Rheumatoid Arthritis: Barrett JH

Morgan AW, Haroon-Rashid L, Martin SG, Gooi HC, Worthington J, Thomson W, Barrett JH, Emery P. · University of Leeds, Leeds, UK. · Arthritis Rheum. · Pubmed #18438843 links to  free full text

Abstract: OBJECTIVE: Many classification systems for the HLA-DRB1 allelic association with rheumatoid arthritis (RA) have been reported, but few have been validated in additional populations. We sought to evaluate 3 different DRB1 allele classification systems in a large cohort of Caucasian RA patients and control subjects in the UK. METHODS: HLA-DRB1 typing was undertaken in 1,325 Caucasian RA patients and 462 healthy Caucasian controls who were residents of the UK. Logistic regression analyses were performed to investigate the different classification systems. RESULTS: We confirmed the association between the susceptibility alleles S2 and S3P, as proposed by Tezenas du Montcel, and the presence of RA in UK Caucasians. A significant hierarchy of risk was observed within the S3P allele group. There was no evidence of a significant association between DRB1*1001 and RA. Our data did not support the hypothesis that an isoleucine at position 67 conferred protection against RA, other than in contrast to the susceptibility alleles. However, the presence of an aspartic acid at amino acid 70 did appear to confer some degree of protection. CONCLUSION: We were unable to fully substantiate any of the 3 recent revisions of the shared epitope hypothesis in this large cohort of Caucasian RA patients and control subjects in the UK. This reinforces the importance of evaluating disease susceptibility alleles in different Caucasian populations as well as in other ethnic groups. In particular, it will be important to clarify the precise DRB1 association in a given population before DRB1 genotyping is incorporated into clinical diagnostic or treatment algorithms.

Morgan AW, Barrett JH, Griffiths B, Subramanian D, Robinson JI, Keyte VH, Ali M, Jones EA, Old RW, Ponchel F, Boylston AW, Situnayake RD, Markham AF, Emery P, Isaacs JD. · Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. · Arthritis Res Ther. · Pubmed #16356189 links to  free full text

Abstract: The Fcgamma receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A-FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13-8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44-17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.

Morgan AW, Keyte VH, Babbage SJ, Robinson JI, Ponchel F, Barrett JH, Bhakta BB, Bingham SJ, Buch MH, Conaghan PG, Gough A, Green M, Lawson CA, Pease CT, Markham AF, Ollier WE, Emery P, Worthington J, Isaacs JD. · Rheumatology and Rehabilitation Research Unit, University of Leeds, UK. · Rheumatology (Oxford). · Pubmed #12649399 links to  free full text

Abstract: OBJECTIVES: To develop a robust assay for genotyping the FcgammaRIIIA-158V/F polymorphism and to confirm the putative association between the FcgammaRIIIA-158V allele and rheumatoid arthritis (RA). METHODS: This allelic association study examined the FcgammaRIIIA-158V/F polymorphism for association with RA. A novel single-stranded conformational polymorphism assay was used to genotype 828 RA patients and 581 controls from the UK. RESULTS: The FcgammaRIIIA-158V allele was associated with both RA (P=0.02) and nodules (P=0.04). Individuals homozygous for this higher affinity allele had a significantly increased risk of RA (OR 1.53, 95% CI 1.08-2.18) and the development of nodules (OR 2.20, 95% CI 1.20-4.01). There was no evidence of an interaction with the shared epitope. CONCLUSIONS: We have developed a novel assay to genotype the FcgammaRIIIA-158F/V polymorphism and confirmed that homozygosity for the FcgammaRIIIA-158V allele is associated with UK Caucasian RA, particularly in those individuals with nodules, suggesting FcgammaRIIIA may play a role in determining disease severity or in the development of nodules per se.

