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Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis.

ABSTRACT: OBJECTIVE:Compare changes in lipids and lipid-associated cardiovascular (CV) risk markers in patients with rheumatoid arthritis (RA) treated with tocilizumab or adalimumab. METHODS:Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4?weeks or adalimumab subcutaneously every 2?weeks for 24?weeks in the ADACTA trial. Lipid and lipid-associated CV risk biomarkers, including high-density lipoprotein-associated serum amyloid-A (HDL-SAA), secretory phospholipase A2 IIA (sPLA2 IIA) and lipoprotein(a) (Lp(a)), were measured at baseline and at week 8. RESULTS:The study included 162 patients treated with tocilizumab and 162 patients treated with adalimumab; HDL-SAA and sPLA2 IIA were measured in a subpopulation of 87 and 97 patients, respectively. Greater increases in mean low-density lipoprotein cholesterol (LDL-C) (0.46?mmol/L (95% CI 0.30 to 0.62)), high-density lipoprotein cholesterol (HDL-C) (0.07?mmol/L (0.001 to 0.14)), total cholesterol (TC) (0.67?mmol/L (0.47 to 0.86)), triglycerides (0.24?mmol/L (0.10 to 0.38)) and TC:HDL ratio (0.27 (0.12 to 0.42)) occurred with tocilizumab from baseline to 8?weeks. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab than adalimumab. Median changes from baseline to week 8 were -3.2 and -1.1?mg/L (p=0.0077) for HDL-SAA and -4.1 and -1.3?ng/mL (p<0.0001) for sPLA2 IIA; difference in adjusted means was -7.12?mg/dL (p<0.0001) for Lp(a). Similar results were observed in efficacy responders and non-responders per American College of Rheumatology and European League against Rheumatism criteria. CONCLUSION:LDL-C and HDL-C increased more with tocilizumab than adalimumab. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab. Lipid change effects of interleukin-6 and tumour necrosis factor (TNF) inhibition, manifest by their net impact on lipids and lipoproteins, are not synonymous; the clinical significance is unclear and requires further study. TRIAL REGISTRATION NUMBER:NCT01119859.; post-results.

SUBMITTER: Gabay C

PROVIDER: S-EPMC5036214 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis.

Gabay Cem C McInnes Iain B IB Kavanaugh Arthur A Tuckwell Katie K Klearman Micki M Pulley Jennifer J Sattar Naveed N

Annals of the rheumatic diseases 20151127 10

<h4>Objective</h4>Compare changes in lipids and lipid-associated cardiovascular (CV) risk markers in patients with rheumatoid arthritis (RA) treated with tocilizumab or adalimumab.<h4>Methods</h4>Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4 weeks or adalimumab subcutaneously every 2 weeks for 24 weeks in the ADACTA trial. Lipid and lipid-associated CV risk biomarkers, including high-density lipoprotein-associated serum amyloid-A (HDL-SAA), se ...[more]

PMID: 26613768

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Project description:Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint pain, swelling, stiffness, and progressive destruction of the small joints of the hands and feet. Treatment of RA has improved over the past decade. With multiple cytokines well-known now to play a role in the pathogenesis of RA, including tumor necrosis factor alpha, interleukin (IL)-1?, and IL-6, many targeted biological treatments against these cytokines have emerged, changing the treatment of this disease. Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA. The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ. Furthermore, efficacy studies of TCZ as both monotherapy and combination therapy will be evaluated. There have been several important clinical trials evaluating the efficacy and safety of TCZ in RA patients; this review summarizes this data from 14 key trials with emphasis on Phase III trials. Review of these trials provides strong evidence that its use, both as monotherapy and in combination with methotrexate or other DMARDs, is an effective treatment in reducing the signs and symptoms of RA. TCZ showed tolerable safety but care is required for its use since there are some important safety concerns including elevated liver enzymes, elevated low-density lipoprotein, infections, and gastrointestinal perforations. Additionally, given the efficacy of TCZ in the treatment of RA, this review discusses how TCZ may be beneficial in the treatment of other autoimmune diseases, spinal disease, cardiovascular disease, organ transplantation, and malignancies where elevated levels of IL-6 may play a role in the pathogenesis of these diseases.

