Tracey Farragher

Association of the HLA-DRB1 Gene With Premature Death, Particularly From Cardiovascular Disease, in Patients With Rheumatoid Arthritis and Inflammatory Polyarthritis

Objective To examine the role of the variants of the PTPN22 and HLA–DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA). Methods Patients were recruited from a primary care–based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA–DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti–cyclic citrullinated peptide (anti-CCP) status, adjusted by age at symptom onset and sex. Results DNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1–2.2]) and from CVD (HR 1.68 [95% CI 1.1–2.7]). This effect was most marked for individuals with the HLA–DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti-CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6–23.2]). No association of the PTPN22 gene with mortality was detected. Conclusion SE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti-CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.

Predictors of response to anti-TNF therapy in ankylosing spondylitis: results from the British Society for Rheumatology Biologics Register

Objective. Few data exist on the use of anti-TNF drugs for AS during routine clinical use in the UK. This report describes an improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) after 6 months of therapy in 261 patients enrolled in a national prospective observational register. Methods. The British Society for Rheumatology Biologics Register (BSRBR) recruited patients starting anti-TNF therapy for AS between 2002 and 2006. Multivariable linear regression models were used to estimate the predictors of absolute improvement in BASDAI and BASFI at 6 months. Covariates included age, gender, disease duration, baseline BASDAI and BASFI, presence of raised inflammatory markers (defined as twice the upper limit of normal) and DMARD therapy. Results. The cohort was young (median age 43 years) and 82% were males. Median baseline BASDAI was 7.6 and BASFI 7.9. At 6 months, the mean improvements in BASDAI and BASFI were 3.6 and 2.6 U, respectively; 52% reached a BASDAI50. Patients with raised inflammatory markers at the start of therapy had a 0.9-U (95% CI 0.2, 1.5) better improvement in BASDAI compared with those without. Lesser responses were seen in those with higher baseline BASFI scores. Women had a 1.1-U (95% CI 0.3, 2.0) greater improvement in BASFI at 6 months, as did those who were receiving concurrent DMARD therapy [0.9 U (95% CI 0.2, 1.7)]. Conclusions. The majority of patients receiving anti-TNF therapy for AS during routine care demonstrated an improvement in disease activity. Raised inflammatory markers at the start of therapy predicted a greater improvement in BASDAI, identifying a group of patients who may be more responsive to anti-TNF therapies, although the results were not confined to this group.

Risk factors for onset of chronic oro-facial pain – Results of the North Cheshire oro-facial pain prospective population study

&NA; Due to the cross‐sectional nature of previous studies, whether mechanical factors predict the onset of Chronic oro‐facial pain remains unclear. Aims of the current study were to test the hypotheses that self‐reported mechanical factors would predict onset of Chronic oro‐facial pain and that any observed relationship would be independent of the confounding effects of psychosocial factors and reporting of other unexplained symptoms. About 1735 subjects who had completed a baseline questionnaire were assessed at 2 year follow‐up for the presence of Chronic oro‐facial pain, psychosocial factors (anxiety and depression, illness behaviour, life stressors and reporting of somatic symptoms), mechanical dysfunction (facial trauma, grinding, phantom bite and missing teeth) and reporting of other unexplained symptoms (chronic widespread pain, irritable bowel syndrome and chronic fatigue). About 1329 subjects returned completed questionnaires (adjusted response rate 87%). About 56 (5%) reported new episodes of Chronic oro‐facial pain at follow‐up. Univariate analyses showed that age, gender, reporting of other unexplained symptoms, psychosocial factors and two self‐report mechanical factors predicted the onset of Chronic oro‐facial pain. However multivariate analysis showed that mechanical factors did not independently predict onset. The strongest predictors were health anxiety (Relative Risk (RR) 2.8, 95% CI 1.3–6.2), chronic widespread pain (RR 4.0 95% C.I. 2.2–7.4) and age (RR 0.2, 95% CI 0.1–0.7). The findings from this prospective study support the hypothesis that psychosocial factors are markers for onset of Chronic oro‐facial pain. The efficacy of early psychological management of Chronic oro‐facial pain to address these factors should be a priority for future investigations.

