D. Symmons

Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti–tumor necrosis factor α therapy: Results from the British Society for Rheumatology Biologics Register

Objective Rheumatoid arthritis (RA) is associated with an increased risk of coronary artery disease, possibly acting via shared mechanisms of inflammation. This study was undertaken to test the hypothesis that the powerful antiinflammatory effect of anti–tumor necrosis α (anti-TNFα) therapy might lead to a reduction in the incidence of myocardial infarction (MI) in patients with RA. Methods Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, we compared MI rates in 8,670 patients with RA treated with anti-TNFα and 2,170 patients with active RA treated with traditional disease-modifying antirheumatic drugs (DMARDs). Results Through July 2006, 63 MIs occurred in the anti-TNFα cohort during 13,233 person-years of followup and 17 MIs occurred in the DMARD cohort during 2,893 person-years of followup, equivalent to a rate of 4.8 events per 1,000 person-years and 5.9 events per 1,000 person-years, respectively. After adjustment for baseline risk factors, there was no reduction in the rate of MI in the anti-TNFα cohort compared with the DMARD cohort (incidence rate ratio 1.44 [95% confidence interval 0.56–3.67]). In an analysis of anti-TNFα–treated patients who responded to the treatment within 6 months versus those who did not, MI rates were found to be 3.5 events per 1,000 person-years in responders and 9.4 events per 1,000 person-years in nonresponders. The adjusted incidence rate ratio (95% confidence interval) for responders compared with nonresponders was 0.36 (0.19–0.69). Conclusion These results indicate that RA patients treated with anti-TNFα do not have a lower incidence of MI compared with RA patients treated with traditional DMARDs. However, the risk of MI is markedly reduced in those who respond to anti-TNFα therapy by 6 months compared with nonresponders. This finding supports the notion that inflammation plays a pivotal role in MI.

Serious Infection Following Anti–Tumor Necrosis Factor α Therapy in Patients With Rheumatoid Arthritis: Lessons From Interpreting Data From Observational Studies

Objective In a recent observational study, we found that the risk of serious infection following anti–tumor necrosis factor α (anti-TNFα) therapy in patients with rheumatoid arthritis (RA) was not importantly increased compared with the background risk in routinely treated RA patients with similar disease severity. Observational data sets are, however, subject to a number of important biases related to selection factors for the timing of starting and stopping therapy. Infection risk is also likely to vary with duration of therapy. This study was undertaken to examine the influences of these biases and of the method of analysis on the risk of infection. Methods We compared the risk of serious infection in 8,659 patients treated with anti-TNFα with that in 2,170 patients treated with traditional disease-modifying antirheumatic drugs (DMARDs) recruited to the British Society for Rheumatology Biologics Register. We applied a number of statistical models in which we varied the length of the followup period by using different definitions of the date of discontinuation of treatment and different lag periods of risk following drug cessation. Results When the at-risk period was defined as “receiving treatment”, the adjusted incidence rate ratio comparing patients receiving anti-TNFα therapy with patients receiving DMARD therapy was 1.22 (95% confidence interval [95% CI] 0.88–1.69). Limiting followup to the first 90 days, however, revealed an adjusted incidence rate ratio of 4.6 (95% CI 1.8–11.9). Rates of infection were increased in the 90 days immediately following drug discontinuation and beyond, explained by selection factors for drug discontinuation. Conclusion These findings show that overall, the way in which UK rheumatologists select patients for starting and discontinuing anti-TNFα therapy explains our previous finding of no increase in risk. However, there may be important increases in true risk, notably early in the course of treatment, that would become more evident depending on the definition of at-risk period.

Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register

Objectives To evaluate the risk of septic arthritis (SA) in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. Methods Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, the authors compared the risk of SA between 11 881 anti-TNF-treated and 3673 non-biological disease-modifying antirheumatic drug (nbDMARD)-treated patients. Results 199 patients had at least one episode of SA (anti-TNF: 179, nbDMARD: 20). Incidence rates were: anti-TNF 4.2/1000 patient years (pyrs) follow-up (95% CI 3.6 to 4.8), nbDMARD 1.8/1000 pyrs (95% CI 1.1 to 2.7). The adjusted HR for SA in the anti-TNF cohort was 2.3 (95% CI 1.2 to 4.4). The risk did not differ significantly between the three agents: adalimumab, etanercept and infliximab. The risk was highest in the early months of therapy. The patterns of reported organisms differed in the anti-TNF cohort. Prior joint replacement surgery was a risk factor for SA in all patients. The rate of postoperative joint infection (within 90 days of surgery) was 0.7%. This risk was not significantly influenced by anti-TNF therapy. Conclusions Anti-TNF therapy use in RA is associated with a doubling in the risk of SA. Physicians and surgeons assessing the RA patient should be aware of this potentially life-threatening complication.

European biologicals registers: methodology, selected results and perspectives.

