Non-HLA gene polymorphisms in juvenile idiopathic arthritis: associations with disease outcome.

OBJECTIVE: To test the hypothesis that non-HLA single-nucleotide polymorphisms (SNPs) associated with the risk of juvenile idiopathic arthritis (JIA) are risk factors for an unfavourable disease outcome at long-term follow-up. METHODS: The Nordic JIA cohort is a prospective multicentre study cohort of patients from the Nordic countries. In all, 193 patients met the inclusion criteria of having an 8 year follow-up assessment and available DNA sample. Seventeen SNPs met the inclusion criteria of having significant associations with JIA in at least two previous independent study cohorts. Clinical endpoints were disease remission, actively inflamed joints and joints with limitation of motion (LOM), articular or extra-articular damage, and history of uveitis. RESULTS: Evidence of associations between genotypes and endpoints were found for STAT4, ADAD1-IL2-IL21, PTPN2, and VTCN1 (p = 0.003-0.05). STAT4_rs7574865 TT was associated with the presence of actively inflamed joints [odds ratio (OR) 20.6, 95% confidence interval (CI) 2.2-> 100, p = 0.003] and extra-articular damage (OR 7.9, 95% CI 1-56.6, p = 0.057). ADAD1_rs17388568 AA was associated with a lower risk of having joints with LOM (OR 0.1, 95% CI 0-0.55, p = 0.016). PTPN2_rs1893217 CC was associated with a lower risk of having joints with LOM (OR 0.2, 95% CI 0-0.99, p = 0.026), while VTCN1_rs2358820 GA was associated with uveitis (OR 3.5, 95% CI 1-12.1, p = 0.029). CONCLUSION: This exploratory study, using a prospectively followed JIA cohort, found significant associations between long-term outcome and SNPs, all previously associated with development of JIA and involved in immune regulation and signal transduction in immune cells.

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.

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.

Treatment of vitiligo with narrowband-UVB (TL01) combined with tacrolimus ointment (0.1%) vs. placebo ointment, a randomized right/left double-blind comparative study.

BACKGROUND: Only a few, small double-blind clinical trials have been reported for the treatment of vitiligo. Narrowband-ultraviolet B (NB-UVB) is an established form of treatment for this condition. Tacrolimus ointment is assumed to have an effect in some patients. OBJECTIVES: To assess the additive effect of tacrolimus ointment (0.1%) once daily in vitiligo patients treated with NB-UVB. METHODS: In a randomized double-blind trial, patients with stable symmetrical vitiligo were treated half-side with tacrolimus ointment (0.1%) and half-side with placebo ointment. Whole body NB-UVB was given twice or thrice weekly for at least 3 months. As a morphometric device, Visitrak(TM) was used to measure the area of the vitiligo target lesions. RESULTS: Of 40 patients, 27 had a better effect on the tacrolimus side. The degree of improvement was significantly better on the tacrolimus side (P = 0.005). The median reduction in the target lesion areas was 42.1% on the tacrolimus side and 29% on the placebo side. There was a correlation between the effect and the number of topical tacrolimus applications (P = 0.044), but there was no correlation with the number of UV treatments given; neither any significance of gender, age, skin type, duration of disease, familial occurrence of vitiligo nor presence of other autoimmune disease or atopy was observed. We found a significant reduction in the patients' subjective disease impact during the treatment period (P < 0.001). CONCLUSION: According to this study, the combination of NB-UVB and tacrolimus ointment (0.1%) is more effective than UV treatment alone in patients with vitiligo. The effect is tacrolimus total dose-dependent.

A comparative study of teleconsultations versus face-to-face consultations.

We compared the diagnoses made by one dermatologist via telemedicine with those of another dermatologist made in a face-to-face consultation. The patients first underwent a teledermatology consultation and then a face-to-face consultation. A general practitioner was present with the patient in the videoconference studio. Videoconferencing equipment connected at 384 kbit/s was used. The doctor-patient relationship and the satisfaction of the patients and dermatologists in the two settings were assessed, as well as technical conditions during the videoconferences. There were 121 patients, with a mean age of 40 years (range 17-82 years). There was a high degree of concordance between the two sets of diagnoses, with 72% complete agreement and 14% partial agreement between the two dermatologists. A total of 116 patients (96% of those included) completed a questionnaire. Both the patients and the dermatologists were in general satisfied with the videoconferences. Videoconferencing with a participating general practitioner may be useful in dermatology, but the technique should be used only for selected patients.

Generalized dystrophic epidermolysis bullosa: identification of a novel, homozygous glycine substitution, G2031S, in exon 73 of COL7A1 in monozygous triplets.

We report monozygous triplets affected with dystrophic epidermolysis bullosa (DEB). The female triplets were delivered by Caesarean section and skin fragility of each child, which was partly induced by trauma, was apparent from the third to fourth day of life. Clinically, the triplets were equally affected. Mutation analysis in this family revealed a novel recessively expressed glycine substitution, G2031S, in exon 73 of the collagen VII gene COL7A1. Most glycine substitutions in this gene region encoding for the triple helical domain of collagen VII are associated with milder, dominantly inherited phenotypes. By contrast, the novel point mutation of this study is clinically silent in the heterozygous state and leads to a severe DEB subtype when homozygous.

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.

The relationship between atherosclerosis of the thoracic aorta and renal scarring in an autopsy material.

With the aim of examining the possible association between atherosclerosis of the aorta and renal scarring, an autopsy study comprising 81 men and 43 women was performed. The per cent intimal surface involved with atherosclerosis in the aorta above the renal arteries was determined by morphometry, and the per cent surface profile of the kidney affected by scarring was measured microscopically in a standardized fashion. In addition, the following variables were determined: the age of the patient, diameter of the renal artery ostia, weight of the kidneys, heart weight, presence or absence of signs of sustained myocardial infarction, highest measured systolic blood pressure and the number of macroscopic renal scars. The data were subjected to both simple correlation and multiple regression analyses. In both men and women there was a significant simple correlation between the degree of atherosclerosis in the aorta and the extent of subcapsular microscopic renal scarring. In men, the prime importance of aortic atherosclerosis for microscopic renal scarring was supported in the multiple regression analysis. In women, this analysis showed that age was the determining predictive factor for microscopical renal scarring. The results may be taken to support the hypothesis that micro-embolism from an atherosclerotic aorta may be a cause of microscopic subcapsular scars in the kidneys.

Familial occurrence of papillary thyroid carcinoma.

We report two kindreds from northern Norway with 7 and 4 cases of papillary thyroid carcinoma in otherwise healthy, nonirradiated subjects. While histologic features were comparable the patient's age at the time of diagnosis was lower and lymph node metastases were more frequent in familial than in nonfamilial cases of papillary thyroid carcinoma from the same region. We conclude that genetic factors can predispose the patient for development of papillary thyroid carcinoma. The high local incidence may be due to interaction between susceptibility gene(s) and environmental factors.