Early functional disability predicts both all-cause and cardiovascular mortality in people with inflammatory polyarthritis: results from the Norfolk Arthritis Register

Objective: To investigate the predictive value of early functional disability in patients with inflammatory polyarthritis (IP), for all-cause and cardiovascular disease (CVD) mortality. Methods: 1010 subjects with new-onset IP from the Norfolk Arthritis Register were studied. All were seen at baseline and at 1 year. Health Assessment Questionnaire (HAQ) scores were obtained at both time points. Vital status at 10 years from registration was established through central records. Mortality (all-cause and CVD) per 1000 person-years were calculated by HAQ stratum (HAQ scores <1, 1–2 and ⩾2). The predictive value of HAQ (per unit increase) at the two time points, adjusted for age at onset of symptom, sex and other factors found to predict mortality, was assessed using Cox regression models. The analysis was repeated for those who satisfied the 1987 American College of Rheumatology criteria for rheumatoid arthritis (RA) by 5 years. Results: By 10 years, 171 (16.9%) subjects had died. 89 deaths (52%) were attributed to CVD. Mortality was greatest in the highest HAQ group at both time points. Following adjustment for other predictors, HAQ score at year 1 remained a significant predictor of all-cause mortality (HR 1.46; 95% CI 1.15 to 1.85) and CVD mortality (HR 1.49; 95% CI 1.12 to 1.97). The predictive value of HAQ at year 1 was similar in the RA subgroup. Conclusions: Our data show that at 1 year of follow-up, HAQ score is an important independent predictor of subsequent all-cause and CVD mortalities in people with IP and RA. Baseline HAQ scores are of less value.

The influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis

Objective To investigate the influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis (IP), and to examine predictors of mortality in relation to disease duration. Methods From 1990 to 1994, patients with recent-onset IP were registered with the Norfolk Arthritis Register (NOAR) and followed up prospectively. Standardized mortality ratios (SMRs) were calculated for all-cause and cardiovascular disease (CVD) mortality and for those who were younger than age 55 years at disease onset and for the first 5 and 10 years of followup. Cox proportional hazards models were developed to assess predictors of early and later mortality. Results Of 1,098 patients, 224 (20%) had died by the end of 2004. All-cause and CVD mortality were increased in rheumatoid factor (RF)–positive patients and in this subgroup, CVD mortality was increased at both early and later followup (SMR 5-year followup 1.93 [95% confidence interval 1.08–3.19]; SMR 10-year followup 2.00 [95% confidence interval 1.37–2.80]). CVD mortality was highest in seropositive patients <55 years of age at disease onset (SMR 5.58 [95% confidence interval 2.24–11.50]). In multivariate models, age at onset, male sex, RF positivity, Health Assessment Questionnaire score ≥1.5, and nodules were predictors of early and later mortality. Conclusion Patients with IP had higher rates of CVD mortality throughout the followup period studied, and this was highest in seropositive patients who were <55 years of age at symptom onset. This subgroup deserves particular attention in terms of disease and risk factor modification. Nodules were independent predictors of CVD mortality, suggesting that extraarticular/vascular inflammation identifies patients at particularly high CVD risk.

Mechanism-Based Urinary Biomarkers to Identify the Potential for Aminoglycoside-Induced Nephrotoxicity in Premature Neonates: A Proof-of-Concept Study

Premature infants are frequently exposed to aminoglycoside antibiotics. Novel urinary biomarkers may provide a non-invasive means for the early identification of aminoglycoside-related proximal tubule renal toxicity, to enable adjustment of treatment and identification of infants at risk of long-term renal impairment. In this proof-of-concept study, urine samples were collected from 41 premature neonates (≤32 weeks gestation) at least once per week, and daily during courses of gentamicin, and for 3 days afterwards. Significant increases were observed in the three urinary biomarkers measured (Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase-associated Lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG)) during treatment with multiple courses of gentamicin. When adjusted for potential confounders, the treatment effect of gentamicin remained significant only for KIM-1 (mean difference from not treated, 1.35 ng/mg urinary creatinine; 95% CI 0.05–2.65). Our study shows that (a) it is possible to collect serial urine samples from premature neonates, and that (b) proximal tubule specific urinary biomarkers can act as indicators of aminoglycoside-associated nephrotoxicity in this age group. Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken.

The role of rheumatoid arthritis genetic susceptibility markers in the prediction of erosive disease in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register

