Ellen Nordal

Ongoing disease activity and changing categories in a long‐term nordic cohort study of juvenile idiopathic arthritis

OBJECTIVE To describe the disease characteristics, long-term course, and outcome of patients with juvenile idiopathic arthritis (JIA) in a population-based setting. METHODS Consecutive cases of JIA from defined geographic areas of Denmark, Finland, Sweden, and Norway in whom disease onset occurred in 1997-2000 were included in a prospective, multicenter cohort study. The study was designed to be as close to a population-based study as possible, with centers participating only if they were able to include in their catchment area all children in whom JIA was diagnosed. RESULTS Of 500 children included, 440 (88.0%) had repeated visits, with the last visit occurring at least 7 years after disease onset (median 98 months, range 84-147 months). Changes in the International League of Associations for Rheumatology category were observed in 10.8% of the children, and, in addition, extended oligoarthritis developed in 34.7% of the group with oligoarticular JIA. During the observation period, 58.0% of the children were treated with disease-modifying antirheumatic drugs, including biologic medications. Ongoing disease activity was mostly mild, but some JIA-related damage developed in 22.9% of the children. At the last followup visit, remission off medication was observed in 42.4% of the children, 8.9% were in remission on medication, and 48.7% were not in remission. The highest rates of remission were observed in patients with persistent oligoarticular JIA and in those with systemic JIA. CONCLUSION In this long-term prospective study of JIA in a population-based Nordic setting, ongoing disease was evident in a majority of the children. The present results underline the need to identify early predictors of outcome, to further improve therapy, and to continue long-term followup of patients with JIA.

Biomarkers of Chronic Uveitis in Juvenile Idiopathic Arthritis: Predictive Value of Antihistone Antibodies and Antinuclear Antibodies

Objective. To study the predictive value of antinuclear autoantibody (ANA) tests and antihistone antibodies (AHA) as risk factors for development of chronic asymptomatic uveitis of insidious onset in juvenile idiopathic arthritis (JIA). Methods. ANA by indirect immunofluorescence using HEp-2 cells (IF-ANA), ELISA for ANA (E-ANA), and AHA were analyzed in sera of 100 children with recent-onset JIA and in 58 control sera. Clinical features, including age at onset, JIA subgroup, and presence of uveitis, were recorded in this prospective population-based cohort study. Results. E-ANA was positive in 4 of the 100 sera, and was not associated with uveitis. Chronic uveitis developed in 16 children with JIA: in 14 of 68 positive for IF-ANA ≥ 80, and in 13 of 44 positive for AHA ≥ 8 U/ml. IgM/IgG AHA were found in higher proportions in children with uveitis (mean 12.4 U/ml) than in those with JIA and no uveitis (mean 6.9 U/ml) or in healthy controls (mean 4.3 U/ml). Conclusion. No association was found between E-ANA and uveitis, and most IF-ANA-positive sera were E-ANA-negative. E-ANA is not clinically relevant in this setting and should never be used to determine frequencies of eye examinations to detect new uveitis in JIA. AHA ≥ 8 U/ml, IF-ANA titer ≥ 320, and young age at onset of arthritis were significant predictors for development of chronic uveitis. The diagnostic value of AHA ≥ 8 U/ml as a biomarker of chronic uveitis in JIA is very similar to IF-ANA ≥ 80.

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.

HLA-B27 Predicts a More Chronic Disease Course in an 8-year Followup Cohort of Patients with Juvenile Idiopathic Arthritis

Objective. We investigated associations of HLA-B27 with clinical manifestations and longterm outcome in a near population-based setting among patients with juvenile idiopathic arthritis (JIA). Methods. We studied clinical and serological data from 410 patients with HLA-B27 results among 440 prospectively collected patients with JIA with 8-year followup data in a Nordic database. The study was structured to be as close to a population-based study as possible. Results. HLA-B27 was analyzed in 93% of patients, and was positive in 21% of the cohort, in 18.4% of the girls and in 25.9% of the boys. Boys who were HLA-B27-positive had significantly higher age at onset compared to HLA-B27-negative boys and compared to both HLA-B27-negative and positive girls. This difference in onset age in relation to HLA-B27 was not found in girls. HLA-B27 was associated with clinical signs of sacroiliitis, enthesitis, and tenosynovitis in boys, but not in girls. After 8 years of disease, 46 children (11.2%) were classified as having enthesitis-related arthritis (ERA). Boys with ERA had clinical signs of sacroiliitis more often than girls with ERA. HLA-B27-positive children, as well as children with clinical signs of sacroiliitis, enthesitis, and hip arthritis, had higher odds of not being in remission off medication after 8 years of disease. Conclusion. In this near population-based Nordic JIA cohort we found significant differences between HLA-B27-positive boys and girls in age at disease onset, clinical signs of sacroiliitis, and ERA classification. HLA-B27 was negatively associated with longterm remission status, possibly because of its association with clinical disease characteristics, such as sacroiliitis, rather than being a general marker of persistent disease.

Chorea in juvenile primary antiphospholipid syndrome : Reversible decreased circulation in the basal ganglia visualised by single photon emission computed tomography

Chorea was observed in a 12-year-old girl with primary antiphospholipid syndrome (APS). She developed severe chorea in a few weeks. On immunosuppressive treatment, including high doses of glucocorticoids and cyclophosphamide, she had a rapid clinical recovery. Single photon emission computed tomography (SPECT) of the brain showed decreased circulation in the basal ganglia and in the medial parts of both temporal lobes. One month after treatment, SPECT was completely normalised. APS in children has a variety of clinical manifestations, and should be suspected in cases of unexplained thromboembolic disease or obscure neurological symptoms.