With the licensing of the first tumour necrosis factor (TNF)α inhibitors, independent academia-initiated but industry-sponsored drug registers were set up by the national rheumatology societies in several European countries in order to monitor the long-term safety and effectiveness of this new generation of drugs. Even though different in some respects of study design and monitoring, the registers share a number of common features: they include all licensed biological agents, they observe the patients for a defined period of time or indefinitely irrespective of the drug given and they use comparator cohorts or national registers in order to put the results into perspective. The registers have been collaborating closely since inception. Three of them (the British, Swedish and German registers) have agreed on a standardised reporting system of adverse events which ensures a high and uniform quality of data submitted to the companies, who subsequently report to the drug regulatory authorities, enabling regulatory requirements on safety surveillance to be fulfilled. In the present work, major results on drug safety with regard to infections, malignancies, cardiovascular events, pregnancy outcomes and deaths are summarised. With an increasing number of new drugs and multiple exposures of individual patients the assignment of events to specific treatments will become exceedingly difficult. This and other methodological challenges and the approaches to cope with them are discussed. A growing dialogue between drug regulatory authorities, academic medicine and companies in order to make best use of the potentials of academia-driven drug registers as new tools for pharmacovigilance with currently described rheumatology registers as prototypes is anticipated.

The performance of anti–cyclic citrullinated peptide antibodies in predicting the severity of radiologic damage in inflammatory polyarthritis: Results from the Norfolk Arthritis Register

Objective Anti–cyclic citrullinated peptide (anti-CCP) antibodies are a stronger predictor of the severity of rheumatoid arthritis than is rheumatoid factor (RF). Their role in predicting outcome in unselected patients with new-onset inflammatory polyarthritis (IP) has not been examined. The aims of this study were to examine the role of baseline RF and anti-CCP antibodies in determining the likelihood of patients having erosions at presentation or in predicting future radiologic damage, and to determine whether anti-CCP antibodies or RF is sufficiently robust to be clinically useful in guiding treatment decisions in early IP. Methods Patients were recruited from the Norfolk Arthritis Register. Logistic regression models were fitted to test the ability of anti-CCP antibodies and RF to predict erosions. Further models were investigated to examine the role of anti-CCP antibodies in patients stratified by RF status. Results The presence of anti-CCP antibodies at baseline was strongly associated with both prevalent erosions (odds ratio [OR] 2.53 [95% confidence interval (95% CI) 1.48–4.30]) and developing erosions at 5 years (OR 10.2 [95% CI 6.2–16.9]). These ORs were higher than those for RF (OR 1.63 [95% CI 0.94–2.82] and OR 3.4 [95% CI 2.2–5.2], respectively). The likelihood ratio (LR) for the prediction of prevalent erosions and erosions at 5 years was highest in the RF−subgroup (LR 2.2 and 5.8, respectively). However, 27% of anti-CCP−patients had developed erosions by 5 years. Conclusion Despite their strong association with the presence, development, and extent of erosions, anti-CCP antibodies alone are not a sufficiently accurate measure upon which to base clinical treatment decisions. Knowledge of anti-CCP antibody status is most informative in RF−negative patients.

Musculoskeletal pain is more generalised among people from ethnic minorities than among white people in Greater Manchester

Objective: To assess the prevalence of musculoskeletal symptoms among the major ethnic minority populations of Greater Manchester. Method: The study group was a community sample of 2117 adults from the Indian, Pakistani, Bangladeshi, and African Caribbean communities. Questionnaires administered by post and by an interviewer were used to assess the presence of any musculoskeletal pain, pain in specific joints, and the level of physical function. Ethnicity was self assigned. The results were compared with those from a recent study in the local white population using the same methodology. Results: Overall response rate was 75% among the south Asian (Indian, Pakistani, and Bangladeshi community and 47% among the African Caribbean community. The profile of musculoskeletal pain among the ethnic minority groups differed from that in the white population. Although musculoskeletal symptoms were slightly more prevalent among people from ethnic minority groups than among the white population, pain in multiple sites was considerably more common among ethnic minorities. Conclusions: The finding that musculoskeletal pain is more widespread among ethnic minority communities in the UK has not previously been reported. This may reflect social, cultural, and psychological differences. The cause of the differences in the profile of pain and the health needs that follow need further investigation.

Time to first occurrence of erosions in inflammatory polyarthritis: Results from a prospective community‐based study

