M.T. Nurmohamed

Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis

Background: Glucocorticoids induce hypercholesterolaemia, a cardiovascular risk factor, in patients with diseases other than rheumatoid arthritis (RA), but the data in RA are contradictory. Objective: To determine the effects of antirheumatic treatment, including prednisolone (combination) therapy on total and high density lipoprotein (HDL) cholesterol levels in RA, taking disease activity into account. Methods: HDL cholesterol and total cholesterol levels were determined in:(a) established RA (b) two cohorts with early active RA, (c) a previously conducted 56 week trial among patients with early RA comparing the value of intensive combination therapy (that included glucocorticoids) with sulfasalazine alone (COBRA trial). Results: In established RA total cholesterol levels were only slightly raised, irrespective of disease activity. However, HDL cholesterol was significantly higher in patients in remission than in patients with active disease. In contrast, in active early RA at baseline total cholesterol was low normal: between 4.6 and 5.1 mmol/l in the different populations. The level of HDL cholesterol was highly dependent on the duration of storage. In both COBRA groups total cholesterol increased by a mean of 0.6 mmol/l. HDL cholesterol increased by more than 50% after treatment, leading to an improvement of the total cholesterol/HDL ratio (atherogenic index). This increase (and index improvement) was much more rapid in the group receiving combination treatment. A similar pattern was seen in the 2001 cohort with early RA. In all the groups with active disease HDL and total cholesterol levels correlated inversely with disease activity. Conclusion: In established, but especially in early RA, disease activity is accompanied by atherogenic lipid levels. This dyslipidaemia can be rapidly reversed by aggressive antirheumatic treatment including glucocorticoids.

Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRÉ Investigation

Objectives: Patients with rheumatoid arthritis (RA) have an increased cardiovascular risk, but the magnitude of this risk is not known precisely. A study was undertaken to investigate the associations between RA and type 2 diabetes (DM2), a well-established cardiovascular risk factor, on the one hand, and cardiovascular disease (CVD) on the other. Methods: The prevalence of CVD (coronary, cerebral and peripheral arterial disease) was determined in 353 randomly selected outpatients with RA (diagnosed between 1989 and 2001, aged 50–75 years; the CARRÉ study) and in participants of a population-based cohort study on diabetes and CVD (the Hoorn study). Patients with RA with normal fasting glucose levels from the CARRÉ study (RA, n = 294) were compared with individuals from the Hoorn study with normal glucose metabolism (non-diabetic, n = 258) and individuals with DM2 (DM2, n = 194). Results: The prevalence of CVD was 5.0% (95% CI 2.3% to 7.7%) in the non-diabetic group, 12.4% (95% CI 7.5% to 17.3%) in the DM2 group and 12.9% (95% CI 8.8% to 17.0%) in those with RA. With non-diabetic individuals as the reference category, the age- and gender-adjusted prevalence odds ratio (OR) for CVD was 2.3 (95% CI 1.1 to 4.7) for individuals with DM2 and 3.1 (95% CI 1.6 to 6.1) for those with RA. There was an attenuation of the prevalences after adjustment for conventional cardiovascular risk factors (OR 2.0 (95% CI 0.9 to 4.5) and 2.7 (95% CI 1.2 to 5.9), respectively). Conclusions: The prevalence of CVD in RA is increased to an extent that is at least comparable to that of DM2. This should have implications for primary cardiovascular prevention strategies in RA.

Endothelial Dysfunction, Inflammation, and Apoptosis in Diabetes Mellitus

Endothelial dysfunction is regarded as an important factor in the pathogenesis of vascular disease in obesity-related type 2 diabetes. The imbalance in repair and injury (hyperglycemia, hypertension, dyslipidemia) results in microvascular changes, including apoptosis of microvascular cells, ultimately leading to diabetes related complications. This review summarizes the mechanisms by which the interplay between endothelial dysfunction, inflammation, and apoptosis may cause (micro)vascular damage in patients with diabetes mellitus.

Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis.