Project description:BackgroundTreatment with tumor necrosis factor inhibitors for rheumatoid arthritis has been associated with a decreased risk of cardiovascular disease in observational studies. There are conflicting data on the influence of tumor necrosis factor inhibitors on lipid levels.ObjectivesTo evaluate the effect of treatment with adalimumab on blood lipid levels, lipoproteins, and atherosclerosis of the carotid artery.MethodsFourteen patients with active rheumatoid arthritis (11 women and 3 men; mean age 63.7 years; median disease duration 9.0 years; and 78% rheumatoid factor positive) were treated with adalimumab 40 mg subcutaneously every 2 weeks and followed for 3 months. The patients had not been treated with adalimumab previously and had not received other tumor necrosis factor inhibitors within the past 3 months or moderate/high dose corticosteroids within the past 2 weeks. The intima-media thickness of the common carotid artery was assessed using B mode ultrasonography. Triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol levels were analyzed in fresh fasting blood samples, whereas apolipoprotein B and apolipoprotein A1 (apoA1) levels were determined in thawed plasma samples using standard turbidimetric immunoassays.ResultsTotal cholesterol (mean = 5.36 vs 5.96 mmol/L; P = 0.005), LDL cholesterol (mean = 3.33 vs 3.77 mmol/L; P = .005), HDL cholesterol (mean = 1.43 vs 1.55 mmol/L; P = 0.048), apolipoprotein B (mean = 1.04 vs 1.13 g/L; P = .012), and apoA1 (mean = 1.42 vs 1.58 g/L; P = 0.005) all increased, but there were no major changes in the LDL to HDL cholesterol ratio (median = 2.56 vs 2.35; P = 0.27) or the apolipoprotein B to apoA1 ratio (mean = 0.76 vs 0.74; P = 0.46). There was no change in triglyceride levels (P = 0.55). Disease activity decreased significantly from baseline to the 3-month evaluation (disease activity score based on 28 joints mean = 5.6 vs 4.1; P = 0.007). An increase in apoA1 correlated with decreases in the patient global assessment of disease severity (r = 0.79; P = 0.001) and C-reactive protein level (r = 0.74; P = 0.003). Changes in the apoliprotein B to apoA1 ratio correlated with changes in erythrocyte sedimentation rate (r = 0.54; P = 0.046). There was no major change in the common carotid artery intima-media thickness (mean = 0.78 vs 0.80 mm; P = 0.48).ConclusionsAlthough these results suggest that control of inflammation could have a beneficial effect on the lipid profile through an increase in HDL cholesterol levels, the observed protective effect on cardiovascular disease events by tumor necrosis factor blockers is likely to be explained by other mechanisms than changes in lipid levels or short-term effects on atherosclerosis of the carotid artery.

Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA.Analyses included patients treated with adalimumab 40 mg once every 2 weeks or tofacitinib 10 mg twice daily (BID) with background methotrexate (MTX) in a 12-month randomized study (NCT00853385), who subsequently received tofacitinib 10 mg BID (with/without background MTX) in an open-label extension (NCT00413699). Patients with treatment-related serious adverse events (AEs) and serious or recurrent infections in the index study were excluded from the extension study. Exposure-adjusted incidence rates of safety-related events were assessed in 3-month and 12-month periods in the year before and in the year after switching. Efficacy was assessed 3 months before, at the time of, and 3 months after switching.There were 233 (107 adalimumab to tofacitinib 10 mg BID, 126 blinded to open-label tofacitinib 10 mg BID) patients included in these analyses. Patients in both treatment sequences had similar incidence rates (per 100 patient-years) of discontinuation due to AEs, serious AEs, and serious infections in the year before and in the year after switching. Incidence rates of AEs were increased in the first 3 months after switching compared with the last 3 months before switching in both treatment groups. Switching from either blinded adalimumab or tofacitinib to open-label tofacitinib resulted in numerically higher incidence of responders for signs and symptoms of disease and improved physical function.Treatment can be directly switched from adalimumab to tofacitinib. A similar safety and efficacy profile was seen when patients received open-label tofacitinib after receiving either blinded adalimumab or tofacitinib.ClinicalTrials.gov Identifiers: NCT00853385 , registered 27 February 2009; NCT00413699 , registered 18 December 2006.

