Mark Lunt

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.

Prevalence and predictors of intense, chronic, and disabling neck and back pain in the UK general population.

Study Design. Multiphase cross-sectional survey of musculoskeletal pain. Objectives. To estimate the prevalence of all reported and clinically significant spinal pain. To identify independent predictors of spinal pain. Methods. A total of 5752 adults sampled from three general practice registers were mailed a screening questionnaire. Subjects who reported the spine as a predominant site of pain were sent a site-specific questionnaire (i.e., back or neck) that asked about severity. Prevalence estimates were calculated and extrapolated to the general population. Predictors of spinal pain were identified using logistic regression with comprehensive adjustment for confounders (including pain at other anatomic sites). Results. The 1-month–period prevalence of all reported spinal pain was 29% (95% confidence interval 27–31%), of which about half was intense, half was chronic, 40% was disabling, and 20% was intense, disabling, and chronic. Most people with back (75%) or neck (89%) pain also reported pain at other sites. Age, female gender (neck pain only), high body mass index, living in an area of raised material deprivation, and south Asian ethnicity were significant predictors of spinal pain with disability. The association between body mass index and deprivation and neck pain was lost after adjustment for pain at other sites. However, even after full adjustment, obesity (OR, 1.7; 95% confidence interval, 1.1–2.5) and high deprivation (OR, 1.7; 95% confidence interval, 1.1–2.7) were predictors of back pain with disability. Conclusions. Adjustment for pain at other sites enabled assessment of whether observed associations were with spinal pain itself or with the other sites of pain. Obesity is an important independent predictor of back pain and its severity. This has implications for primary prevention. The prevalence of spinal pain with disability continues to rise into old age. This has implications for healthcare planning.

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.

Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s

Background: There is increased cardiovascular disease mortality in rheumatoid arthritis. This may reflect an increased prevalence of cardiovascular disease or an increased case fatality in patients with rheumatoid arthritis. Objectives: To examine whether rheumatoid patients with disease onset in the 1980s–1990s have increased mortality, and to compare cardiovascular admission rates in rheumatoid patients with those of the general population. Methods: An inception cohort of 1010 rheumatoid patients attending Stockport rheumatology clinics between 1981 and 1996 was followed up to December 2002 through the Office for National Statistics. Standardised mortality ratios (SMR) were calculated for all-cause and cause specific mortality, using the population of Stockport as reference. Cardiovascular disease admission rates were ascertained for a subgroup of patients using national hospital episode statistics; standardised cardiovascular disease admission rates (SAR) and SMRs were calculated for this subgroup. Results: 470 patients (48%) died during a median follow up of 11.4 years. All-cause mortality was increased in men (SMR = 1.45 (95% confidence interval, 1.22 to 1.71)) and women (SMR = 1.84 (1.64 to 2.05)), as was cardiovascular disease mortality in men (SMR = 1.36 (1.04 to 1.75) and women (SMR = 1.93 (1.65 to 2.26)). No difference in cardiovascular disease admission rates was observed in men (SAR 1.20 (0.89 to 1.58) or women (SAR = 1.10 (0.88 to 1.36)), despite excess cardiovascular disease mortality in this subgroup. Conclusions: Patients with rheumatoid arthritis have reduced life expectancy and excess cardiovascular disease mortality. Nevertheless, standardised admission rates for cardiovascular disease were not raised. This suggests either that cardiovascular disease in rheumatoid arthritis has a higher case fatality than in the general population or that it often goes unrecognised before the fatal event.

Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS)

Abstract The aim of this analysis was to determine the influence of lifestyle, anthropometric and reproductive factors on the subsequent risk of incident vertebral fracture in men and women aged 50–79 years. Subjects were recruited from population registers from 28 centers across Europe. At baseline, they completed an interviewer-administered questionnaire and had lateral thoraco-lumbar spine radiographs performed. Repeat spinal radiographs were performed a mean of 3.8 years later. Incident vertebral fractures were defined morphometrically and also qualitatively by an experienced radiologist. Poisson regression was used to determine the influence of the baseline risk factor variables on the occurrence of incident vertebral fracture. A total of 3173 men (mean age 63.1 years) and 3402 women (mean age 62.2 years) contributed data to the analysis. In total there were 193 incident morphometric and 224 qualitative fractures. In women, an age at menarche 16 years or older was associated with an increased risk of vertebral fracture (RR=1.80; 95%CI 1.24, 2.63), whilst use of hormonal replacement was protective (RR=0.58; 95%CI 0.34, 0.99). None of the lifestyle factors studied including smoking, alcohol intake, physical activity or milk consumption showed any consistent associations with incident vertebral fracture. In men and women, increasing body weight and body mass index were associated with a reduced risk of vertebral fracture though, apart from body mass index in men, the confidence intervals embraced unity. For most variables the strengths of the associations observed were similar using the qualitative and morphometric approaches to fracture definition. In conclusion our data suggest that modification of other lifestyle risk factors is unlikely to have a major impact on the population occurrence of vertebral fractures. The important biological mechanisms underlying vertebral fracture risk need to be explored using new investigational strategies.

Incidence of Distal Forearm Fracture in British Men and Women

Abstract: Fracture of the distal forearm is one of the most frequent osteoporotic fractures. However, there are few data concerning its incidence in Britain. The aim of this study was to determine the incidence of distal forearm fracture in adult British men and women. Six centers took part in the study: Aberdeen, Hull, Nottingham, Portsmouth, Southampton and Truro. At each center, men and women aged 35 years and over with an incident distal forearm fracture and who resided in the catchment area of the main hospital at that center, were identified during a 12 month period. Incident fractures were identified from all possible point-of-contact sources in each locality, including accident and emergency records, fracture clinics, ward listings and plaster room registers. The population at risk was defined geographically according to postcode and the denominator obtained from 1991 census data mapped to these postcodes. During the 12 month study period, 3161 individuals with distal forearm fracture were identified. The age-adjusted incidence, age 35 years and over, was 36.8/10 000 person-years in women and 9.0/10 000 person-years in men. In women, the incidence of fracture increased progressively with age from the perimenopausal period, while in men the incidence remained low until later life. Fractures were more frequently left-sided (55.6%) and 19.4% of subjects required hospitalization. On the basis of these data we estimate that 71 000 adult men and women sustain a distal forearm fracture in Britain each year. Compared with previous British surveys the pattern of incidence with age appears to have changed in women, the reason for this is unclear.

Incidence of limb fracture across Europe: Results from the European prospective osteoporosis study (EPOS)

Abstract: The aim of this population-based prospective study was to determine the incidence of limb fracture by site and gender in different regions of Europe. Men and women aged 50–79 years were recruited from population registers in 31 European centers. Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. Subjects were subsequently followed up using an annual postal questionnaire which included questions concerning the occurrence of new fractures. Self-reported fractures were confirmed where possible by radiograph, attending physician or subject interview. There were 6451 men and 6936 women followed for a median of 3.0 years. During this time there were 140 incident limb fractures in men and 391 in women. The age-adjusted incidence of any limb fracture was 7.3/1000 person-years [pyrs] in men and 19 per 1000 pyrs in women, equivalent to a 2.5 times excess in women. Among women, the incidence of hip, humerus and distal forearm fracture, though not ‘other’ limb fracture, increased with age, while in men only the incidence of hip and humerus fracture increased with age. Among women, there was evidence of significant variation in the occurrence of hip, distal forearm and humerus fractures across Europe, with incidence rates higher in Scandinavia than in other European regions, though for distal forearm fracture the incidence in east Europe was similar to that observed in Scandinavia. Among men, there was no evidence of significant geographic variation in the occurrence of these fractures. This is the first large population-based study to characterize the incidence of limb fracture in men and women over 50 years of age across Europe. There are substantial differences in the descriptive epidemiology of limb fracture by region and gender.

