Rheumatoid Arthritis: Førre Ø

Hollan I, Mikkelsen K, Førre Ø. · Revmatismesykehuset, 2609 Lillehammer. · Tidsskr Nor Laegeforen. · Pubmed #16327849 links to  free full text

Abstract: BACKGROUND: Traditional treatment of rheumatoid arthritis has been directed against joint damage, not against increased cardiovascular morbidity. METHODS: The article is based on a search in Medline, bibliography of relevant articles, abstracts from congresses of rheumatology, and discussions with experts. RESULTS AND INTERPRETATION: Rheumatoid arthritis is an independent predictor for coronary artery disease, the main cause of premature mortality in rheumatoid patients. Cardiovascular prophylaxis in rheumatoid arthritis should be prioritised. Treatments of traditional cardiovascular risk factors and of inflammation both seem to be important in reducing cardiovascular morbidity. Insight in accelerated atherosclerosis in inflammatory rheumatic diseases may improve our understanding of the pathogenesis of atherosclerosis generally.

Johnsen V, Førre Ø, Haga HJ, Kvien TK, Mikkelsen K, Nordvåg BY, Rødevand E. · Revmatologisk avdeling, Sørlandet sykehus, 4604 Kristiansand. · Tidsskr Nor Laegeforen. · Pubmed #12822010 links to  free full text

Abstract: BACKGROUND: During the last decade patients with active rheumatoid arthritis have been offered early and aggressive drug therapy in order to decrease the damaging effect of inflammation on cartilage and bone. Combination of two or more disease-modifying antirheumatic drugs has been used more frequently to achieve better efficacy than with monotherapy without increasing drug side effects. MATERIALS AND METHODS: We have studied available rheumatological literature to find the best documented drug combinations. RESULTS: The combination of methotrexate, sulfasalazine and hydroxychloroquine seems to be a well documented alternative, and so is the combination of methotrexate and cyclosporine. Modern biologic drugs like etanercept, infliximab and anakinra work best in combination with methotrexate. INTERPRETATION: The combination of two or more disease-modifying antirheumatic drugs can be a good alternative to monotherapy in the treatment of patients with active rheumatoid arthritis, either when monotherapy has failed or unacceptable side effects have occurred, or as a first choice in patients who need very early and aggressive therapy. Combination therapy should only be initiated by a rheumatologist, after informed consent. A safe clinical and chemical monitoring must be organized in cooperation with the patient and the primary physician.

Magitta NF, Bøe Wolff AS, Johansson S, Skinningsrud B, Lie BA, Myhr KM, Undlien DE, Joner G, Njølstad PR, Kvien TK, Førre Ø, Knappskog PM, Husebye ES. · Centre of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. · Genes Immun. · Pubmed #18946481 No free full text.

Abstract: Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six different autoimmune diseases, that is autoimmune Addison's disease (n=333), type 1 diabetes (n=1086), multiple sclerosis (n=502), rheumatoid arthritis (n=945), systemic lupus erythematosus (n=156) and juvenile idiopathic arthritis (n=505), against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the coding SNP rs12150220 revealed significant association with autoimmune Addison's disease compared with controls (OR=1.25, 95% CI: 1.06-1.49, P=0.007), and with type 1 diabetes (OR=1.15, 95% CI: 1.04-1.27, P=0.005). Trends toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious, multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases.

Viken MK, Sollid HD, Joner G, Dahl-Jørgensen K, Rønningen KS, Undlien DE, Flatø B, Selvaag AM, Førre Ø, Kvien TK, Thorsby E, Melms A, Tolosa E, Lie BA. · Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway. · Hum Immunol. · Pubmed #17869649 No free full text.

