Sylvain Mathieu

Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials

CONTEXT As of 2005, the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trials findings in member journals. OBJECTIVE To assess the proportion of registered trials with results recently published in journals with high impact factors; to compare the primary outcomes specified in trial registries with those reported in the published articles; and to determine whether primary outcome reporting bias favored significant outcomes. DATA SOURCES AND STUDY SELECTION MEDLINE via PubMed was searched for reports of randomized controlled trials (RCTs) in 3 medical areas (cardiology, rheumatology, and gastroenterology) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors. DATA EXTRACTION For each included article, we obtained the trial registration information using a standardized data extraction form. RESULTS Of the 323 included trials, 147 (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly specified). Trial registration was lacking for 89 published reports (27.6%), 45 trials (13.9%) were registered after the completion of the study, 39 (12%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome. Among articles with trials adequately registered, 31% (46 of 147) showed some evidence of discrepancies between the outcomes registered and the outcomes published. The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6% (19 of 23). CONCLUSION Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent.

Cardiovascular profile in ankylosing spondylitis: A systematic review and meta‐analysis

Rheumatoid arthritis is associated with increased cardiovascular risk. In ankylosing spondylitis (AS), there is a paucity of information concerning this risk. Our objective was to assess the incidence of myocardial infarction (MI) or strokes and the cardiovascular risk profile in AS patients.

Trend towards increased arterial stiffness or intima–media thickness in ankylosing spondylitis patients without clinically evident cardiovascular disease

OBJECTIVES Increased incidence of cardiovascular disease (CVD) has been observed in AS. The reasons of this increase are not fully understood (greater prevalence of traditional cardiovascular risks, consequences of treatment (NSAID) or biological inflammation). The objectives of this study are to assess intima-media thickness (IMT) and arterial stiffness (i.e augmentation index AIx), markers of sub-clinical atherosclerosis in AS patients and to examine the effects of TNF-alpha inhibitors on arterial stiffness in active AS patients. METHODS Sixty AS patients were enrolled with 60 healthy controls. Their BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) scores, ESR and CRP levels were recorded. Subclinical atherosclerosis was assessed by measurement of AIx by pulse wave analysis and IMT by carotid echography. RESULTS We found significantly increased IMT in the AS group compared with healthy controls. After adjustment for confounding factors, an underlying trend towards increased IMT was still present (P = 0.06). No difference was found in arterial stiffness between the two groups. AS patients, treated or not with anti-TNF-alpha at baseline, had significantly increased IMT and AIx or a trend towards increase. IMT was positively correlated with tobacco use, WHR and blood pressure but not correlated with CRP level. Despite improvement in markers of disease activity, arterial stiffness was unchanged after 14 weeks of treatment with TNF antagonists. CONCLUSION This study shows a trend towards increased subclinical atherosclerosis in AS patients. TNF-alpha blockade does not seem to improve arterial stiffness in AS patients, but our results lack statistical power.

The effect of TNF-alpha blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis.

OBJECTIVES Changes in the lipid profile have been described in patients with rheumatoid arthritis (RA) following therapy with tumor necrosis factor (TNF)-alpha blocking agents. However, thus far, results have been inconsistent. Therefore, we investigated changes in lipid levels after TNF-alpha blocking therapy using meta-analysis of published data. METHODS The literature was searched to identify studies assessing changes in total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol, triglycerides, atherogenic index (ie, TC/HDLc ratio), and apolipoprotein levels in response to TNF-alpha blocking therapy. Weighted mean levels of lipids at different time points and subsequent changes in these lipid levels between these time points were calculated with multivariate linear mixed models. RESULTS Data were available on TC in 15 studies encompassing 766 RA patients and on HDLc in 14 studies encompassing 736 RA patients. TC increased significantly (maximum increase of 10%) and HDLc increased significantly in the first 2 to 6 weeks of therapy (maximum increase of 7%), after which it remained more or less stable. The atherogenic index did not significantly change over time. There was too limited information to evaluate changes in other lipids and apolipoproteins. CONCLUSIONS TNF-alpha blocking therapy has a modest effect on TC and HDLc levels in RA patients with no significant overall effect on the atherogenic index. Whether TNF-alpha blocking effects on qualitative lipid changes (structure and function) are more relevant to their presumed vascular benefits requires further study.