Project description:Lower levels of low-density lipoprotein (LDL) cholesterol may be associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). This study was undertaken to determine whether the complex relationship between levels of LDL and high-density lipoprotein (HDL) cholesterol and CV risk is different in RA patients as compared to non-RA controls.Using data from a US health insurance plan (2003-2012), we conducted a cohort study that included patients with RA and non-RA control subjects matched with regard to age, sex, and index date. The nonlinearity of associations between lipid levels and incidence of major adverse CV events (MACE) was tested. We used multivariable Cox proportional hazards regression models to examine for an interaction between lipid levels and RA status in relation to the risk of MACE, after adjustment for CV risk factors.In total, 16,085 RA patients and 48,499 non-RA controls were studied. The mean age was 52.6 years and 78.6% were women. The relationship between LDL cholesterol levels and incidence of MACE was nonlinear and similar between RA patients and non-RA controls (P for interaction?=?0.72). No significant increase in CV risk was observed between the lowest quintile of LDL cholesterol levels (?91.0 mg/dl) and the second, third, or fourth quintiles, whereas the highest quintile (>190.0 mg/dl) conveyed a 40% increase in risk of MACE (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.17-1.68). The relationship between HDL cholesterol levels and incidence of MACE was also nonlinear and similar between RA patients and non-RA controls (P for interaction?=?0.39). Compared to the lowest quintile of HDL cholesterol levels, each successive quintile was associated with a reduced risk of MACE (HR 0.45, 95% CI 0.48-0.72 for lowest quintile [?43.0 mg/dl] versus highest quintile [>71.0 mg/dl]).The complex relationship between LDL cholesterol levels, HDL cholesterol levels, and risk of MACE was nonlinear in RA patients and also not statistically significantly different from that in an age- and sex-matched non-RA cohort.

Project description:BackgroundSince receiving a positive recommendation in England, Wales and Scotland, tocilizumab (TCZ) is one of the options available to clinicians for the treatment of rheumatoid arthritis (RA) patients in the UK.ObjectiveThe objective of this study was to evaluate the cost effectiveness of adding TCZ to the current treatment sequence of RA patients from a UK payer's perspective over a patient lifetime horizon.MethodsAn individual sampling model was developed to synthesise all clinical and economic inputs. Two scenarios were explored separately: patients contraindicated to methotrexate (MTX) and those MTX tolerant. For each scenario, the analysis compared three strategies. The standard of care (SoC) strategy included a sequence of the most commonly prescribed biologics; the other two comparator strategies considered the addition of TCZ to SoC at first line and second line. Patient characteristics were representative of UK patients. Treatment efficacy and quality-of-life evidence were synthesised from clinical trials and secondary sources. An analysis of a patient registry informed the model parameters regarding treatment discontinuation. The safety profile of all treatments in a given strategy was based on a network meta-analysis and literature review. Resource utilisation, treatment acquisition, administration, monitoring and adverse event treatment costs were considered. All costs reflect 2012 prices. Uncertainty in model parameters was explored by one-way and probabilistic sensitivity analysis.ResultsIn the MTX-contraindicated population, if TCZ was added to the SoC in first line, the estimated incremental cost-effectiveness ratio (ICER) was £7,300 per quality-adjusted life-year (QALY) gained; if added in second line, the estimated ICER was £11,400 per QALY. In the MTX-tolerant population, the estimated costs and QALYs of the TCZ strategy were similar to those of the SoC strategy. Sensitivity analysis showed that parameters that affect the treatment cost (such as patient weight) can have a noticeable impact on the overall cost-effectiveness results. The majority of the other sensitivity analyses resulted in modest changes to the ICER.ConclusionFor the treatment of RA in MTX-tolerant and contraindicated patients, the addition of TCZ to the SoC was estimated to be a cost-effective strategy.

Dataset Information

Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis.

Publications

Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis.

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