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of beta cells in the pancreas. The CTSL2 gene encodes the cysteine protease cathepsin V involved in antigen presentation in human cortical thymic epithelial cells, and involvement of the protease in autoimmunity has been suggested. This study aimed to evaluate CTSL2 as a candidate gene for T1D, and test whether the gene predisposes more generally to autoimmune diseases. Four polymorphisms aiming at tagging the CTSL2 locus were genotyped in 421 T1D families, and subsequently in 861 rheumatoid arthritis patients, 530 juvenile idiopathic arthritis patients, and 559 controls of Norwegian origin. Additionally, DNA from 83 German myasthenia gravis (MG) patients and 244 controls were investigated. A polymorphism, rs16919034, situated downstream of CTSL2 was associated with T1D (60.8%T, p = 0.008; p(c) = 0.03). An association with early-onset MG (45% in cases vs 36.6% in controls; p = 0.03) was observed for another polymorphism (rs4361859) situated upstream of the gene, but within the same linkage disequilibrium block. No association was observed in rheumatoid arthritis or juvenile idiopathic arthritis. Our findings suggest that the CTSL2 gene is associated with T1D and with early-onset MG.

Flatø B, Hoffmann-Vold AM, Reiff A, Førre Ø, Lien G, Vinje O. · Department of Rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, 0027 Oslo, Norway. · Arthritis Rheum. · Pubmed #17075863 links to  free full text

Abstract: OBJECTIVE: To compare the clinical, functional, and radiographic outcomes in patients with enthesitis-related arthritis (ERA) with those in patients with other subtypes of juvenile idiopathic arthritis (JIA) and healthy controls, and to determine genetic markers, patient characteristics, and early disease variables that predict the development of remission, sacroiliitis, and physical limitations in ERA. METHODS: Fifty-five children with ERA who were first admitted to Rikshospitalet Medical Center between 1980 and 1985 were studied. Patients with oligoarthritis or polyarthritis who were admitted during the same period (n = 55) and individuals from a national population registry (n = 55) were matched for sex and age and used as controls. Health status was assessed after a median of 15.3 years of disease (range 11.7-21.9 years) and, in some patients, was reassessed after a median of 23.0 years (range 19.7-29.4 years) of disease, by use of the 36-item Short Form health survey and the Health Assessment Questionnaire. Clinical and radiographic examinations were performed at the 15-year followup visit. Variables relating to the onset of disease were retrospectively obtained by chart review. HLA alleles were determined by genotyping and serologic testing. RESULTS: Patients with ERA had lower levels of physical functioning, poorer physical health, and more bodily pain compared with patients with oligoarthritis or polyarthritis (after a median of 15.3 and a median of 23.0 years) and normal controls (after a median of 15.3 years). Among patients with ERA, remission occurred in 44%, sacroiliitis was observed in 35%, and reduced spinal flexion was observed in 75%. Predictors of failure to attain disease remission included the following: ankylosing spondylitis (AS) in a first-degree relative, the presence of HLA-DRB1*08, and ankle arthritis within the first 6 months. HLA-DPB1*02 was a protective factor, whereas a persistently elevated erythrocyte sedimentation rate (ESR), and hip arthritis within the first 6 months were risk factors for sacroiliitis. Female sex, a family history of AS, and high numbers of affected joints within the first 6 months predicted poor physical health status after 23 years. Male sex was associated with reduced anterior flexion of the spine. CONCLUSION: In this study, patients with ERA had poorer physical outcomes compared with patients with oligoarticular or polyarticular JIA and controls from the general population. A family history of related diseases, sex, the presence of HLA-DRB1*08, the absence of HLA-DPB1*02, a persistently elevated ESR, early hip or ankle arthritis, and high numbers of affected joints were predictors of an unfavorable outcome.

Selvaag AM, Flatø B, Dale K, Lien G, Vinje O, Smerdel-Ramoya A, Førre Ø. · Department of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway. · J Rheumatol. · Pubmed #16758503 No free full text.