Characteristics of a prevalent vertebral deformity predict subsequent vertebral fracture: results from the European Prospective Osteoporosis Study (EPOS).

The presence of a prevalent vertebral deformity increases the risk of a future vertebral fracture. The aim of this study was to determine whether certain characteristics of the prevalent deformity, including its shape and location in the spine, influenced this effect. The 3100 men and 3500 women who took part in this analysis were recruited from population registers for participation in the European Prospective Osteoporosis Study (EPOS). Subjects had lateral thoracic and lumbar spine x-rays at baseline, and again after a mean interval of 3.8 years. Prevalent morphometric vertebral deformities on the baseline film were identified by the McCloskey-Kanis method. Incident fractures were defined as vertebrae that also satisfied the McCloskey-Kanis criterion for prevalent deformities on the follow-up film, and in addition had at least one height (anterior, mid, or posterior) which had reduced by at least 20% between films. Poisson regression was used to assess the association between various characteristics of the prevalent deformity and the risk of an incident vertebral fracture, with generalised estimating equations used to allow for the fact that each subject contributed several vertebrae to the analysis. The risk of an incident fracture increased with the number of prevalent deformities: relative risk (RR) for one prevalent deformity 3.2 (95% confidence interval (CI); 2.1, 4.8); 9.8 (95% CI;6.1, 15.8) for 2; and 23.3 (95% CI;15.3, 35.4) for 3 or more. Relative risks differed significantly according to the shape of the prevalent deformity, ranging from 5.9 (95% CI; 4.1, 8.6) if the anterior and mid heights were reduced to 1.6 (95% CI;0.8, 3.2) if the posterior and mid heights were reduced. Risks varied also according to the severity of the deformity. There were fivefold differences in relative risk of incident fracture depending on the location of the prevalent deformity within the spine. Compared to vertebrae in subjects with no deformities at baseline, the relative risk of an incident fracture within three vertebrae of a prevalent deformity was greater (7.7 (95% CI;5.6, 10.5)) than the risk in more distant vertebrae (4.0 (95% CI;2.6, 6.0)). In summary, the risk of a subsequent vertebral fracture in individuals with preexisting deformities is importantly influenced by the characteristics of these deformities.

Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis

Objective: To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) agents. Methods: UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28). Results: Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage. Conclusion: The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22.

Prevalent Vertebral Deformity Predicts Incident Hip though not distal Forearm Fracture: Results from the European Prospective Osteoporosis Study

Abstract: The presence of a vertebral deformity increases the risk of subsequent spinal deformities. The aim of this analysis was to determine whether the presence of vertebral deformity predicts incident hip and other limb fractures. Six thousand three hundred and forty-four men and 6788 women aged 50 years and over were recruited from population registers in 31 European centers and followed prospectively for a median of 3 years. All subjects had radiographs performed at baseline and the presence of vertebral deformity was assessed using established morphometric methods. Incident limb fractures which occurred during the follow- up period were ascertained by annual postal questionnaire and confirmed by radiographs, review of medical records and personal interview. During a total of 40 348 person-years of follow-up, 138 men and 391 women sustained a limb fracture. Amongst the women, after adjustment for age, prevalent vertebral deformity was a strong predictor of incident hip fracture, (rate ratio (RR) = 4.5; 95% CI 2.1–9.4) and a weak predictor of ‘other’ limb fractures (RR = 1.6; 95% CI 1.1–2.4), though not distal forearm fracture (RR = 1.0; 95% CI 0.6–1.6). The predictive risk increased with increasing number of prevalent deformities, particularly for subsequent hip fracture: for two or more deformities, RR = 7.2 (95% CI 3.0–17.3). Amongst men, vertebral deformity was not associated with an increased risk of incident limb fracture though there was a nonsignificant trend toward an increased risk of hip fracture with increasing number of deformities. In summary, prevalent radiographic vertebral deformities in women are a strong predictor of hip fracture, and to a lesser extent humerus and ‘other’ limb fractures; however, they do not predict distal forearm fractures.