Febrile neutropenia in children with cancer : A retrospective Norwegian multicentre study of clinical and microbiological outcome

Our objective was to describe clinical and laboratory characteristics, treatment and outcome among Norwegian children with cancer suffering from chemotherapy-induced febrile neutropenia (FN). We retrospectively reviewed data on paediatric FN episodes in 7 Norwegian hospitals during a 2.5-y period. A total of 236 episodes of FN occurred in 95 children. Acute lymphoblastic leukaemia was the most common diagnosis (49 patients). Blood cultures yielded growth in 39 episodes (17%). Primary empirical antibiotic regimens could be assigned to 2 main groups: 1) benzylpenicillin or ampicillin and an aminoglycoside (58%) or 2) a regimen based on third-generation cephalosporins (42%). There were no statistically significant differences in outcome between the 2 regimens in terms of need to change initial antibiotic treatment, d of fever or maximum C-reactive protein values. One infection-related death (fungal septicaemia) occurred during the study period. We conclude that incidence of septicaemia and clinical outcome is similar to recent international trials on paediatric FN, but antibiotic treatment in Norway differs from international guidelines. However, patients in our study were successfully and safely treated, irrespective of the primary empirical antibiotic regimen.

Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

Objectives Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. Methods Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. Results We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. Conclusions The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Anti-type II collagen antibodies, anti-CCP, IgA RF and IgM RF are associated with joint damage, assessed eight years after onset of juvenile idiopathic arthritis (JIA).

BackgroundEarly appearance of antibodies specific for native human type II collagen (anti-CII) characterizes an early inflammatory and destructive phenotype in adults with rheumatoid arthritis (RA). The objective of this study was to investigate the occurrence of anti-CII, IgM RF, IgA RF and anti-CCP in serum samples obtained early after diagnosis, and to relate the occurrence of autoantibodies to outcome after eight years of disease in children with juvenile idiopathic arthritis (JIA).MethodsThe Nordic JIA database prospectively included JIA patients followed for eight years with data on remission and joint damage. From this database, serum samples collected from 192 patients, at a median of four months after disease onset, were analysed for IgG anti-CII, IgM RF, IgA RF and IgG anti-CCP. Joint damage was assessed based on Juvenile Arthritis Damage Index for Articular damage (JADI-A), a validated clinical instrument for joint damage.ResultsElevated serum levels of anti-CII occurred in 3.1%, IgM RF in 3.6%, IgA RF in 3.1% and anti-CCP in 2.6% of the patients. Occurrence of RF and anti-CCP did to some extent overlap, but rarely with anti-CII. The polyarticular and oligoarticular extended categories were overrepresented in patients with two or more autoantibodies. Anti-CII occurred in younger children, usually without overlap with the other autoantibodies and was associated with high levels of C-reactive protein (CRP) early in the disease course. All four autoantibodies were significantly associated with joint damage, but not with active disease at the eight-year follow up.ConclusionsAnti-CII, anti-CCP, IgA RF and IgM RF detected early in the disease course predicted joint damage when assessed after eight years of disease. The role of anti-CII in JIA should be further studied.

Temporomandibular Joint Involvement is Associated with Quality of Life, Disability and High Disease Activity in Juvenile Idiopathic Arthritis

To evaluate the demographic, disease activity, disability, and health‐related quality of life (HRQOL) differences between children with juvenile idiopathic arthritis (JIA) and their healthy peers, and between children with JIA with and without clinical temporomandibular joint (TMJ) involvement and its determinants.

Long-term outcome in juvenile-onset mixed connective tissue disease: a nationwide Norwegian study.

Objectives To describe the characteristics, outcome and predictive factors of juvenile mixed connective tissue disease (JMCTD) in a nationwide cohort of patients. Methods We examined 55 patients with JMCTD after a mean disease duration of 16.2 years (SD 10.0). Patients were registered according to Kasukawas criteria. Remission criteria were defined according to those for juvenile idiopathic arthritis, plus absence of cytopenia, myositis, progressive sclerodactyly, lung and oesophageal manifestations. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index and the Juvenile Arthritis Damage Index (JADI). Medical records were reviewed for early predictors for outcome, which were assessed by multivariate logistic regression analyses. Results Three patients developed systemic lupus erythematosus (SLE). Fifty-two patients had continuous JMCTD; the most common manifestations were: Raynaud (100%), arthritis (94%), puffy hands (77%) and pulmonary manifestations (58%). SLE-like, systemic sclerosis (SSc)-like and polymyositis (PM)-like findings were found in 98%, 77% and 48%, respectively. Over time, SLE-like and PM-like manifestations decreased, and SSc-like findings increased. At follow-up, 35 patients (67%) had active disease and 17 (33%) were in remission. In 34 patients (65%), SLICC or JADI≥1 assessments indicated organ damage. Active disease was associated with higher anti-ribonucleoprotein antibody titres at follow-up and positive rheumatoid factor (RF) at diagnosis and follow-up. Conclusions Most patients with JMCTD had active disease and organ damage after a mean follow-up of 16.2 years. Active disease was associated with higher anti-ribonucleoprotein antibody levels and positive RF. The presence of RF at diagnosis predicted persistent disease activity.