Abstract: OBJECTIVE: To describe radiographic findings at disease onset and 3-year followup in patients with juvenile rheumatoid arthritis (JRA) and juvenile spondyloarthropathy (JSpA), to assess radiographic progression and its predictors, and to prospectively assess clinical outcome and predictors of persistent disease at 3-year followup. METHODS: A total of 197 patients with JRA/JSpA were examined every 6 months for 3 years. Radiographic examination was performed at baseline and 3-year followup of knees and ankles (all patients) and of other joints on clinical indication. Remission was defined as minimum 6 months without medication and no clinical signs of active disease. RESULTS: Radiographic abnormalities were found in 88% of the patients at onset and in 81% after 3 years. Frequency of swelling/osteoporosis decreased and frequency of abnormal growth increased from baseline to followup. Knees, hands, and wrists had most frequently radiographic abnormalities. Radiographic progression occurred in 38% of the patients. Joints with swelling/osteoporosis on radiographs, young age, and a large number of mobility-restricted joints at baseline were predictors of radiographic progression. At 3 years, 26% of the patients were in remission and 75% had been treated with disease-modifying antirheumatic drugs. Reduced well-being, a large number of active joints and negative antinuclear antibody at baseline were predictors of persistent disease after 3 years. CONCLUSION: After 3 years most patients had radiographic abnormalities and persistent disease. Young age, many affected joints, reduced well-being, and negative antinuclear antibody at onset increased the risk of radiographic progression and persistent disease after 3 years.

Selvaag AM, Lien G, Sørskaar D, Vinje O, Førre Ø, Flatø B. · Department of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway. · J Rheumatol. · Pubmed #15940778 No free full text.

Abstract: OBJECTIVE:. To describe the 3 year disease course in early juvenile rheumatoid arthritis (JRA) and juvenile spondyloarthropathy (JSpA), to compare the health status after 3 years of followup with that of normal controls, and to investigate the relationship between physical function at followup and disease characteristics recorded during the first 6 months. METHODS: One hundred and ninety-seven children (median age 6:6 yrs) with JRA and JSpA and disease duration <1.5 years were examined by a pediatric rheumatologist every 6 months for a median of 3.1 years. Controls were randomly selected from the National Population Register. Physical and psychosocial health was assessed by means of the Child Health Questionnaire and the Childhood Health Assessment Questionnaire (CHAQ). Disease course was analyzed by analysis of variance for repeated measurements. RESULTS: Health status and disease activity improved over time. Treatment with disease modifying antirheumatic drugs was started in 58% of the patients at baseline. Patients with persistent oligoarthritis had the most favorable disease course. The patients with juvenile ankylosing spondylitis (JAS), syndrome of seronegative enthesopathy and arthropathy (SEA), and rheumatoid factor (RF) positive polyarthritis had the poorest health status. A significant improvement for the whole group was observed after 3 years in all measures of disease activity and health status, except pain. Patients had poorer physical function and general health and more pain than controls. Predictors of reduced physical function at followup were a high CHAQ disability index and a poor well-being assessed during the first 6 months. CONCLUSION: Health status and disease activity improved over time in patients under medical treatment. The patients with JAS/SEA and RF positive polyarthritis had poorer health than the patients in other subtypes. A high disability index and a poor well-being at baseline predicted reduced physical function after 3 years.

Lien G, Selvaag AM, Flatø B, Haugen M, Vinje O, Sørskaar D, Dale K, Egeland T, Førre Ø. · Rikshospitalet University Hospital, Oslo, Norway. <> · Arthritis Rheum. · Pubmed #15751052 links to  free full text

Abstract: OBJECTIVE: To explore early changes and predictors of bone mass in children with juvenile idiopathic arthritis (JIA) in order to identify patients who will develop bone mass reductions. METHODS: We conducted a prospective cohort study of 108 children with early JIA (ages 6-18 years; mean disease duration 19.3 months) who were individually matched with 108 healthy children for age, sex, race, and county of residence. Bone mass and changes in total body, spine, femur, and forearm bone mineral density and bone mineral content (BMC), body composition, growth, and biochemical parameters of bone turnover were examined at baseline and at followup a mean of 24 months later. Low bone mass was defined as a Z score >1 SD below the reference population. RESULTS: Of the 200 children evaluated at followup, the 100 healthy children had greater gains in total body BMC (P = 0.035), distal radius BMC (P < 0.001), and total body lean mass (P < 0.001) than did the 100 JIA patients. Low or very low total body BMC was observed in 24% of the patients and 12% of the healthy children. Bone formation, bone resorption, and weight-bearing activities were reduced in the patients compared with the healthy children. Multiple regression analysis showed that in patients with JIA, serum bone-specific alkaline phosphatase, serum C-telopeptide of type I collagen, and weight-bearing activities were independent predictors of changes in total body BMC. Total body BMC was lower in patients with polyarticular onset than in those with oligoarticular disease onset. CONCLUSION: Patients with JIA have moderate reductions in bone mass gains, bone turnover, and total body lean mass early in the disease course.

