etanercept for all aspects impaired by JIA. Information on HRQoL is crucial to understand the complete impact of etanercept treatment on patients with JIA and their families.

Disease activity patterns in juvenile systemic lupus erythematosus and its relation to early aggressive treatment.

This study aimed to determine disease activity patterns in juvenile systemic lupus erythematosus (jSLE) and its relation to early treatment. All jSLE patients who visited the outpatient departments of three Dutch university hospitals for at least 6 months were included. Data were retrospectively collected from each patient visit and hospitalization. Patient characteristics, clinical and laboratory findings categorized in organ systems, flare rate, medication use and disease course were analysed. Included were 35 patients (female 77%; White 47%) with a total follow-up of 142 years. Median age at diagnosis was 12.8 years. Flare rate was 0.45/ patient-year. An organ system not earlier involved was affected in 34% of flares. Identifiable disease activity patterns were: chronic active (49%), relapse remitting (14%) and long quiescence (37%), with no significant difference in organ involvement at diagnosis. Positive anti-Sm and non-White ethnicity were significantly associated with a chronic active pattern. In 14 patients with severe symptoms at diagnosis, treatment with intravenous cyclophosphamide and/or biologics and/or intravenous methylprednisone in the first 6 months resulted in a long quiescence pattern in seven patients. In conclusion, distinct disease activity patterns are identifiable in children. Suppression of disease with early aggressive treatment may decrease the rate of progression.

Strong relationships between disease activity, foot-related impairments, activity limitations and participation restrictions in children with juvenile idiopathic arthritis.

OBJECTIVES: To assess possible relationships between disease activity, foot-related impairments, activity limitations and participation restrictions in children with juvenile idiopathic arthritis (JIA). METHODS: Thirty-four children were studied. Disease activity was assessed with the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71). Foot-related impairments, activity limitations and participation restrictions were measured with the Juvenile Arthritis Foot Disability Index (JAFI), the Childhood Health Assessment Questionnaire (CHAQ), self-reported or parent-reported and doctor-reported VAS scales. Relationships were quantified with Spearman's correlation coefficient. RESULTS: The mean age was 12.4±3.7 years, the median disease duration 1.5 years (interquartile range (IQR) 1.0-4.0), 88% were girls, and 76% had polyarticular disease course. The median JADAS-71 score (range 0-101) was 6 (IQR 1-13). On the JAFI sub-scores (range 0-4) 88% of the children reported some foot-related impairments (median 1.1, IQR 0.4-2.0); 82% reported some foot-related activity limitations (median 0.9, IQR 0.3-2.0), and 65% reported some foot-related participation restrictions (median 0.6, IQR 0-2.1). The median CHAQ score was 0.9 (IQR 0.1-1.8). The JADAS-71 correlated with all impairment, activity limitation and participation restriction variables (r=0.48-0.81, p<0.01). Most of the impairment variables correlated with activity limitation (r=0.39, p<0.05 to r=0.92, p<0.01) and participation restriction variables (r=0.44, p<0.05 to r=0.81, p<0.01). All activity limitation variables correlated with participation restriction variables (r=0.62-0.84, p<0.01). CONCLUSIONS: We observed strong relationships between disease activity, foot-related impairments, activity limitations and participation restrictions in children with JIA, and therefore suggest that standard screening for foot problems should be included in follow-up care for JIA patients.

Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register.

OBJECTIVE: We undertook an observational study to obtain a complete overview of the long-term effectiveness and safety of etanercept in patients with different juvenile idiopathic arthritis (JIA) subtypes. METHODS: At baseline we collected patient and disease characteristics of all Dutch patients with JIA who started treatment with etanercept. Disease activity was evaluated (at start of the study, after 3 months and then yearly) according to the JIA core set of the American College of Rheumatology paediatric definition for 30, 50 and 70% improvement (ACR Pedi 30, 50 and 70). Use of etanercept and concomitant drugs was monitored. Adverse events were recorded. RESULTS: We included 146 patients with JIA with a median follow-up of 2.5 years per patient (range 0.3-7.3). JIA subtypes represented: 27% systemic, 8% polyarticular rheumatoid factor positive, 38% polyarticular rheumatoid factor negative, 19% oligoarticular extended, 3% enthesitis-related and 5% psoriatica. Most patients (77%) met the criteria of the ACR Pedi 30 in the first 3 months of treatment. For the majority of patients this improvement was sustained; 53 (36%) of all patients met the remission criteria. No other second-line agents were needed in 43 patients. Although patients with systemic JIA responded initially less to etanercept therapy than patients from other subtypes, those who did respond showed equal effectiveness in the long term. Serious adverse events rate was low (0.029 per patient year). CONCLUSIONS: Etanercept is effective and safe in JIA, even for a large proportion of the patients with systemic JIA. The greatest improvement occurred in the first 3 months of treatment, and was sustained for a long time in most patients (up to 75 months).

