Samantha L. Hider

Rheumatoid arthritis association at 6q23

The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 × 10−5 − 5 × 10−7 in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 × 10−8) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-α–induced protein 3 (TNFAIP3).

Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients

We investigated the effect of single-nucleotide polymorphisms (SNPs) spanning 10 methotrexate (MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1 (RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient cohort. Tagging SNPs were selected and genotyping was performed in 309 patients with predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were detected with efficacy (P-trend ⩽0.05) including four SNPs in the ATIC gene (rs12995526, rs3821353, rs7563206 and rs16853834), six SNPs in the SLC19A1 gene region (rs11702425, rs2838956, rs7499, rs2274808, rs9977268 and rs7279445) and a single SNP within the GGH gene (rs12681874). Five SNPs were significantly associated with adverse events; three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline significance in the FPGS gene. The results suggest that genetic variations in several key MTX pathway genes may influence response to MTX in the RA patients. Further studies will be required to validate these findings and if confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA.

Depression in RA patients treated with anti-TNF is common and under-recognized in the rheumatology clinic

OBJECTIVES Depression is common in RA and may be influenced by both disease activity and severity. The aims of this study were to investigate the prevalence of depression in RA patients starting anti-TNF therapy, to investigate how mood alters after exposure to anti-TNF and to determine whether depression is recognized and appropriately managed in the clinic. METHODS Patients starting anti-TNF therapy were assessed for depression using the Hospital Anxiety and Depression Scale (HADS-D), and classified as depressed with an HADS-D of > or =8. Change in mood was assessed at 6 weeks, 4 months and 12 months. Disease activity data were recorded at baseline, 3 and 12 months. Patients who remained persistently depressed at 4 months had their clinical case notes reviewed to determine whether their low mood had been recognized or treated. RESULTS Depression was common in this cohort. Depressed patients had higher disease activity scores (DAS28) at all time points, and patients with persistent depression had smaller reductions in DAS28 [median (interquartile range or IQR) change DAS28 1.71 (0-2.6) vs 2.2 (1.5-3.2); P = 0.005]. Only 57% (13/23) patients with persistent depression at 4 months had their depression recognized or managed within the rheumatology clinic. CONCLUSIONS Depression is common but under-recognized in RA patients starting on anti-TNF therapy. Patients with persistent depression tended to respond less well to anti-TNF, with smaller reductions in DAS28. Given that a significant reduction in DAS28 is a requirement for continuing therapy, recognition and appropriate management of depression may improve TNF effectiveness.

Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis

Purpose: Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX. Methods: Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome. Results: 309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81). Conclusions: Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.

MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms.

Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83–1.32) and OR=0.81 (95% CI 0.53–1.24), respectively; toxicity: OR=1.38 (95% CI 0.90–2.12) and OR=1.19 (95% CI 0.80–1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.

Increased risk of vascular disease associated with gout: A retrospective, matched cohort study in the UK Clinical Practice Research Datalink

Objectives To determine whether gout increases risk of incident coronary heart disease (CHD), cerebrovascular (CVD) and peripheral vascular disease (PVD) in a large cohort of primary care patients with gout, since there have been no such large studies in primary care. Methods A retrospective cohort study was performed using data from the Clinical Practice Research Datalink (CPRD). Risk of incident CHD, CVD and PVD was compared in 8386 patients with an incident diagnosis of gout, and 39 766 age, sex and registered general practice-matched controls, all aged over 50 years and with no prior vascular history, in the 10 years following incidence of gout, or matched index date (baseline). Multivariable Cox Regression was used to estimate HRs and covariates included sex and baseline measures of age, Body Mass Index, smoking, alcohol consumption, Charlson comorbidity index, history of hypertension, hyperlipidaemia, chronic kidney disease, statin use and aspirin use. Results Multivariable analysis showed men were at increased risk of any vascular event (HRs (95% CIs)) HR 1.06 (1.01 to 1.12), any CHD HR 1.08 (1.01 to 1.15) and PVD HR 1.18 (1.01 to 1.38), while women were at increased risk of any vascular event, HR 1.25 (1.15 to 1.35), any CHD HR 1.25 (1.12 to 1.39), and PVD 1.89 (1.50 to 2.38)) but not any CVD. Conclusions In this cohort of over 50s with gout, female patients with gout were at greatest risk of incident vascular events, even after adjustment for vascular risk factors, despite a higher prevalence of both gout and vascular disease in men. Further research is required to establish the reason for this sex difference.

Prescription and comorbidity screening following consultation for acute gout in primary care