Smerdel A, Dai KZ, Lorentzen AR, Flatø B, Maslinski S, Thorsby E, Førre Ø, Spurkland A. · Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. · Genes Immun. · Pubmed #15129233 No free full text.

Abstract: T-cell-specific adapter protein (TSAd) involved in the negative control of T-cell activation is encoded by the SH2D2A gene. Our recent studies indicate that homozygosity for short (ie GA(13) and GA(16)) alleles of the SH2D2A gene promoter is associated with development of multiple sclerosis. To study whether the same SH2D2A promoter polymorphism also contributes to the genetic susceptibility to develop juvenile rheumatoid arthritis (JRA), we examined 210 JRA patients and 558 healthy unrelated controls from Norway. The frequency of the short allele GA(13) was increased among the JRA patients compared to control (0.098 vs 0.05; P(n=8)=0.042). There was a significant increased frequency of HLA-DRB1(*)08-positive patients carrying two copies of 'short' alleles GA(13) and/or GA(16) compared to healthy controls (16% vs 6%; P(n=4)=0.016). Our data indicate that the 'short' alleles of the SH2D2A promoter could contribute to the genetic susceptibility to JRA.

Lien G, Flatø B, Haugen M, Vinje O, Sørskaar D, Dale K, Johnston V, Egeland T, Førre Ø. · Department of Rheumatology, Rikshospitalet University Hospital, Oslo 0027, Norway. · Arthritis Rheum. · Pubmed #12905475 links to  free full text

Abstract: OBJECTIVE: To determine the frequency of low bone mineral content (BMC) and low bone mineral density (BMD) as long-term complications in adolescents with early-onset juvenile idiopathic arthritis (JIA), and to identify disease variables, patient characteristics, and biochemical bone markers related to low bone mass. METHODS: One hundred five (87%) of 121 adolescent patients with early-onset JIA (ages 13-19 years, 80 girls and 25 boys, mean age at onset of JIA 2.8 years), from a cohort first admitted to the hospital between 1980 and 1985, were assessed after a mean disease duration of 14.2 years. BMC and BMD of the total body, the lumbar spine at L2-L4, and the femoral neck were measured by dual-energy x-ray absorptiometry. Age- and sex-specific reference values from a pooled, healthy reference population were used to calculate Z scores. Low bone mass was defined as a Z score less than -1 SD. RESULTS: Among the 103 adolescent JIA patients who underwent total-body imaging, 41% had low total-body BMC and 34% had low total-body BMD. Compared with adolescent JIA patients who had normal total-body BMC, those with low BMC had lower mean weight (P < 0.001), height (P < 0.001), lean mass (P < 0.001), and remission rates (P = 0.016), had longer duration of active disease (P = 0.013), had higher numbers of active and mobility-restricted joints (P < 0.001 and P = 0.001, respectively), had more disability (P = 0.011), had higher frequencies of joint erosions (P < 0.001), and had higher erythrocyte sedimentation rates (P = 0.033). In multiple linear regression analyses of total-body BMC, 88% of the variance was explained by the duration of active disease, the number of joints with restricted mobility, the bone area, urinary deoxypyridinoline values, age, weight, and height. CONCLUSION: Forty-one percent of the adolescents with early-onset JIA had low bone mass >11 years after disease onset. The development of low total-body BMC was related to the duration of active disease, disease severity, measures of bone resorption, weight, and height.

Selvaag AM, Flatø B, Lien G, Sørskaar D, Vinje O, Førre Ø. · Department of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway. · J Rheumatol. · Pubmed #12858465 No free full text.