No radiographic wrist damage after treatment to target in recent-onset juvenile idiopathic arthritis.

BACKGROUND: To evaluate radiographic progression of patients with new-onset juvenile idiopathic arthritis (JIA) in response to an early, tightly-controlled, treatment-to-target. METHODS: Patients with JIA participating in the BeSt-for-Kids-study, randomized to 3 treatment strategy arms, were eligible if at least 1 conventional wrist-radiograph was available. Bone damage as reflected by carpal length was assessed using the Poznanski-score. The BoneXpert-method was used to determine the Bone Age (BA, > 5 years) and bone mineral density (BMD) of the wrist. These scores were evaluated over time and compared between the treatment arms and mean JADAS10-score using linear mixed models corrected for age and symptom duration. RESULTS: In 60 patients, 252 radiographs were analysed. Baseline age and symptom duration were different between the arms. No difference in comparison to the healthy reference population was found at baseline for the Poznanski-score (IQR varying from - 0,82; 0.68), nor for BA (varying from - 0.88 to 0.74). Baseline BMD was statistically significantly lower in arm 3 (initial treatment with etanercept and methotrexate) (- 1.48; - 0.68) compared to arm 1 (- 0.84; - 0.04) and arm 2 (- 0.93; 0.15). After treatment to target inactive disease, the Poznanski-scores and the BA remained clinically unchanged, while the BMD in arm 3 improved (p < 0.05 vs arm 1). CONCLUSIONS: Recent-onset JIA patients, treated-to-target aimed at inactive disease, showed no signs of radiographic wrist damage (Poznanski-score, BA or BMD) either at baseline or at follow-up, irrespective of treatment arm. A lower BMD at baseline in arm 3, initially treated with methotrexate and etanercept, improved significantly after treatment. TRIAL REGISTRATION: NTR, NL1504 (NTR1574). Registered 01-06-2009.

The TRAF1/C5 region is a risk factor for polyarthritis in juvenile idiopathic arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic disorder in which both genetic and environmental factors are involved. Recently, we identified the TRAF1/C5 region (located on chromosome 9q33-34) as a risk factor for rheumatoid arthritis (RA) (p(combined) = 1.4 x 10(-8)). In the present study the association of the TRAF1/C5 region with the susceptibility to JIA was investigated. METHODS: A case-control association study was performed in 338 Caucasian patients with JIA and 511 healthy individuals. We genotyped the single nucleotide polymorphism rs10818488 as a marker for the TRAF1/C5 region. RESULTS: The A allele was associated with the susceptibility to rheumatoid factor-negative polyarthritis with an 11% increase in allele frequency (OR 1.54, 95% CI 1.09 to 2.18; p = 0.012). This association was stronger when combining subtypes with a polyarticular phenotype (OR 1.46, 95% CI 1.12 to 1.90; p = 0.004). In addition, we observed a trend towards an increase in A allele frequency in patients with extended oligoarthritis versus persistent oligoarthritis (49%, 38% respectively); p = 0.055. CONCLUSIONS: Apart from being a well replicated risk factor for RA, TRAF1/C5 also appears to be a risk factor for the rheumatoid factor-negative polyarthritis subtype of JIA and, more generally, seems to be associated with subtypes of JIA characterised by a polyarticular course.

Development of a web-based register for the Dutch national study on biologicals in JIA: www.ABC-register.nl.

OBJECTIVES: Most clinical studies use paper case record forms (CRFs) to collect data. In the Dutch multi-centre observational study on biologicals we encountered several disadvantages of using the paper CRFs. These are delay in data collection, lack of overview in collected data and difficulties in obtaining up-to-date interim reports. Therefore, we wanted to create a more effective method of data collection compared with CRFs on paper in a multi-centre study. METHODS: We designed a web-based register with the intention to make it easy to use for participating physicians and at the same time accurate and up-to-date. Security demands were taken into account to secure the safety of the patient data. RESULTS: The web-based register was tested with data from 161 juvenile idiopathic arthritis patients from nine different centres. Internal validity was obtained and user-friendliness guaranteed. To secure the completeness of the data automatically generated e-mail alerts were implemented into the web-based register. More transparency of data was achieved by including the option to automatically generate interim reports of data in the web-based register. The safety was tested and approved. CONCLUSIONS: By digitalizing the CRF we achieved our aim to provide easy, rapid and safe access to the database and contributed to a new way of data collection. Although the web-based register was designed for the current multi-centre observational study, this type of instrument can also be applied to other types of studies. We expect that especially collaborative study groups will find it an efficient tool to collect data.