Cardiovascular events in ankylosing spondylitis: An updated meta-analysis

OBJECTIVES Rheumatoid arthritis is associated with increased cardiovascular risk. In the guidelines, ankylosing spondylitis (AS) is considered to have an equally high cardiovascular risk. The literature findings remain controversial. This study aims to assess the risk of myocardial infarction (MI) and stroke in AS patients. METHODS An updated meta-analysis with a new systematic literature review using PubMed was conducted up to January 2014. Incidence of MI or stroke was calculated by metaproportion. RESULTS In addition to the 11 previously included studies, six new studies assessed the occurrence of MI or stroke in AS patients. (1) MI. A total of 2131 MI were reported in AS patients (n = 27,532) over a mean follow-up of 15 years: incidence 5.3% (1.6%-11.0%), i.e., 0.36/100 pyrs. Seven studies revealed 17,410 MI [2.5% (95% CI: 1.8%-3.4%)] in the control group (n = 1,349,964). Meta-analysis of the seven longitudinal studies showed a significant increase in MI [OR = 1.60 (95% CI: 1.32-1.93)] in AS patients. (2) Stroke. In 11 longitudinal studies (n = 51,990), 1807 strokes were reported in AS patients over 17.6 years of follow-up: incidence 3.6% (1.5%-6.5%), i.e., 0.24/100 pyrs. Three studies reported 22,899 strokes in controls (n = 1,239,041), giving an incidence of 1.78% (1.75%-1.80%). A significant increase in stroke [OR = 1.50 (95% CI: 1.39-1.62)] in AS patients was found. CONCLUSION AS patients appear to have a higher risk of MI and stroke. Management of cardiovascular risk factors and control of systemic inflammation should be taken into account in AS to decrease this high cardiovascular risk.

Spondyloarthropathies: An independent cardiovascular risk factor?

An increase in cardiovascular mortality and morbidity has been convincingly documented in rheumatoid arthritis. Data on spondyloarthropathies are more limited. Here, we discuss published studies indicating that patients with spondyloarthropathies are at increased risk for cardiovascular disease. The excess risk is probably multifactorial, being related both to chronic systemic inflammation and to high prevalences of conventional cardiovascular risk factors. Cardiovascular risk management in patients with spondyloarthropathies requires optimal control of disease activity combined with interventions targeting conventional cardiovascular risk factors.

Cardiovascular risk in rheumatoid arthritis.

The objectives of this review are to discuss data on the cardiovascular risk increase associated with rheumatoid arthritis (RA), the effects of RA treatments on the cardiovascular risk level, and the management of cardiovascular risk factors in patients with RA. Overall, the risk of cardiovascular disease is increased 2-fold in RA patients compared to the general population, due to the combined effects of RA and conventional risk factors. There is some evidence that the cardiovascular risk increase associated with nonsteroidal anti-inflammatory drug therapy may be smaller in RA patients than in the general population. Glucocorticoid therapy increases the cardiovascular risk in proportion to both the current dose and the cumulative dose. Methotrexate and TNFα antagonists diminish cardiovascular morbidity and mortality rates. The management of dyslipidemia remains suboptimal. Risk equations may perform poorly in RA patients even when corrected using the multiplication factors suggested by the EUropean League Against Rheumatism (EULAR) (multiply the score by 1.5 when two of the following three criteria are met: disease duration longer than 10 years, presence of rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibodies, and extraarticular manifestations). Doppler ultrasonography of the carotid arteries in patients at moderate cardiovascular risk may allow a more aggressive approach to dyslipidemia management via reclassification into the high-risk category of patients with an intima-media thickness greater than 0.9 mm or atheroma plaque.