Thomson W, Barrett JH, Donn R, Pepper L, Kennedy LJ, Ollier WE, Silman AJ, Woo P, Southwood T, Anonymous00181. · Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. · Rheumatology (Oxford). · Pubmed #12364641 links to  free full text

Abstract: OBJECTIVE: To determine the HLA associations with juvenile idiopathic arthritis (JIA) and its subgroups as defined by the International League of Associations for Rheumatology (ILAR) classification criteria. METHODS: Five hundred and twenty-one UK Caucasian JIA patients and 537 UK Caucasian controls were typed for HLA class II alleles. Phenotype and haplotype frequencies were compared between all JIA cases and controls and between the seven ILAR-defined JIA subgroups. RESULTS: Three haplotypes (DRB1*08-DQA1*0401-DQB1*0402; DRB1*11-DQA1*05-DQB1*03; DRB1*1301-DQA1*01-DQB1*06) were associated with increased risk and one (DRB1*04-DQA1*03-DQB1*03) with decreased risk of JIA. However, in each case the frequencies also varied between JIA subgroups. CONCLUSION: This study categorically demonstrates that there are multiple HLA class II associations with JIA. It has also, for the first time, defined these associations in the seven different ILAR subgroups in UK JIA cases. Although there are a number of common associations, each ILAR subgroup exhibits different patterns of HLA associations, suggesting that the ILAR classification system does define genetically distinct groups of patients.

Donn RP, Barrett JH, Farhan A, Stopford A, Pepper L, Shelley E, Davies N, Ollier WE, Thomson W. · Arthritis Research Campaign Epidemiology Unit, Manchester, UK. · Arthritis Rheum. · Pubmed #11315919 links to  free full text

Abstract: OBJECTIVE: To investigate the involvement of candidate cytokine genes in the pathogenesis of juvenile idiopathic arthritis (JIA). METHODS: Single nucleotide polymorphisms and intragenic microsatellite markers within 8 candidate cytokine genes (interleukin-1alpha [IL-1alpha], IL-2, IL-4, IL-6, IL-10, interferon-alpha1 [IFNA1], interferon-gamma [IFNG], and interferon regulatory factor 1 [IRF-1]) were investigated in 417 Caucasian patients with clinically characterized JIA and a panel of 276 unrelated, healthy Caucasian controls, all from the United Kingdom. RESULTS: A novel 3'-untranslated region (3'UTR) polymorphism in IRF-1 was found to be associated with susceptibility to JIA (corrected P = 0.002). No significant association with IL-1alpha, IL-2, IL-4, IL-6, IL-10, IFNA1, or IFNG was observed. CONCLUSION: An association between JIA and a previously unreported 3'UTR polymorphism of IRF-1 was observed. This association was not found to be specific to any particular JIA subgroup. This suggests that IRF-1 may contribute to a common pathogenesis shared by all JIA patients, regardless of clinical phenotype. This is most likely to be a genetic contribution to the chronic inflammatory process that underlies JIA pathology.

Bowden AP, Barrett JH, Fallow W, Silman AJ. · Arthritis Research Campaign Epidemiology Unit, University of Manchester, UK. · J Rheumatol. · Pubmed #11246676 No free full text.

Abstract: OBJECTIVE: To assess the effect on fetal outcome, and development of the child over the first 8 months of life, of rheumatoid arthritis (RA) during pregnancy. METHODS: Women with RA or undifferentiated inflammatory polyarthritis (IP) were recruited from throughout the UK and followed prospectively from late pregnancy to 8 months postpartum. Matched controls were obtained from general practitioners. The babies' health at birth and development at 8 months were monitored by the weight, head circumference, and length. Potential confounding variables were noted. RESULTS: One hundred thirty-three women with RA or undifferentiated IP took part in the study. There were 5 (4%) admissions for hypertension during pregnancy and no cases of preeclampsia. Cesarean section was common (23%). Matched controls were found for 103 (77%) subjects. There were no significant differences between groups in head circumference or length at birth. Babies born to women with arthritis had lower mean birth weight than controls [3.3 kg (standard deviation 0.5) compared to 3.5 kg (0.4); p = 0.004], even after adjustment for potential confounding factors. Within the patient group those whose arthritis was in remission had significantly heavier babies than those with active disease [mean 3.5 kg (0.5) compared with 3.3 kg (0.5); p = 0.04]. This trend was still apparent at 8 months, but differences were no longer statistically significant. CONCLUSION: This is the first relatively large prospective study of the effects on mother and baby of RA during pregnancy. The results suggest that, although disease improves in most women during pregnancy, it is still sufficiently active to have a modest negative effect on birth weight.