Abstract: OBJECTIVE: To assess the determinants and responsiveness of the Norwegian version of the Child Health Questionnaire (CHQ) in patients with early juvenile idiopathic arthritis (JIA) and to compare health status in patients and controls. METHODS: A total of 116 children (median age 8.4 yrs) with JIA and < 2.5 years of disease duration (median 11.0 mo) were examined by a pediatric rheumatologist and reassessed after a median of 10.0 months. Physical and psychosocial health were assessed by means of the CHQ, which provides summary scores for physical and psychosocial health, the Childhood Health Assessment Questionnaire (CHAQ), and the Child Behavior Checklist (CBCL, n = 32). Matched controls (n = 116), randomly selected from the general population, completed the CHQ at baseline. RESULTS: The patients with JIA had poorer physical health and slightly impaired psychosocial health compared with the controls [41.2 +/- 13.6 vs 55.2 +/- 7.3 (p < 0.001) and 51.0 +/- 7.5 vs 54.1 +/- 5.7 (p = 0.002), respectively]. The most important determinants of the CHQ physical summary score were the child's pain, morning stiffness, the CHAQ disability index, erythrocyte sedimentation rate (ESR), overall well-being, and physician's global assessment of disease activity. The psychosocial summary score correlated with the CBCL level of internalizing, externalizing, and total behavior problems. The standardized response mean for the physical summary score was large (0.96) for those who improved, and moderate (-0.60) for those who became worse. CONCLUSION: The CHQ discriminated between patients with early JIA and controls. The most important determinants of the CHQ physical summary score were the child's pain, morning stiffness, CHAQ, ESR, overall well-being, and physician's global assessment of disease activity. The CHQ was sensitive to clinical changes in children with JIA.

Smerdel A, Lie BA, Finholt C, Ploski R, Førre Ø, Undlien DE, Thorsby E. · Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. · Tissue Antigens. · Pubmed #12622778 No free full text.

Abstract: Juvenile idiopathic arthritis (JIA) is an HLA-associated rheumatic disease with onset in childhood. We recently reported that allele 5 at microsatellite D6S265 in the HLA class I region is associated with JIA, independent of linkage disequilibrium with the high risk DR8-DQ4 haplotype. In the present study, we investigated whether alleles at D6S265, or other markers in this region, also modify the risk for JIA on other haplotypes, i.e., DRB1*1301-DQB1*0603 or DRB1*1101/4-DQB1*0301. We observed a significant association with allele 6 at D6S265 on the DRB1*1301-DQB1*0603 haplotype. We also noted an association with allele 3 at D6S265, when carried on the DRB1*1101/4-DQB1*0301 haplotype. Our results further support an additional JIA susceptibility gene in the HLA class I region in linkage disequilibrium with alleles at D6S265.

Flatø B, Lien G, Smerdel A, Vinje O, Dale K, Johnston V, Sørskaar D, Moum T, Ploski R, Førre Ø. · Center for Rheumatic Diseases, Rikshospitalet University Hospital, Oslo, Norway. · J Rheumatol. · Pubmed #12563700 No free full text.

Abstract: OBJECTIVE: To describe the physical and psychosocial outcome in patients with juvenile rheumatoid arthritis (JRA), compared with subjects in the general population, and to determine patient characteristics, HLA alleles, and disease variables within the first 6 months of disease onset that predict persistent disease, joint erosions, and physical disability. METHODS: A cohort of 268 (85%) of 316 patients with JRA first admitted to the hospital between 1980 and 1985 were examined after a median of 14.9 years (range 11.7-25.1) of disease duration. Controls matched for age, sex, and geographic region were randomly selected from the general population. Patients' medical records were retrospectively reviewed. Clinical examinations and radiographs of the hips, ankles, and affected joints were obtained. HLA-DRB1 and DPB1 alleles were determined by genotyping and HLA-B27 by serologic testing. Physical and psychosocial health status was assessed using the Short-Form Health Survey (SF-36) and the Health Assessment Questionnaire (HAQ). RESULTS: At followup, 133 patients with JRA (50%) were in remission, 63 (24%) had developed joint erosions, and 93 (36%) had impaired physical functioning (HAQ > 0.0). Patients had greater disability, more bodily pain, and poorer general health than controls. Comparable levels of education, social function, and mental health were found, but the patients had higher rates of unemployment than controls (19% vs 7%; p < 0.001). Predictors of persistent disease and joint erosions were: young onset age and large numbers of affected joints, long duration of elevated erythrocyte sedimentation rate (ESR), and positive IgM rheumatoid factor (RF) within the first 6 months. Additionally, persistent disease was predicted by the presence of DRB1*08, and joint erosions were predicted by symmetric arthritis and DRB1*08 and HLA-B27 in combination. DRB1*01 was a predictor of joint erosions in the pauciarticular onset type (n = 163). Predictors of physical disability were: female sex, symmetric arthritis, hip joint involvement, long duration of elevated ESR and IgM RF. CONCLUSION: Compared with healthy controls, patients with JRA had impaired physical health and lower employment rates after more than 11 years of disease duration. Elevated ESR, extensive and symmetric arthritis, positive IgM RF, DRB1*08, DRB1*01, HLA-B27 and DRB1*08 in combination, early onset, and female sex were early risk factors for an unfavorable outcome.