Effects of 14 weeks of TNF alpha blockade treatment on lipid profile in ankylosing spondylitis

OBJECTIVE Cardiovascular morbidity and mortality seem to be increased in ankylosing spondylitis, perhaps as the result of biological inflammation and consecutive dyslipidemia. This study aims to investigate the impact of TNF alpha-inhibitors, an effective treatment, on lipid profile. METHODS Thirty-four ankylosing spondylitis (AS) patients with active disease undergoing anti-TNF alpha therapy (n=20, infliximab; n=7, etanercept; n=7, adalimumab) were recruited. Disease activity parameters, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were assessed at baseline and after 14 weeks of treatment. RESULTS After 14 weeks of TNF alpha blockade treatment, there was a significant increase in levels of total cholesterol (5.08+/-1.20 vs. 4.73+/-1.12 mmol/l; p=0.01) and HDL-cholesterol (1.61+/-0.47 vs. 1.47+/-0.35 mmol/l; p=0.008), but no resulting change in the atherogenic index (3.43+/-1.13 vs. 3.35+/-0.93; p=0.87). There was also no change in concentrations of triglycerides (1.33+/-1.22 vs. 1.27+/-0.98 mmol/l; p=0.794) and LDL-cholesterol (3.15+/-0.99 vs. 2.91+/-0.93 mmol/l; p=0.24). TNF alpha inhibitor treatment was followed by a significant improvement in all disease activity parameters: VAS pain or VAS disease activity, BASDAI or BASFI and systemic inflammation. Sub-group analysis showed that monoclonal antibodies increased total and LDL-cholesterol levels but did not change the atherogenic index. Conversely, 14 weeks of etanercept treatment was followed by no change in lipid profile. CONCLUSION TNF alpha inhibitors may be successful in reducing cardiovascular risk in AS, as in RA, but not by affecting lipid profile. However, there is insufficient documented evidence, and long-term investigations are needed to define the possible protective mechanisms of TNFalpha inhibitor treatment in spondylarthropathies.

No significant change in arterial stiffness in RA after 6 months and 1 year of rituximab treatment

OBJECTIVE The excess cardiac risk, found in RA has been attributed to biological inflammation. Effective control of inflammation may be of benefit in reducing cardiovascular risk in RA patients. The aim of this study is to investigate the effects of 24 and 52 weeks of rituximab treatment on arterial stiffness and cardiovascular risk factors. METHODS Arterial stiffness was measured by augmentation index (AIx) and pulse wave velocity (PWV), and other cardiovascular risk factors (lipid profile, blood pressure) were collected in active RA patients. RESULTS Thirty-three patients, of whom 29 were females, with a mean age of 60.9 (12.0) years were included. Thirty patients had positive RFs, 27 had positive anti-CCP antibody and 93.9% (n = 31) were erosive. Nineteen patients were non-responders to anti-TNF-α treatments. After rituximab treatment, no change was observed in arterial stiffness, neither after 6 nor after 12 months [PWV 8.1 (3.1) m/s at baseline, 8.1 (2.8) at 6 months, 8.0 (2.7) at 1 year, P = 0.924; and AIx 30.4 (8.2)% at baseline, 28.6 (7.6) at 6 months, 29.4 (6.7) at 1 year, P = 0.216]. Total and low-density lipoprotein cholesterol levels increased significantly but high-density lipoprotein (HDL) and triglyceride levels were unchanged. The atherogenic index (total cholesterol/HDL cholesterol) was increased, but not to a level of significance. No change was found in other cardiovascular risk factors. DAS-28 according to levels of ESR and CRP and biologic inflammation were significantly improved. CONCLUSION Arterial stiffness did not improve after 6 and 12 months of rituximab therapy. The treatment had a beneficial effect on biologic inflammation and disease activity, but caused a pro-atherogenic lipid profile.

Predictive Factors of Rituximab Response in Rheumatoid Arthritis: Results From a French University Hospital

To study the influence of several factors (rheumatoid factor [RF], anti–cyclic citrullinated peptide [anti‐CCP], serum Ig level, and Epstein‐Barr virus [EBV] load) on clinical response to rituximab (RTX) after 6 months in rheumatoid arthritis (RA) patients.