Myerscough A, John S, Barrett JH, Ollier WE, Worthington J. · University of Manchester, UK. · Arthritis Rheum. · Pubmed #11145035 links to  free full text

Abstract: OBJECTIVE: To seek potential autoimmune disease susceptibility loci by testing for linkage and linkage disequilibrium between insulin-dependent diabetes mellitus (IDDM) susceptibility loci and rheumatoid arthritis (RA). METHODS: Five IDDM susceptibility loci map to 2 chromosomal regions, chromosome 2q31-34 (IDDM7, 12, and 13) and chromosome 6q25-27 (IDDM5 and 8). Microsatellite markers within these regions were genotyped in 255 RA families, by fluorescence-based genotyping technology. Evidence for linkage disequilibrium was assessed using the extended transmission disequilibrium test (ETDT) program. RESULTS: With the ETDT, we found evidence for linkage disequilibrium of the marker D6S446, at IDDM8, with RA (P < 0.0001). There was additional evidence for linkage disequilibrium with 2 markers at IDDMS (D6S311 and D6S440) (P = 0.016 and P = 0.017, respectively). There was no evidence for significant linkage disequilibrium of RA with any markers at IDDM7, 12, or 13. CONCLUSION: These results support the hypothesis that there are autoimmune disease genes at IDDM5 and IDDM8.

Thomas E, Barrett JH, Donn RP, Thomson W, Southwood TR. · ARC Epidemiology Unit, University of Manchester, UK. · Arthritis Rheum. · Pubmed #10902751 links to  free full text

Abstract: OBJECTIVE: To use statistical techniques to identify underlying subtypes of juvenile idiopathic arthritis (JIA) that best explain the observed relationships of clinical and laboratory variables, and to compare the statistically derived subtypes with those defined by the International League of Associations for Rheumatology (ILAR) criteria and examine them for HLA associations. METHODS: Information on 572 patients diagnosed as having JIA was summarized by 10 clinical and laboratory categorical variables (age at onset, large joint involvement, small joint involvement, polyarthritis, symmetric arthritis, spinal pain, fever, psoriasis, antinuclear antibodies [ANA], and rheumatoid factor). Latent class analysis (LCA) was used to identify underlying ("latent") classes that explained the relationships among the observed variables. Statistical models incorporating 5-8 latent classes were applied to the data. RESULTS: The 7-class model was the most appropriate. Patterns of joint involvement and the presence of ANA were influential in determining latent classes. There was some correspondence between the latent classes and the ILAR categories, but they did not coincide completely. Significant differences between the latent classes were seen for 3 HLA haplotypes (DRB1*04-DQA1*03-DQB1*03, DRB1*13-DQA1*01-DQB1*06, and DRB1*08-DQA1*0401-DQB1*0402). CONCLUSION: LCA provides a novel approach to the task of identifying homogeneous subtypes within the umbrella of JIA. In further work, the identified latent classes will be examined for associations with other candidate genes and for differences in outcome.

Barrett JH, Brennan P, Fiddler M, Silman A. · University of Manchester, UK. · Arthritis Rheum. · Pubmed #10817553 links to  free full text

Abstract: OBJECTIVE: To test the hypothesis that breast-feeding increases the risk of postpartum flare in inflammatory polyarthritis. METHODS: We compared disease activity during pregnancy and at 6 months postpartum among 49 non-breast-feeders, 38 first-time breast-feeders, and 50 repeat breast-feeders. RESULTS: After we adjusted for possible confounders, including treatment, first-time breast-feeders had increased disease activity 6 months postpartum, based on self-reported symptoms, joint counts, and C-reactive protein levels. CONCLUSION: Postpartum flare may be induced by breast-feeding.