Haugen MA, Lien G, Flatø B, Kvammen JA, Vinje O, Sørskaar D, Førre Ø. · Rikshospitalet, Sognsvannsveien, Norway. · Arthritis Rheum. · Pubmed #12522836 links to  free full text

Abstract: OBJECTIVE: Growth abnormalities and poor nutritional status have been reported in children with juvenile idiopathic arthritis (JIA). The aim of this study was to evaluate the impact of juvenile chronic rheumatic disease on current nutritional status in adult patients in remission or with active disease. METHODS: One hundred thirty-eight women and 82 men, aged >20 years, with JIA were studied after a mean disease duration of 15.5 +/- 2.3 years. Eighty-four (61%) of the women and 49 (60%) of the men were in remission. Forty-one healthy women and 54 healthy men served as a reference group. Body composition was analyzed by dual-energy x-ray absorptiometry. RESULTS: There was no difference in height or body mass index (BMI) between patients and healthy subjects. However, female patients with systemic disease had significantly reduced BMI compared with those with pauciarticular JIA (P < 0.001), and female patients who used or had been using corticosteroids had significantly lower weight, height, and BMI compared with the patients who had never used corticosteroids (P < 0.05). Female patients in remission had significantly more lean body mass compared with healthy controls (P < 0.05) and significantly less body fat was found in both women and men (P < 0.01 for both). Patients with active disease had the same amount of lean body mass as the healthy controls, but significantly less body fat (P < 0.05 for women and P < 0.01 for men). CONCLUSION: Adult patients with JIA had attained normal height, weight, and BMI, with the exception of women with systemic JIA and those who were using or had used corticosteroids. Patients with JIA in remission seemed to have a better nutritional status than healthy subjects.

Smerdel A, Lie BA, Ploski R, Koeleman BP, Førre Ø, Thorsby E, Undlien DE. · Institute of Immunology and Center for Rheumatic Diseases, Rikshospitalet University Hospital, N-0027 Oslo, Norway. · Arthritis Rheum. · Pubmed #12115193 links to  free full text

Abstract: OBJECTIVE: Juvenile idiopathic arthritis (JIA) is associated with particular alleles at 3 different HLA loci: HLA-A, HLA-DR/DQ, and HLA-DP. These associations are independent of each other (i.e., they cannot be explained by the known linkage disequilibrium between alleles at these loci). The purpose of this study was to look for additional JIA susceptibility genes in the HLA complex. METHODS: One hundred two Norwegian JIA patients and 270 healthy individuals, all carrying the DQ4;DR8 haplotype, were investigated by scanning approximately 10 megabases of DNA covering the HLA complex with microsatellite polymorphisms. An expectation-maximization algorithm was used to estimate haplotype frequencies, and the distribution of microsatellite alleles on the high-risk DQ4;DR8 haplotype was compared between patients and controls, to exclude effects secondary to linkage disequilibrium with these susceptibility genes. RESULTS: Allele 5 at the microsatellite locus D6S265 (D6S265* 5), 100 kb centromeric of HLA-A, showed a strong positive association with the disease (odds ratio 4.7, corrected P < 10(-6)). Haplotype analysis demonstrated that the D6S265*5 association was not caused by linkage disequilibrium to the gene encoding HLA-A*02, which has previously been reported to be associated with JIA. Instead, our data suggested that a gene in linkage disequilibrium with D6S265*5, but distinct from HLA-A*02, is involved in the predisposition to JIA. CONCLUSION: We found that D6S265*5 could be a marker for an additional susceptibility gene in JIA which is distinct from A*02, adding to the risk conferred by DQ4;DR8.