Objectives. Recent whole-genome and candidate gene association studies in RA have identified a number of single nucleotide polymorphisms (SNPs) that predispose to disease with moderate risk. It remains poorly understood how recently identified genetic factors may contribute to RA severity. We therefore sought to investigate the role of recently identified RA susceptibility SNP markers in predicting erosive outcome in patients with recent-onset inflammatory polyarthritis (IP). Methods. DNA and X-ray data were available for 1049 patients who were registered between 1990 and 2003 with the Norfolk Arthritis Register (NOAR); a primary care-based inception cohort of patients with recent-onset IP. Demographic and clinical data were recorded at inclusion, and at yearly assessments thereafter. Patients were genotyped for 18 SNP markers. The presence of serum anti citrullinated peptide antibodies (ACPAs) was assessed in samples collected at inclusion to the NOAR. The association of serological and genetic markers with poor radiological (Larsen) score at Years 1 and 5, and erosions at Years 1 and 5 was investigated. Results. Baseline ACPA positivity was associated with erosive disease and higher radiological damage. SNP markers within the TRAF1/C5 locus were associated with erosive disease at Year 1 [rs2900180: odds ratio (OR) 1.53 (95% CI 1.14, 2.05)] and Year 5 [rs2900180: OR 1.47 (95% CI 1.07, 2.02)]. None of the SNP markers tested was associated with Larsen score. Conclusion. Our results are in keeping with a previous report and suggest that the TRAF1/C5 region is associated with risk of development of radiological erosions in IP/RA patients. The finding requires replication in other large data sets.

Early treatment with, and time receiving, first disease-modifying antirheumatic drug predicts long-term function in patients with inflammatory polyarthritis

Objectives To investigate the influence of early disease-modifying antirheumatic drug (DMARD) treatment on long-term functional outcome in patients with recent-onset inflammatory polyarthritis (IP), and the impact of the duration of first and subsequent DMARD treatment. Methods 642 subjects from a primary care registry of patients with new-onset IP, recruited 1990–4, were followed up for 10 years. Mean change in Health Assessment Questionnaire (HAQ) scores between baseline and 10 years were compared by time to, and time receiving, first DMARD treatment and total time receiving treatment, using linear regression. Adjustment for time-dependent confounders and censoring was performed using marginal structural weights. Results When adjusted for baseline and subsequent disease severity, those treated early (<6 months from symptom onset) experienced a non-significant improvement in function compared with those never treated (adjusted mean difference in change (adj_MDIC) in HAQ −0.24; 95% CI −0.58 to 0.09); and a significant benefit for each additional month of treatment within 6 months of the onset of symptoms (adj_MDIC −0.10; 95% CI −0.19 to −0.02). Patients who discontinued their first DMARD within 6 months experienced a significant deterioration in long-term function (adj_MDIC in HAQ 0.28; 95% CI 0.04 to 0.52), while those who continued their first treatment for > 3 years experienced an improvement (adj_MDIC in HAQ −0.37; 95% CI −0.77 to 0.04). Conclusions The importance of time to, and response to, first DMARD treatment and total duration of DMARD treatment in modifying the 10-year function in patients with IP has been demonstrated.

Benefit of early treatment in inflammatory polyarthritis patients with anti–cyclic citrullinated peptide antibodies versus those without antibodies

To compare the clinical utility of anti–cyclic citrullinated peptide (anti‐CCP) antibodies and rheumatoid factor (RF) testing in predicting both functional outcome and response to treatment in early inflammatory polyarthritis (IP) patients.

Association of functional outcome with both personal- and area-level socioeconomic inequalities in patients with inflammatory polyarthritis

Objective To describe the relationship between baseline area- and person-level social inequalities and functional disability at 3 years in patients with early inflammatory polyarthritis (IP). Methods A total of 1,393 patients with new-onset IP were recruited and allocated an Index of Multiple Deprivation (IMD) 2004 score based on their area of residence, and a social class based on baseline self-reported occupation. Differences in the Health Assessment Questionnaire (HAQ) score at baseline and 3 years by IMD or social class were tested. The mean 3-year change in HAQ score was compared by IMD and social class, and interactions between these measures examined. Results Patients from more deprived areas had poorer 3-year HAQ outcome than those from less deprived areas (P = 0.019, adjusted for baseline HAQ score, age, sex, and symptom duration). The mean difference in HAQ change was most notable between the most deprived (IMD4) and least deprived areas (IMD1) (0.22; 95% confidence interval [95% CI] 0.11, 0.34). There was also a significant difference in HAQ score change between patients of the highest (SCI and II) and lowest social class (SCIV and V) (0.11; 95% CI 0.02, 0.20). For the mean (95% CI) 3-year change in HAQ score, a significant interaction exists between IMD score and social class and their association with HAQ scores (P = 0.001) to modify outcome: IMD1/SC I and II −0.23 (95% CI −0.40, −0.06) versus IMD 4/SC IV and V 0.15 (95% CI −0.05, 0.34). Conclusion Person- and area-level inequalities combine to modify outcome for rheumatoid arthritis. A persons social circumstance and residential environment have independent effects on outcome and are not just alternative measures of the same exposure.