Wiles N, Symmons DP, Harrison B, Barrett E, Barrett JH, Scott DG, Silman AJ. · University of Manchester Medical School, UK. · Arthritis Rheum. · Pubmed #10403260 links to  free full text

Abstract: OBJECTIVE: To examine the effect of delay between symptom onset and notification to an arthritis register and the effect of application of the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 criteria in a cumulative manner on estimates of the incidence of rheumatoid arthritis (RA). METHODS: General practitioners and/or hospital consultants in the Norwich Health Authority, Norfolk, UK, notified the Norfolk Arthritis Register (NOAR) of all patients who had onset of inflammatory polyarthritis (swelling of > or =2 joints) during 1990. The patients were assessed within 2 weeks of notification and annually thereafter. The ACR 1987 criteria for RA were applied at each assessment. Age- and sex-specific incidence rates were calculated. RESULTS: If up to 12 months elapsed from symptom onset to notification to NOAR and the ACR criteria were applied at the baseline assessment, RA incidence estimates, age-adjusted to the population of England and Wales, were 30.8/100,000 for women and 12.7/100,000 for men. If up to 5 years elapsed from symptom onset to notification, these estimates rose by 45% for women and 36% for men. If up to 5 years elapsed between symptom onset and notification and the criteria were applied cumulatively, the estimates rose by 75% and 93% for women and men, respectively, compared with the 1-year data, reaching 54.0/100,000 for women and 24.5 per 100,000 for men. CONCLUSION: Accurate estimation of the incidence of RA requires long-term followup of patients who present with undifferentiated inflammatory polyarthritis. The highest age-adjusted estimates from this study are probably the best that are available.

Barrett JH, Brennan P, Fiddler M, Silman AJ. · Arthritis Research Campaign Epidemiology Unit, University of Manchester, UK. · Arthritis Rheum. · Pubmed #10366115 links to  free full text

Abstract: OBJECTIVE: To ascertain the influence of pregnancy on disease activity in women with rheumatoid arthritis (RA) during pregnancy and postpartum. METHODS: One hundred forty pregnant women were recruited from a nationwide campaign and were followed prospectively in the last trimester and at 1 and 6 months postpartum. Standardized assessment of joint symptoms, examination of inflamed joints, and the Health Assessment Questionnaire (HAQ) were the main measures of disease activity. RESULTS: There was only a modest fall in HAQ scores during pregnancy, with >25% of women having substantial levels of disability. Other parameters of disease activity showed a greater trend toward improvement, although only 23 (16%) were in complete remission (no joints with active disease and no therapy). Similarly, there was relatively little change in the distribution of HAQ scores from pregnancy to postpartum. There was, however, a statistically significant increase in the mean number of inflamed joints compared with the findings during pregnancy. Analysis of the possible influence of treatment suggested that therapy was associated with more severe disease and was not related to reduction in disease activity. CONCLUSION: This, the largest prospective study of the influence of pregnancy on RA activity, has demonstrated widespread variability in disease response.

Donn RP, Farhan AJ, Barrett JH, Thomson W, Worthington J, Ollier WE. · ARC/ERU, Manchester, UK. · Rheumatology (Oxford). · Pubmed #10342632 links to  free full text

Abstract: OBJECTIVE: To determine whether interleukin 1 alpha (IL-1alpha) polymorphisms are associated with UK oligoarticular juvenile chronic arthritis (JCA). PATIENTS AND CONTROLS: A well-characterized population of 164 UK Caucasian oligo-JCA patients and a control panel of 173 unrelated healthy UK Caucasian individuals. METHODS: The IL-1alpha promoter mutation at -889 was examined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The cases and controls were also genotyped for an IL-1alpha intronic microsatellite repeat. RESULTS: No association was observed between IL-1alpha polymorphisms and UK oligoarticular JCA patients. In particular, no association between IL-1alpha polymorphisms and chronic anterior uveitis was found. CONCLUSIONS: IL-1alpha is not associated with oligoarticular JCA in UK patients. This differs markedly to findings for IL-1alpha in Norwegian JCA patients.