OBJECTIVE To describe prescribing patterns and cardiovascular risk factor screening in patients, following consultation for acute gout in primary care. METHODS This study was undertaken in two inter-linked regional primary care databases: Consultations in Primary Care Archive (CiPCA) and Prescriptions in Primary Care Archive (PiPCA). During 2001-04, consultations in CiPCA were identified at 10 participating practices from gout-related Read morbidity codes. Lipid, blood pressure, glucose and renal function monitoring were identified from Read codes and consultation free text over the next month. Prescriptions for traditional NSAIDs, gastroprotective agents, colchicine, coxibs, corticosteroids, analgesic agents and urate-lowering therapies (ULTs) issued to these patients over the subsequent 12 months were identified from PiPCA. RESULTS Six hundred and seventy-three new gout consultations were identified. Monitoring of lipids (5%), blood pressure (26%), glucose (6%) and renal function (21%) within 1 month of index consultation were infrequently recorded. There were 583 consultations for acute gout. Traditional NSAIDs (68%) were most commonly prescribed, followed by colchicine (15%), coxibs (5%) and analgesia only (5%). Seven per cent did not receive a prescription. The most frequently prescribed traditional NSAIDs were diclofenac (41%) and indomethacin (32%). Gastroprotection was co-prescribed with NSAIDs for 17% of patients. Sixty six per cent of patients treated with colchicine were prescribed high-dose regimens (500 microg at least four times daily). ULTs were prescribed within 12 months in 23% of patients. Nineteen per cent of ULTs were prescribed during acute attack. CONCLUSIONS Primary care acute gout management is suboptimal. Education of general practitioners about acute gout management and cardiovascular risk is a priority.

The impact of low back-related leg pain on outcomes as compared with low back pain alone: a systematic review of the literature.

Objectives:Low back pain (LBP) with leg pain, especially with findings of nerve root involvement, is considered as a poor prognostic indicator although it seems to have a favorable natural resolution. It is unclear whether patients with LBP and leg pain are at the more severe end of the spectrum as compared with patients with LBP alone or whether they are a distinct subgroup that would perhaps benefit from early identification of the condition and more targeted interventions. The purpose of this study was to investigate the impact of LBP-related leg pain on outcomes and use of health resources as compared with patients with LBP alone. Methods:Systematic review of studies reporting separate outcomes of patients with LBP and LBP with leg pain and synthesis of available evidence. Literature search of all English language peer-reviewed publications was conducted using MEDLINE, EMBASE, and CINAHL for the years 1994 to 2010. Results:Of the papers retrieved, 9 were included in the review. The heterogeneity of studies allowed only narrative analysis of findings. All studies reported worse health outcomes and increased use of health care with radiation of leg pain distally and with neurological findings, with the exception of psychological outcomes. Discussion:LBP with pain radiating to the leg appears to be associated with increased pain, disability, poor quality of life, and increased use of health resources compared with LBP alone. These findings argue for early identification of these cases by health care professionals and pursuing effective treatments.

Health-related quality of life in gout: a systematic review

Objectives. To identify the instruments that have been used to measure health-related quality of life (HRQOL) in gout and assess their clinimetric properties, determine the distribution of HRQOL in gout and identify factors associated with poor HRQOL. Methods. Medline, CINAHL, EMBASE and PsycINFO were searched from inception to October 2012. Search terms pertained to gout, health or functional status, clinimetric properties and HRQOL. Study data extraction and quality assessment were performed by two independent reviewers. Results. From 474 identified studies, 22 met the inclusion criteria. Health Assessment Questionnaire Disability Index (HAQ-DI) and Short Form 36 (SF-36) were most frequently used and highest rated due to robust construct and concurrent validity, despite high floor and ceiling effects. The Gout Impact Scale had good content validity. Gout had a greater impact on physical HRQOL compared to other domains. Both gout-specific features (attack frequency and intensity, intercritical pain and number of joints involved) and comorbid disease were associated with poor HRQOL. Evidence for objective features such as tophi and serum uric acid was less robust. Limitations of existing studies include cross-sectional design, recruitment from specialist clinic settings and frequent use of generic instruments. Conclusion. Most studies have used the generic HAQ-DI and SF-36. Gout-specific characteristics and comorbidities contribute to poor HRQOL. There is a need for a cohort study in primary care (where most patients with gout are treated) to determine which factors predict changes in HRQOL over time. This will enable those at risk of deterioration to be identified and better targeted for treatment.

Increased cardiovascular mortality associated with gout: a systematic review and meta-analysis

Background Hyperuricaemia, the biochemical precursor to gout, has been shown to be an independent risk factor for mortality from cardiovascular disease (CVD), although studies examining the clinical phenomenon of gout and risk of CVD mortality report conflicting results. This study aimed to produce a pooled estimate of risk of mortality from cardiovascular disease in patients with gout. Design Systematic review and meta-analysis. Methods Electronic bibliographic databases were searched from inception to November 2012, with results reviewed by two independent reviewers. Studies were included if they reported data on CVD mortality in adults with gout who were free of CVD at time of entry into the study. Pooled hazard ratios (HRs) for this association were calculated both unadjusted and adjusted for traditional vascular risk factors. Results Six papers, including 223,448 patients, were eligible for inclusion (all (CVD) mortality n = 4, coronary heart disease (CHD) mortality n = 3, and myocardial infarction mortality n = 3). Gout was associated with an excess risk of CVD mortality (unadjusted HR 1.51 (95% confidence interval, CI, 1.17–1.84)) and CHD mortality (unadjusted HR 1.59, 95% CI 1.25–1.94)). After adjusting for traditional vascular risk factors, the pooled HR for both CVD mortality (HR 1.29, 95% CI 1.14–1.44) and CHD mortality (HR 1.42, 95% CI 1.22–1.63) remained statistically significant, but none of the studies reported a significant association with myocardial infarction. Conclusions Gout increases the risk of mortality from CVD and CHD, but not myocardial infarction, independently of vascular risk factors.