Flatø B, Smerdel A, Johnston V, Lien G, Dale K, Vinje O, Egeland T, Sørskaar D, Førre Ø. · Center for Rheumatic Diseases, Rikshospitalet University Hospital, Oslo, Norway. · Arthritis Rheum. · Pubmed #11953976 No free full text.

Abstract: OBJECTIVE: To assess the frequency of sacroiliitis and the radiographic and clinical outcome in juvenile idiopathic arthritis (JIA) and determine patient characteristics, early disease variables, and genetic markers that predict development of sacroiliitis. METHODS: We performed a retrospective cohort study of 314 (79%) of the 400 JIA patients first admitted to the hospital between 1980 and 1985. The participants were examined after a median disease duration of 14.9 years (range 11.7-25.1). Radiographs of the sacroiliac joints, hips, ankles, and tarsi were obtained and studied in a blinded manner by 2 radiologists. The presence of HLA-DRB1 and DPB1 alleles was determined by genotyping and that of HLA-B27 by serologic testing. Variables relating to the onset and course of the disease were obtained by chart reviews. RESULTS: Twenty (6%) of the JIA patients developed radiographic sacroiliitis according to the New York criteria. In 9 patients (45%), sacroiliitis had not been demonstrated before the followup examination. At followup, spinal flexion (lateral and anterior) was reduced in 70-75% of patients with sacroiliitis and in 30-35% of those without sacroiliitis. Compared with the JIA patients without sacroiliitis, those with sacroiliitis more frequently had inflammatory back pain, enthesitis, radiographic changes in the hips and calcanei, erosions of any peripheral joint, and uveitis. Predictors of sacroiliitis were HLA-B27, absence of DPB1*02, hip joint involvement within the first 6 months, and disease onset after age 8 years. The following factors were more common among patients in whom sacroiliitis developed than in other JIA patients: DRB1*04, male sex, family history of ankylosing spondylitis, psoriasis, inflammatory back pain, and enthesitis within the first 6 months. CONCLUSION: In the current study, radiographically evident sacroiliitis had developed in 6% of JIA patients after a median disease duration of 14.9 years. HLA-B27, absence of DPB1*02, late onset of disease, and early hip involvement were predictors of sacroiliitis.

Smerdel A, Ploski R, Flatø B, Musiej-Nowakowska E, Thorsby E, Førre Ø. · Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. · Ann Rheum Dis. · Pubmed #11874841 links to  free full text

Abstract: BACKGROUND: Juvenile idiopathic arthritis (JIA) is strongly associated with the DR8-DQ4 haplotype. The genes encoding DR8 and DQ4 are in strong linkage disequilibrium (LD) and occur together on the same HLA haplotype in almost all patients and controls. Because of the strong LD it is not clear whether DR8, DQ4, or both, are primarily associated with JIA. OBJECTIVE: To unveil the primary association of JIA--that is, with DR8 or DQ4. METHODS: DRB1, DQA1, and DQB1 alleles of 585 Norwegian and 47 Polish unrelated patients with JIA (categorised as pauciarticular and rheumatoid factor negative polyarticular JIA), and of 3155 Norwegian and 158 Polish unrelated controls, were typed using a polymerase chain reaction or oligonucleotide hybridisation and sequence-specific primers method. RESULTS: Several haplotypes which encoded DR8 (that is, carried DRB1*08) and which did not encode DQ4 (that is, did not carry DQA1*0401) were found. Such haplotypes were found in three Norwegian patients and two controls (p=0.029). In the Polish population such haplotypes were found among four patients with JIA and two controls (p=0.025). No haplotypes which carried DQA1*0401 and DQB1*0402 in the absence of DRB1*08 were found, either among patients with JIA (Polish and Norwegian) or among the controls (Polish). CONCLUSION: On the DR8-DQ4 haplotype the DRB1*08 allele is primarily associated with JIA.