Background: Rheumatoid arthritis is characterised by inflammation and an increased cardiovascular risk. It was recently shown that active early rheumatoid arthritis is associated with dyslipidaemia, which may partially explain the enhanced cardiovascular risk. However, it is unknown when this dyslipidaemia starts. Objective: To investigate the progression of the lipid profile over time and the influence of inflammatory parameters on this lipid profile, in people who later developed rheumatoid arthritis. Methods: Levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), triglycerides, apolipoprotein AI (apo AI), apolipoprotein B (apo B) and lipoprotein(a) (Lp(a)) were determined in 1078 stored, deep-frozen, serial blood bank samples, collected between 1984 and 1999, of 79 blood donors who later developed rheumatoid arthritis. These samples were compared with 1071 control samples of unselected blood donors, matched for age, sex and storage time. Results: Samples of patients who later developed rheumatoid arthritis showed, on average, 4% higher total cholesterol, 9% lower HDLc, 17% higher triglyceride and 6% higher apo B levels than matched controls (p⩽0.05). The magnitude of the differences in lipid levels between groups, explained by C reactive protein (CRP), was limited. For example, only 3.6% of the difference in HDLc levels between the groups was explained by the CRP concentrations. Conclusion: Patients who later develop rheumatoid arthritis have a considerably more atherogenic lipid profile than matched blood donors at least 10 years before onset of symptoms. As inflammation only marginally explains the differences between the two groups, a modulating effect of lipids on inflammatory processes is hypothesised.

EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update

Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.

Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis.

Background: Immunogenicity, specifically the onset of antibodies against tumour necrosis factor (TNF) blocking agents, seems to play an important role in non-response to treatment with these drugs. Objectives: To assess the relation of clinical response of ankylosing spondylitis (AS) to etanercept with etanercept levels, and the presence of antibodies to etanercept. Methods: Patients with AS were treated with etanercept 25 mg twice weekly, according to the international Assessment in Ankylosing Spondylitis (ASAS) working group consensus statement. Sera were collected at baseline and after 3 and 6 months of treatment. Clinical response was defined as a 50% improvement or as an absolute improvement of 2 points on a (0–10 scale) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Functional etanercept levels were measured by a newly developed ELISA, measuring the binding of etanercept to TNF. Antibodies against etanercept were measured with a two-site assay and antigen binding test. Clinical data were used to correlate disease activity with serum etanercept levels. Results: In all, 53 consecutive patients were included. After 3 months of treatment 40 patients (76%) fulfilled the response criteria. Mean etanercept levels were 2.7 mg/litre and 3.0 mg/litre after 3 and 6 months respectively. Characteristics and etanercept levels of responders and non-responders were similar. No antibodies to etanercept were detected with any of the assays. Conclusion: Etanercept levels of responders and non-responders were similar and no antibodies to etanercept were detected with any of the assays. This study indicates that etanercept is much less immunogenic compared with the other TNF-blocking agents.

Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients

Objective To investigate the relationship between serum etanercept levels and clinical response. Methods In 292 etanercept-treated patients with rheumatoid arthritis clinical and pharmacological data were determined at baseline and after 1, 4 and 6 months of etanercept treatment. Differences in etanercept levels between good, moderate and European League Against Rheumatism (EULAR) non-responders were assessed after 6 months of therapy. Results After 6 months of therapy etanercept levels were significantly higher in good responders (median (IQR) 3.78 (2.53–5.17)) compared with both moderate 3.10 (2.12–4.47) and EULAR non-responders 2.80 (1.27–3.93) (all p<0.05). There was a significant association between clinical response and serum etanercept levels (regression coefficient 0.54, 95% CI 0.21 to 0.86, p=0.001). When patients were categorised into quartiles according to the height of etanercept levels, the lowest quartile (etanercept level <2.1 mg/l) comprised 40% of all non-responders. The highest quartile (etanercept level >4.7 mg/l) comprised 35% of all good EULAR responders. Anti-etanercept antibodies were detected in none of the sera. Conclusion The authors demonstrated that lower etanercept levels were associated with non-response. Therapeutic drug monitoring and the possibility of the adjusted dosing regimes in the selected groups of patients should be investigated further as a possible tool to optimise treatment with etanercept.

Improvement of Lipid Profile Is Accompanied by Atheroprotective Alterations in High-Density Lipoprotein Composition Upon Tumor Necrosis Factor Blockade A Prospective Cohort Study in Ankylosing Spondylitis

