Alan J. Silman

Background: The increased mortality observed in patients with rheumatoid arthritis is partly due to an increased occurrence of serious infections. A retrospective study from the Mayo Clinic found that infection risk is increased in rheumatoid arthritis. In particular, serious infection was associated with severe disease and use of corticosteroids. Robust estimates are required from prospective studies of incident cases. Objective: To examine the risk of infection leading to hospitalisation and potential factors associated with this risk in an unselected population of patients with inflammatory polyarthritis. Design: A prospective cohort study comparing infection incidence in new-onset patients with inflammatory polyarthritis with local population experience. Patients and methods: 2108 patients with inflammatory polyarthritis from a community-based register were studied and followed up annually (median 9.2 years). The rate of hospitalisations for serious infection was compared with the rate of hospitalisations in the regional population. The contribution of potential predictors was assessed by undertaking a within-cohort analysis. Results: Overall, the incidence of infection was more than two and a half times that of the general population (varying by site). History of smoking, corticosteroid use and rheumatoid factor were found to be significantly independent predictors of infection-related hospitalisation. Patients with inflammatory polyarthritis with all three factors were more than seven times as likely to be hospitalised compared with the rest of the cohort. Discussion: These findings provide background data on the risk of infection associated with rheumatoid arthritis, and are of particular interest given the current awareness of the risk of infection associated with anti-tumour necrosis factorα treatments.

Over 3500 patients with recent onset inflammatory polyarthritis (IP) have been recruited by the Norfolk Arthritis Register (NOAR) since 1990. Longitudinal data from this cohort have been used to examine the prevalence and predictors of remission, functional disability, radiological outcome, cardiovascular mortality and co-morbidity and the development of non-Hodgkin's lymphoma. Rheumatoid factor titre, high baseline C-reactive protein and high baseline HAQ score are all predictors of a poor outcome. There is a strong association between possession of the shared epitope and the development of erosions. Patients who satisfy the American College of Rheumatology criteria for rheumatoid arthritis (RA) have a worse prognosis than those who do not. However, it appears that these patients are a poorly defined subset of all those with IP rather than having an entirely separate disease entity. New statistical techniques offer exciting possibilities for using longitudinal datasets such as NOAR to explore the long-term effects of treatment in IP and RA.

There is increasing interest in attempting to understand what the risk factors are that lead to the development of rheumatoid arthritis (RA). Twin studies have proved a genetic role but also quantified the non‐genetic risk. There is thus scope for identifying environmental predictors that might offer a strategy to prevent the disease. Changes in the female hormonal environment such as in pregnancy, breastfeeding and the use of the oral contraceptive (OC) pill appear to have a role. Of the traditional lifestyle exposures, cigarette smoking has been associated with a consistently increased risk that might also apply to the passive inhalation of smoke. Occupation probably has a minor influence, although exposure to silica dust is of aetiological importance. Recent studies have highlighted a role for diet, with suggestions that diets high in caffeine, low in antioxidants and high in red meat may contribute to an increased risk. The most plausible environmental exposure is infection and although several decades of study have produced few definitive candidate organisms, Epstein–Barr virus (EBV) remains an interesting target.

The founders of the Arthritis Reseach Campaign (arc) Epidemiology Unit were Kellgren and Lawrence. Their initial work was conducted in miners and then in the general population. They pioneered standardized methods of interview, examination and X-ray evaluation. They also played a key role in the early development of classification criteria for use in epidemiological surveys. The second director, Philip Wood, focused on understanding the impact of rheumatic diseases on the individual and on society. He was largely responsible for the International Classification of Impairments Disabilities and Handicaps. In the last 30 yrs, developments in statistics, computing and genetics have enabled the basic questions of disease aetiology to be re-examined. The third director, Alan Silman, took over in 1988. The Unit now has three research divisions: Genetics and Genomics, Outcome Studies and Population Surveys.