OBJECTIVE To examine the time of occurrence of first radiographic erosions in a cohort of patients with inflammatory polyarthritis. METHODS Patients were recruited through the Norfolk Arthritis Register, which follows up patients annually. Patients with features of rheumatoid arthritis (other than erosions) sufficient, together with erosions, to meet the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 revised criteria were requested to undergo radiographic examinations of the hands and feet at the first and/or second annual followup visits. All patients were requested to undergo radiographic examinations at the fifth annual followup visit. The most recent erosion-free radiograph was identified for 416 eligible patients, and these data were used to derive the duration of disease since the recalled date of onset of first symptoms. The rate of occurrence of first erosions was then determined (as a cumulative prevalence and as an incidence rate using Poisson regression) from analysis of followup films. Patients were assumed to be free of erosions at symptom onset. RESULTS The cumulative prevalence of erosions in patients whose first film was obtained 12-24 months after disease onset was 36%, equivalent to an incidence rate of 24.5/1,000 patient-months. We identified 3 analysis groups of patients who were free of erosions based on films obtained 12-24 months, 24-36 months, and 36-60 months since the recalled date of onset of first symptoms. New erosions were observed in all 3 groups, with cumulative prevalences of 23%, 28%, and 47%, respectively. These were equivalent to first-erosion incidence rates/1,000 patient-months of 5.4 (95% confidence interval [95% CI] 3.8-83), 6.8 (95% CI 4.7-10.0), and 13.0 (95% CI 8.9-19.2), respectively. CONCLUSION Many patients with erosive disease first develop their erosions >2 years from disease onset.

Benchmarking: the five year outcome of rheumatoid arthritis assessed using a pain score, the Health Assessment Questionnaire, and the Short Form-36 (SF-36) in a community and a clinic based sample

BACKGROUND Treatment, and therefore outcome, of rheumatoid arthritis (RA) will improve in the next few years. However, improvement in outcome can only be judged against the probability of certain outcomes with current conventional treatment. AIM To document the five year outcome of RA in the late 1990s. SETTING Norfolk Arthritis Register (NOAR). DESIGN Longitudinal observational cohort study. METHODS 318 patients with recent onset inflammatory polyarthritis recruited by NOAR in 1990–91 completed five years of follow up. Four groups were assessed: the whole cohort, all those referred to hospital, those who satisfied criteria for RA at baseline, and those referred to hospital who satisfied criteria for RA at baseline. Outcome was assessed with a visual analogue scale for pain, the Health Assessment Questionnaire (HAQ), and the Short Form-36 (SF-36). RESULTS Of the RA hospital attenders, 50% had a visual analogue scale pain score of 5 cm or less and an HAQ score of 1.125 or less. SF-36 scores were reduced in all domains. Results are presented as cumulative percentages. CONCLUSIONS These results can be used for comparison and to set targets for improvement.

Occurrence of rheumatoid arthritis is not increased in the first degree relatives of a population based inception cohort of inflammatory polyarthritis.

OBJECTIVE: To determine the risk of rheumatoid arthritis (RA) in first degree relatives of a true population based sample of probands with inflammatory polyarthritis. METHODS: In a case-control study, a two stage screening procedure was used to ascertain the prevalence of RA in 518 first degree relatives of 207 Norfolk Arthritis Register cases registered in 1990 and 414 first degree relatives of 180 local controls. An initial joint symptom and medical history questionnaire was followed by a physical examination, and serological and radiological evaluation of those with symptoms. RESULTS: The prevalence of RA in the first degree relatives of all the Norfolk Arthritis Register cases was 7.7/1000, compared with 4.8/1000 in the first degree relatives of the controls, with a risk ratio of 1.6 (95% confidence interval 0.3 to 8.7). This very modest increase was also seen when the analysis was restricted to the first degree relatives of Norfolk Arthritis Register cases who satisfied the American Rheumatism Association criteria for RA: prevalence rate 7.2/1000. CONCLUSION: There was no evidence of an important increased familial risk of RA in this community based sample. These data are compatible with others from immunogenetic studies showing only weak HLA associations with community ascertained RA.

The PTPN22*C1858T functional polymorphism is associated with susceptibility to inflammatory polyarthritis but neither this nor other variants spanning the gene is associated with disease outcome

Background: The PTPN22 gene has been widely confirmed as a susceptibility gene for rheumatoid arthritis (RA) in populations of Northern European descent. The aim of the current study was to explore the role of variants spanning the PTPN22 gene in determining susceptibility to and outcome of inflammatory polyarthritis (IP). Patients and methods: Single nucleotide polymorphism (SNP) variants spanning the gene were genotyped using the Sequenom MassArray platform and tested, firstly for their association with susceptibility to IP. Genotype frequencies were compared between new onset IP cases (n = 843) and population controls (n = 471). Secondly, a within-cohort analysis was performed testing each variant for association with a number of clinical outcome measures reflecting disease severity including radiological erosions, physical function, measured using the Health Assessment Questionnaire (HAQ) score, and disease activity at defined time-points following disease presentation. Results: A significant association between carriage of the PTPN22*1858T allele and IP (odds ratio (OR) = 1.4 (95% CI 1.1–1.9), p = 0.02) was observed. The strength of the effect was similar in the RA subgroup (OR = 1.4 (95% CI 1.0–1.9), p = 0.05). No association between IP susceptibility and any of the other SNPs was detected. No association was detected for any of the SNPs tested, including the PTPN22*C1858T polymorphism, for either erosive status, Larsen score by 5 years or other markers of clinical outcome. Conclusion: The PTPN22*C1858T polymorphism is associated with susceptibility to IP, but we have found no evidence for association of this or other variants spanning the gene with clinical outcome measures.