OBJECTIVE Cardiovascular mortality is increased in ankylosing spondylitis (AS), and inflammation plays an important role. Inflammation deteriorates the lipid profile and alters high-density lipoprotein cholesterol (HDL-c) composition, reflected by increased concentrations of serum amyloid A (SAA) within the particle. Anti-tumor necrosis factor (anti-TNF) treatment may improve these parameters. We therefore undertook the present study to investigate the effects of etanercept on lipid profile and HDL composition in AS. METHODS In 92 AS patients, lipid levels and their association with the inflammation markers C-reactive protein (CRP), erythrocyte sedimentation rate, and SAA were evaluated serially during 3 months of etanercept treatment. HDL composition and its relationship to inflammation markers was determined in a subgroup of patients, using surface-enhanced laser desorption/ionization time-of-flight analysis. RESULTS With anti-TNF treatment, levels of all parameters of inflammation decreased significantly, whereas total cholesterol, HDL-c, and apolipoprotein A-I (Apo A-I) levels increased significantly. This resulted in a better total cholesterol:HDL-c ratio (from 3.9 to 3.7) (although the difference was not statistically significant), and an improved Apo B:Apo A-I ratio, which decreased by 7.5% over time (P=0.008). In general, increases in levels of all lipid parameters were associated with reductions in inflammatory activity. In addition, SAA was present at high levels within HDL particles from AS patients with increased CRP levels and disappeared during treatment, in parallel with declining plasma levels of SAA. CONCLUSION Our results show for the first time that during anti-TNF therapy for AS, along with favorable changes in the lipid profile, HDL composition is actually altered whereby SAA disappears from the HDL particle, increasing its atheroprotective ability. These findings demonstrate the importance of understanding the role of functional characteristics of HDL-c in cardiovascular diseases related to chronic inflammatory conditions.

Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: A case series and cohort study

OBJECTIVE We observed 3 patients who developed severe venous and arterial thromboembolic events during treatment with adalimumab, 2 of whom had rheumatoid arthritis (RA) and 1 of whom had psoriatic arthritis. Antiadalimumab antibodies were detected in all 3 patients. We undertook this study to determine whether the development of antiadalimumab antibodies was associated with thromboembolic events during adalimumab treatment. METHODS A retrospective search (with blinding with regard to antiadalimumab antibody status) for thromboembolic events was performed in a prospective cohort of 272 consecutively included adalimumab-treated RA patients. Incidence rates were calculated and hazard ratios (HRs) were estimated using Cox regression. None of the index patients were part of the cohort. RESULTS Antiadalimumab antibodies were detected in 76 of 272 patients (28%). Eight thromboembolic events were found, 4 of which had occurred in patients with antiadalimumab antibodies. The incidence rate was 26.9/1,000 person-years for patients with antiadalimumab antibodies and 8.4/1,000 person-years for patients without those antibodies (HR 3.8 [95% confidence interval 0.9-15.3], P = 0.064). After adjustment for duration of followup, age, body mass index, erythrocyte sedimentation rate, and prior thromboembolic events, the HR was 7.6 (95% confidence interval 1.3-45.1) (P = 0.025). CONCLUSION These findings suggest that the occurrence of venous and arterial thromboembolic events during adalimumab treatment is higher in patients with antiadalimumab antibodies than in those without antiadalimumab antibodies. Patient numbers were relatively small; therefore, validation in other cohorts is mandatory.

Changes in lipid profile during infliximab and corticosteroid treatment in rheumatoid arthritis

Objective: To evaluate the effects of infliximab and corticosteroid treatment on the lipid profile in patients with active rheumatoid arthritis (RA). Methods: Infliximab infusions were given at weeks 0, 2, 6 and then every 8 weeks. Before each infusion, disease activity parameters (Disease Activity Index 28-Joint Score (DAS28)) C reactive protein (CRP) and lipid levels (total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, apolipoprotein A1 (apo A1) and apolipoprotein B) were measured in 80 consecutive patients with RA, who completed the study period of 48 weeks. Longitudinal analyses were used to investigate (1) the course of lipid levels over a period of time and (2) the relationship between lipids, prednisone dose and disease activity. Results: Infliximab treatment causes a significant reduction in disease activity and a concomitant decrease in prednisone dose. Although they initially improved significantly, all lipid levels had returned to baseline levels after 48 weeks, except for apo A1. Longitudinal analyses revealed significant yet opposite associations between lipid levels and disease activity and between lipid levels and prednisone dose. DAS28 improvement by 1 point was associated with an increase of 0.016 mmol/l (0.618 mg/dl) total cholesterol and 0.045 mmol/l (1.737 mg/dl) HDL-cholesterol. Reduction of 10 mg prednisone was associated with a decrease of 0.04 mmol/l (1.544 mg/dl) total cholesterol and 0.16 mmol/l (6.177 mg/dl) HDL-cholesterol. Conclusion: Overall, no changes in serum lipid levels were observed after 48 weeks of infliximab treatment. The initial beneficial effects of infliximab on the lipid profile, by means of a reduction of disease activity, are attenuated by a concomitant decrease in prednisone dose.