The British Society for Rheumatology (BSR) established a nationwide register for patients with rheumatological disorders treated with biologic agents. The register is designed as a national prospective study whose primary purpose is to assess long term toxicity from the use of these agents in routine practice. In addition, the data will be capable of addressing the benefits from their use in relation to their toxicity. One specific feature of the BSR register is the recruitment and collection of data from a parallel comparison group, comprising patients with active rheumatoid arthritis treated with conventional disease modifying agents. Both class specific and drug specific analyses of the group treated with biologicals are planned.

Background: Epidemiologic studies suggest that the antioxidant potential of dietary carotenoids may protect against the oxidative damage that can result in inflammation. Objective: We investigated the hypothesis that some dietary carotenoids are associated with a reduced risk of developing inflammatory polyarthritis (IP). Design: The European Prospective Investigation of Cancer Incidence (EPIC)-Norfolk study is a population-based, prospective study of >25000 subjects who completed a baseline 7-d diet diary and were followed up to identify new cases of IP, which was defined as synovitis that affected ≥2 joint groups. Dietary carotenoid intakes were computed from the diet diaries of these subjects, and a nested, case-control analysis was undertaken to compare carotenoid intake between case subjects and age- and sex-matched control subjects. Results: Eighty-eight incident cases of IP that occurred in the population surveyed were ascertained via the Norfolk Arthritis Register. The mean daily intakes of zeaxanthin and β-cryptoxanthin were 20% and 40% lower, respectively, in the cases than in the 176 controls, but there were no significant differences in the intakes of either lutein or lycopene. Those subjects in the top one-third of intake of zeaxanthin and β-cryptoxanthin were at a lower risk of developing IP than were subjects in the lowest one-third [odds ratios (95% CI): 0.48 (0.24, 0.94) and 0.51 (0.25, 1.02) for zeaxanthin and β-cryptoxanthin, respectively]. The association with β-cryptoxanthin was significant after adjustments were made for total energy and protein intakes and for cigarette smoking. Conclusion: These data are consistent with previous evidence showing that a modest increase in β-cryptoxanthin intake, equivalent to one glass of freshly squeezed orange juice per day, is associated with a reduced risk of developing inflammatory disorders such as rheumatoid arthritis.

Objective: The American College of Rheumatology (ACR) 1987 criteria for rheumatoid arthritis (RA) can be applied in 2 formats, a standard “x/y” list and a decision tree. This study evaluated the performance of the decision tree compared with the list approach in the ascertainment of RA in subjects with new‐onset inflammatory polyarthritis (IP) over the first 5 years of observation. Moreover, the use of clinical surrogates to substitute for missing rheumatoid factor (RF) and radiologic erosion data was assessed for validity and for its influence on the resulting RA prevalence estimates.Methods: In this population‐based prospective study, 848 subjects with new‐onset IP were interviewed and examined at baseline, with followup at 1, 2, 3, and 5 years. RF and erosion status were determined at prespecified time points. The list criteria were applied cumulatively, while the decision tree was applied cross‐sectionally using either data surrogates or the actual reported data. RA prevalence in the 848 subjects and agreement in classification between the 2 methods was assessed at each time point. The influence of using clinical surrogates on RA prevalence estimates at 5 years and the agreement between surrogate and real results were also analyzed.Results: At baseline, RA prevalence was higher using the decision tree compared with the list approach (63% versus 47%; P = 0.0001); by 5 years of followup, RA estimates were approximately equal (69% versus 72%) and agreement between the approaches was good (κ = 0.67). The use of surrogates had little influence on RA prevalence at 5 years, although substitution of metacarpophalangeal joint swelling for erosion produced a higher RA prevalence estimate (78% versus 70%). Although there was only weak agreement between surrogate and real data, the use of the surrogate data provided good to very good agreement between the approaches in categorizing subjects as RA positive (κ = 0.61–0.72).Conclusion: Over 5 years, the 2 formats of the ACR criteria for RA performed similarly, with no important differences between them. The use of surrogates for missing radiologic and serologic data did not have any major influence on disease classification. Although the RA criteria were not originally derived from subjects with early disease in a population setting, this study shows that the use of the decision tree approach with the option of substituting clinical surrogates for missing laboratory data is an appropriate alternative to the conventional list approach.

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.