Patrick Kiely

The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review

OBJECTIVES Patients with RA have an increased prevalence of cardiovascular disease (CVD). This is due to traditional risk factors and the effects of chronic inflammation. MTX is the first-choice DMARD in RA. We performed a systematic literature review to determine whether MTX affects the risk of CVD in patients with RA. METHODS We searched Medline, Embase, Cochrane database, database of abstracts of reviews of effects, health technology assessment and Science Citation Index from 1980 to 2008. Conference proceedings (British Society of Rheumatology, ACR and EULAR) were searched from 2005 to 2008. Papers were included if they assessed the relationship between MTX use and CVD in patients with RA. Two reviewers independently assessed each title and abstract for relevance and quality. RESULTS A total of 2420 abstracts were identified, of which 18 fulfilled the inclusion criteria. Two studies assessed the relationship between MTX use and CVD mortality, one demonstrated a significant reduction in CVD mortality and the second a trend towards reduction. Five studies considered all-cause CVD morbidity. Four demonstrated a significant reduction in CVD morbidity and the fifth a trend towards reduction. MTX use in the year prior to the development of RA decreased the risk of CVD for 3-4 years. Four studies considered myocardial infarction, one demonstrated a decreased risk and three a trend towards decreased risk with MTX use. CONCLUSION The current evidence suggests that MTX use is associated with a reduced risk of CVD events in patients with RA. This suggests that reducing the inflammation in RA using MTX not only improves disease-specific outcomes but may also reduce collateral damage such as atherosclerosis.

Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review

OBJECTIVES RA is associated with early ischaemic heart disease. This appears to be driven largely by the presence of chronic inflammation. Studies suggest that treatment with disease-modifying drugs such as MTX may reduce the incidence of cardiovascular events in RA. Anti-TNF therapies significantly reduce inflammation in RA. However, the extent to which these agents also reduce cardiovascular disease (CVD) is uncertain. The purpose of this study was to explore the effect of anti-TNF agents on CVD in RA using a systematic literature review. METHODS We searched for studies of adults with RA treated with TNF antagonists where cardiovascular outcomes were recorded using MEDLINE, EMBASE, Cochrane Database, Database of Abstracts and Reviews of Effects, Health Technology Appraisal, Science Citation Index and Clinical Evidence from 1989 to 2010. Conference proceedings for the British Society of Rheumatology, ACR and EULAR between 2005 and 2009 were hand searched. Two reviewers assessed abstracts for inclusion and then quality of selected papers was assessed. RESULTS A total of 1840 abstracts were identified and 20 articles were suitable for inclusion. Information was obtained on the effect of TNF antagonists on overall CVD events, myocardial infarction, strokes and heart failure. CONCLUSION In many studies, TNF antagonists appear to reduce the likelihood of CVD in individuals with RA. Reassuringly, there does not appear to be an increased risk of cardiac failure. However, the reduction in CVD is not as consistently seen as with studies of MTX.

Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010–2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. The level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1–10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.

What makes osteoarthritis painful? The evidence for local and central pain processing

OA is a chronic arthritic disease characterized by pain, local tissue damage and attempts at tissue repair. Historically, cartilage damage was believed to be the hallmark of OA. However, since cartilage is an avascular, aneural tissue, the mechanisms of pain are likely to be complex and influenced by non-cartilaginous structures in the joint including the synovium, bone and soft tissue. Imaging studies reveal the presence of synovitis and bone marrow lesions that may mediate pain. The presence of local joint inflammation and altered cartilage and bone turnover in OA implicates a potential role for a range of molecular mediators in OA pain. Mechanisms of pain perception may include the activation and release of local pro-inflammatory mediators such as prostaglandins and cytokines accompanied by the destruction of tissue, which is mediated by proteases. However, clinically, there is often disparity between the degree of pain perception and the extent of joint changes in subjects with OA. Such observations have prompted work to investigate the mechanisms of central pain perception in OA. Functional MRI has identified multiple areas of the brain that are involved in OA pain processing. These data demonstrate that pain perception in OA is complex in being influenced by local factors and activation of central pain-processing pathways. In this review, we will discuss current concepts underlying the pathophysiology of pain perception in OA and suggest possible directions for the future management of pain in this condition based on recent clinical studies.

Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders

OBJECTIVE To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. CONCLUSION Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Contemporary patterns of care and disease activity outcome in early rheumatoid arthritis: the ERAN cohort

OBJECTIVES To report from the Early Rheumatoid Arthritis Network (ERAN), time from symptom onset to start of therapy, treatment choices and disease outcome in early RA. METHODS Patients with newly diagnosed RA were prospectively enrolled from 19 centres in the UK and Eire. Standardized information was collected on case report forms at first presentation, 3-6 months, 1 yr and annually thereafter. The choice and intensity of drug treatment was left to the discretion of individual centres. RESULTS A total of 808 patients were recruited between 2002 and 2007, with a mean follow-up of 16 (0-60) months. Of them, 62% fulfilled four or more ACR criteria for RA at first visit. The median time from onset of symptoms to referral to secondary care was 4 months [interquartile range (IQR) 2-9, n = 655] and to start of first DMARD 8 months (IQR 4-13, n = 638). DMARDs were prescribed in 97% of the patients, initially as monotherapy in 91%, and as combination therapy in 9%. The second DMARD (n = 220) was a switch to another as monotherapy in 52% and step-up to combination therapy in 48%. The proportions with a 28-joint disease activity score >5.1 at baseline and 3 yrs were 46 and 19%, >3.2 were 84 and 54% and <2.6 were 6 and 33%, respectively. CONCLUSIONS Patients presenting with RA in ERAN do not receive DMARDs promptly, largely due to delays in referral to secondary care. Contemporary treatment practice is to start with DMARD monotherapy, and to use combination DMARDs as second-line therapy in approximately half of them. Over 3 yrs the proportion of patients continuing to have active disease remains high.

Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative

Objective. To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA). Methods. A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008–09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice. Results. A total of 49 242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice. Conclusions. Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice.

Hand and foot surgery rates in rheumatoid arthritis have declined from 1986 to 2011, but large-joint replacement rates remain unchanged: results from two UK inception cohorts.

To assess whether there have been any secular changes in orthopedic interventions in patients with rheumatoid arthritis (RA) since 1986, as examined in 2 early rheumatoid arthritis (RA) inception cohorts with up to 25 years of followup.

Reliability and Validity of the Myositis Disease Activity Assessment Tool

OBJECTIVE To test the interrater reliability and validity of the Myositis Disease Activity Assessment Tool, which consists of the Myositis Intention-to-Treat Activity Index and the Myositis Disease Activity Assessment Visual Analog Scales. METHODS Two phases of the study were conducted to assess the reliability and validity of the tool, which was modified following the first phase. In the first phase of the reliability study, 123 adult myositis patients were evaluated in 7 centers, and in the second phase 40 patients were evaluated in 2 centers. The validity study included 294 patients in 5 centers in the first phase and 65 patients in 3 centers in the second phase. The interrater reliability was assessed using intraclass correlation coefficients. The criterion validity was calculated using sensitivity, specificity, and positive predictive value (PPV) of a grade of A in any system. Spearmans rank correlation coefficient was used to measure the convergent validity of cross-sectional scores between the 2 instruments. RESULTS There was a 2:1 ratio of female to male patients. There was no significant difference in mean age at diagnosis (46.3 versus 46.8 years) and mean disease duration (7.7 versus 10 years) between the 2 groups recruited for the different phases of the study. There was an improvement in interrater reliability in the second phase of the study. There was a significant improvement in the validity of the assessment tool following modification of the tool. The sensitivity, specificity, and PPV of a grade of A in any system improved from 86%, 92%, and 67% in the first phase to 96%, 94%, and 83%, respectively, in the second phase. Convergent validity between the 2 activity tools showed good correlation, ranging from 0.8 to 0.94, for the individual organ systems. CONCLUSION This is the first major attempt to assess the reliability and validity of a disease activity index in myositis. Our findings indicate that, following within-study modification, the tool appears to be a reliable and valid instrument to assess myositis disease activity.

The relation between composite ultrasound measures and the DAS28 score, its components and acute phase markers in adult RA

OBJECTIVES Ultrasound (US) provides measurements of synovial morphology and vascularity. However, on an individual joint basis in RA, US measures do not relate well to clinical signs. This study investigates the relationship between composite US measures and the 28-joint disease activity score (DAS28), its components and acute phase markers in adult RA. METHODS RA synovial disease activity was recorded in 50 patients by: (i) the DAS28 score; (ii) ESR and CRP; and (iii) US using Grey scale (GS) and power Doppler (PD) measures of PIP and MCP joints to derive composite US scores based on abnormal counts and severity. A total of 25 control subjects were studied to define normal US appearances. The relation between each measure of synovial disease was determined by Spearman correlation analysis. RESULTS There was a significant relation between the DAS28 and the GS joint count (GSJC, Spearmans r = 0.4; P = 0.004) and severity score (GSJS, r = 0.34; P = 0.016) and the PD joint count (PDJC, r = 0.32; P = 0.028). There was a significant relation between the ESR and PDJC (r = 0.37; P = 0.007) and PD joint severity score (PDJS, r = 0.38; P = 0.006) and between the CRP and PDJS (r = 0.29; P = 0.04). The remaining components of the DAS28 related poorly to all US measures, except the tender joint count, which related significantly to the GS but not the PD measures. CONCLUSIONS Composite US markers of synovial disease relate significantly to the DAS28 score and ESR/CRP in adult RA, but not as well with individual clinical joint counts and the patients global assessment.