Lillemor Berntson

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.

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 condylar alterations in juvenile idiopathic arthritis most common in longitudinally severe disease despite medical treatment

BackgroundJuvenile idiopathic arthritis (JIA) is an autoimmune, heterogeneous disease and the temporomandibular joint (TMJ) can be affected, with consequences for mandibular growth and function. The aim of this study was to evaluate the importance of longitudinal medical treatment and the burden of disease activity on the development of temporomandibular condylar alterations as judged on panoramic radiographs.MethodsThe study was a retrospective evaluation of dental and medical records in consecutive JIA patients referred to three specialist dental clinics in Sweden during an eight-year period. Data on the total pharmacological treatment and disease activity were evaluated longitudinally from disease onset to the time of the panoramic examination, during a median observation period of 2.5 years. The radiographs were analysed in terms of structural and shape alterations in the condyles and judged dichotomously.ResultsPanoramic examinations were analysed in 158 patients from 266 referrals diagnosed with JIA. Condylar alterations (shape or structural) were seen in 68 patients (43%). Patients with condylar alterations were more extensively treated over time compared with those without condylar alterations. Powerful disease activity and/or potent medication at any time during the course of the disease implied an increased risk of alterations.ConclusionsPatients with JIA who require more intensive medication over time run the greatest risk of condylar alterations. As yet, current medical programmes have not been specified for the TMJ and more knowledge in this area is needed.

Gut microbiota-host interactions and juvenile idiopathic arthritis.

BackgroundJuvenile idiopathic arthritis is the most common form of chronic arthritis in children. There is mounting evidence that the microbiota may influence the disease.Main bodyRecent observations in several systemic inflammatory diseases including JIA have indicated that abnormalities in the contents of the microbiota may be factors in disease pathogenesis, while other studies in turn have shown that environmental factors impacting the composition of the microbiota, such as delivery mode and early exposure to antibiotics, affect the risk of chronic inflammatory diseases including JIA. Microbial alterations may predispose to JIA through a variety of mechanisms, including impaired immunologic development, alterations in the balances of pro- versus anti-inflammatory bacteria, and low-grade mucosal inflammation. Additional confirmatory studies of microbiota aberrations and their risk factors are needed, as well as additional mechanistic studies linking these alterations to the disease itself.ConclusionsThe microbiota may influence the risk of JIA and other systemic inflammatory conditions through a variety of mechanisms. Additional research is required to improve our understanding of the links between the microbiota and arthritis, and the treatment implications thereof.

Changes in fecal microbiota and metabolomics in a child with juvenile idiopathic arthritis (JIA) responding to two treatment periods with exclusive enteral nutrition (EEN)

The microbiome and immune system of the digestive tract are highly important in both health and disease. Exclusive enteral nutrition (EEN) is a common anti-inflammatory treatment in children with Crohn’s disease in the European countries, and the mechanism is most likely linked to changes in the intestinal microbiome. In the present study, EEN was given in two treatment periods several months apart to a patient with very severe, disabling juvenile idiopathic arthritis (JIA), with a remarkable clinical response as the result. The aim of the present study was to study how the EEN treatment influenced the microbiome and metabolome of this patient. Fecal samples from before, during, and between treatments with EEN were studied. The microbiome was analyzed by sequencing of 16S rRNA amplicons using Illumina MiSeq, and the metabolome was analyzed using nuclear magnetic resonance. The microbiome changed markedly from treatment with EEN, with a strong reduction of the Bacteroidetes phylum. Metabolic profiles showed clear differences before, during, and between treatment with EEN, where butyrate, propionate, and acetate followed a cyclic pattern with the lowest levels at the end of each treatment period. This patient with JIA showed remarkable clinical improvement after EEN treatment, and we found corresponding changes in both the fecal microbiome and the metabolome. Further studies are needed to explore the pathophysiological role of the intestinal canal in children with JIA.

Psoriasis and associated variables in classification and outcome of juvenile idiopathic arthritis - an eight-year follow-up study

BackgroundTo study the impact of psoriasis and features associated with psoriasis on classification and outcome in a population-based follow-up cohort of children with juvenile idiopathic arthritis (JIA).MethodsIn all, 440 children with JIA were followed for a median of 8 years in a prospective Nordic population-based cohort study. Data for remission was available for 427 of these children. The presence of psoriasis, psoriasis-like rash, dactylitis, nail pitting, enthesitis, tenosynovitis and heredity was assessed in relation to ILAR classification and remission.ResultsClinical findings associated with psoriasis developed consecutively during the 8-year period. Six of 14 children with psoriasis were not classified as juvenile psoriatic arthritis according to the ILAR criteria at 8 year follow-up. Dactylitis was more common in children with early onset of JIA. After 8 years we found a cumulative median number of eleven arthritic joints in children with psoriasis or psoriasis-like rash compared with six in the rest of the cohort (p = 0.02). Also, the chance for not being in remission after 8 years increased significantly in patients with psoriasis, psoriasis-like rash or at least two of: 1) first-degree heredity for psoriasis or psoriatic arthritis, 2) dactylitis or 3) nail pitting, compared with the rest of the group (OR 3.32, p = 0.010).ConclusionsOur results indicate a more severe disease over time in psoriasis-associated JIA, as features of psoriasis develop during the disease course. This group is a major challenge to encompass in a future JIA classification in order to facilitate early tailored treatment.

Up Regulated Complement and Fc Receptors in Juvenile Idiopathic Arthritis and Correlation with Disease Phenotype

PurposeThe progress in identifying immunological mechanisms in juvenile idiopathic arthritis (JIA) has partly been hampered by the fact that the disease is heterogeneous. Here we have investigated complement and Fc receptors, as part of the inflammatory process, in two subgroups of JIA.MethodsBlood from 26 patients with oligoarticular or polyarticular course type JIA and 21 healthy age and sex-matched controls were investigated by FACS and immunoassays.ResultsIncreased numbers of monocytes and augmented plasma levels of C-reactive protein, C3a and IgG were found in both JIA subgroups. However, only polyarticular patients exhibited increased expression of Fc gamma receptor (FcγR) II and III and complement receptor (CR) 1 on monocytes along with enhanced CR1 expression on B cells. A correlation was observed between degree of receptor expression and C3a levels in the patients.ConclusionsComplement and Fc receptors are up regulated in children with multiple joint involvements, thus highlighting these pathways in the pathogenesis of polyarticular JIA.