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Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. 70DERAA74, D70 and I67 protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1*0401∼*0404>*0101∼*1001 (*0404>*0101: P=0.0003). HLA-DRB1*0401/*0404 compound heterozygosity conferred a risk similar to *0401 homozygosity (P=0.70). Protective effects of D70 and I67 were similar. Predictions of the D70 model fitted the data better than those of the I67 model. The protective effect of D70 showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P=5.8 × 10−4), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P=0.0012). In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D70 specifically protected against antibody-positive RA. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Inflammatory Bowel Disease (which includes Crohn''s Disease and Ulcerative Colitis), is a chronic condition characterised by substantial morbidity. Inflammatory Bowel Disease patients are considered expensive to manage, hence accurate estimates of care costs are crucial to help healthcare providers plan clinical management. The aim of this study is to estimate the cost of care for Crohn''s Disease and Ulcerative Colitis patients in the United Kingdom and Western mainland Europe. Methods: Decision models were built to simulate the natural disease history of Crohn''s Disease and Ulcerative Colitis, informed by United Kingdom and European clinical pathways. A healthcare provider perspective was adopted, model inputs were informed by published sources and expert opinion, and UK healthcare costs were used (2008 prices). Cohorts of 25year old patients presenting with symptoms of varying severity were modelled over ten years, and annual treatment costs calculated per patient. Results: The average annual cost of care per Crohn''s Disease/Ulcerative Colitis patient was £631/£762 (United Kingdom) and £838/£796 (Europe). Most costs were incurred immediately following diagnosis, particularly in European Crohn''s patients, reflecting the earlier use of more aggressive treatments. Surgery, hospitalisation, and the use of biological therapies and mesalazine (in Ulcerative Colitis) were key cost drivers. The total annual cost to the United Kingdom National Health Service of caring for Inflammatory Bowel Disease patients was estimated to be £131million. Conclusions: This study confirms that Inflammatory Bowel Disease patients are expensive to manage and illustrates the importance of differentiating between alternative clinical management scenarios. [Copyright &y& Elsevier]

Objective: To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA)., Methods: Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework., Results: The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P < 0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P < 0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001)., Conclusion: PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.

Introduction: IL-10 is an immunoregulatory cytokine which may modulate disease expression in rheumatoid arthritis (RA). The IL-10 gene is highly polymorphic with a number of single nucleotide polymorphisms in the promoter region and two microsatellite loci, IL10.R and IL10.G, 4 kb and 1.1 kb 5' of the transcription initiation site. It has been reported that allele 2 of the IL10.R microsatellite (IL10.R2) is associated with increased IL-10 secretion and IL10.R3 with reduced secretion. Subsequently, over-representation of IL10.R2 and under-representation of IL10.R3 in three independent RA groups has been reported. The aim of the current study is to determine whether there is an association between the IL10.R2 allele and RA in two ethnically distinct populations., Methods: IL10.R genotypes were determined by semi-automated DNA sequencing technology in 186 UK Caucasians and 138 South Africans of Zulu or Sotho origin, fulfilling the 1987 American College of Rheumatology (ACR) criteria for RA. The Caucasian patients had relatively severe disease and comprised 75 patients with RA vasculitis, 22 with Felty's syndrome and 89 who had undergone a joint replacement (hip or knee) within 15 years of the onset of disease. Allele frequencies were compared with 296 Caucasians and/or 73 South Africans., Results: The frequency of the IL10.R2 allele was significantly greater in the South Africans (RA and controls) than in the Caucasians (0.78 vs 0.66, P=1 x 10(-6)), while the frequency of IL10.R3 was less common (0.16 vs 0.3, P=1 x 10(-8)). No differences were observed in either IL10.R2 or IL10.R3 frequencies between patients and controls in either population., Conclusions: We were unable to confirm any association between IL10.R alleles and RA in this study. However, significant differences were demonstrated in the frequency of IL10.R2 and IL10.R3 between the two ethnic groups. The relatively high frequency of IL10.R2 in the South African population (0.78) would have reduced the power to detect an association with RA.

Objective: To test for association of T cell receptor (TCR) V alpha polymorphisms and rheumatoid arthritis (RA) in British and Swiss white populations., Methods: TCRAV polymorphisms were analysed in RA patients and controls by single strand conformational polymorphism (SSCP) analysis. Associations were sought between defined genotypes and RA, and the effect of HLA-DR4 status analysed. Putative associations were then retested further in new groups of patients and controls. Overall, 360 RA patients and 197 controls were studied., Results: No association between TCRAV5S1, V6S1, V8S1, V17S1 or V21S1 polymorphisms and RA were observed in the initial population screened. Stratification for DR4 status showed an increase of V5S1*01/*01 in DR4 positive versus DR4 negative patients (chi 2 = 7.19, p = 0.028 (2df), p = 0.14 after correction for multiple comparisons). This putative association was tested in three further patient groups, none of which showed significant increase of V5S1*01/*01 in DR4 positive patients, although an overall trend towards an increase in V5S1*01/*01 was observed., Conclusion: No evidence was found for a strong association of TCRAV genes and RA in a white population. However, these results suggest a weak association of V5S1*01/*01 with DR4 positive RA, although this requires confirmation using larger groups of patients and controls.