Iris Navarro-Millán

Systematic Review of Tocilizumab for Rheumatoid Arthritis: A New Biologic Agent Targeting the Interleukin-6 Receptor

BACKGROUND Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, represents a new treatment strategy for patients with rheumatoid arthritis (RA) and is currently approved in the United States for RA patients who have failed to improve with at least one anti-tumor necrosis factor therapy. OBJECTIVE The goal of this study was to summarize the efficacy and safety profile of TCZ. METHODS A systematic literature review was conducted to identify English-language articles within PubMed and the Cochrane Library from January 1989 to August 2011 reporting results from Phase III TCZ double-blind, randomized controlled trials (RCTs), noncontrolled clinical trials, and open-label extensions with a duration ≥6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, or 70 response rates; tender/swollen joint count; Health Assessment Questionnaire-Disability Index; radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in Phase III RCTs. Relevant studies were selected to evaluate TCZs pharmacokinetics and pharmacodynamics. RESULTS Ten published clinical trials (7 Phase III, 3 Phase II) for TCZ were retrieved (7833 articles initially identified) from PubMed and 31 from the Cochrane library. Compared with methotrexate (MTX) monotherapy, TCZ 8 mg/kg IV monotherapy had higher rates of ACR20 (P < 0.001), ACR50 (P = 0.002), and ACR70 (P < 0.001) scores at week 24. TCZ 8 mg/kg IV plus oral MTX had a higher ACR20 response rate than oral MTX plus placebo in patients with RA who failed to respond to MTX or anti-tumor necrosis factor therapy (P < 0.001). Patients receiving TCZ 8 mg/kg had less radiographic progression on the Genant-modified Sharp score (85% had no progression) than the control group (67% had no progression) (P < 0.001). The rate of serious infections was 4.7 events/100 patient-years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis was observed with TCZ compared with placebo. CONCLUSION The short-term efficacy and safety profile of TCZ is promising. Additional long-term safety data are needed to better characterize the risk-benefit profile of this agent.

Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial.

OBJECTIVE To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. METHODS This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. RESULTS At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). CONCLUSION Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined.

Systematic Review of Tumor Necrosis Factor Inhibitor Discontinuation Studies in Rheumatoid Arthritis

BACKGROUND Anti-tumor necrosis factor agents (anti-TNFs) have changed the course of rheumatoid arthritis (RA) for more than a decade. Use of these medications often results in remission, or at least low disease activity (LDA), but at a substantial cost. It has been postulated that discontinuation of these medications among patients with RA in remission or LDA may be possible without an associated increase in RA disease activity. OBJECTIVE The goal of this systematic literature review was to summarize published articles regarding discontinuation of anti-TNFs in patients with RA. METHODS A systematic literature review was conducted to identify English-language articles indexed in PubMed from July 1999 through June 2013 reporting results regarding anti-TNF discontinuation in patients with RA. Study designs included observational longitudinal studies and clinical trials. Outcomes had to include 1 of the following: time to flare after anti-TNF discontinuation, failure to remain in remission, or proportion of patients in LDA or remission at the end of the study. RESULTS Ten studies examined discontinuation of anti-TNF therapies in RA. Inclusion criteria varied significantly across studies in terms of disease activity status (remission or LDA) and duration of this disease status (1 year or 1 month) before discontinuation being attempted. Results from larger studies (eg, >100 patients) suggest that the proportion of patients who discontinued anti-TNF and did not have an increase in disease activity ranged from 24% to 81%. In 3 studies that evaluated durability of LDA or remission after anti-TNF discontinuation, the mean time to relapse varied from 15 weeks to 17 months. In studies that analyzed radiographic data, once therapies were reinitiated after an increase in disease activity was detected, patients generally did not experience progression in structural damage. CONCLUSIONS Discontinuation of anti-TNF therapy is achievable for many RA patients who start in clinical remission or LDA. However, heterogeneous inclusion criteria and highly variable outcome definitions across studies make it difficult to efficiently summarize the literature on this topic or to conduct a meta-analysis. There is a lack of evidence regarding how to best predict which patients have the greatest likelihood of continuing to do well after discontinuation of anti-TNF therapy.

Predicting low disease activity and remission using early treatment response to antitumour necrosis factor therapy in patients with rheumatoid arthritis: exploratory analyses from the TEMPO trial

Objective To derive and validate decision trees to categorise rheumatoid arthritis (RA) patients 12 weeks after starting etanercept with or without methotrexate into three groups: patients predicted to achieve low disease activity (LDA) at 1 year; patients predicted not to achieve LDA at 1 year and patients who needed additional time on therapy to be categorised. Methods Data from RA patients enrolled in the TEMPO trial were analysed. Classification and regression trees were used to develop and validate decision tree models with week 12 and earlier assessments that predicted long-term LDA. LDA, defined as disease activity score in 28 joints (DAS28) ≤3.2 or clinical disease activity index ≤10.0, was measured at 52 or 48 weeks. Demographics, laboratory data and clinical data at baseline and to week 12 were analysed as predictors of response. Results 39% (67/172) of patients receiving etanercept and 60% (115/193) of patients receiving etanercept plus methotrexate achieved LDA at week 52. For patients receiving etanercept, 53% were predicted to have LDA, 39% were predicted not to have LDA and 8% could not be categorised using DAS28 criteria at week 12. For patients receiving etanercept plus methotrexate, 63% were predicted to have LDA, 25% were predicted not to have LDA and 12% could not be categorised. Conclusion Most (80–90%) patients in TEMPO initiating etanercept with or without methotrexate could be predicted within 12 weeks of starting therapy as likely to have LDA or not at week 52. However, approximately 10–20% of patients needed additional time on therapy to decide whether to continue treatment.

Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration

Objective To examine the association of serum lipids, inflammation and seropositivity on coronary heart disease (CHD) and stroke in patients with rheumatoid arthritis (RA). Methods The incidence of hospitalised myocardial infarction (MI) or stroke was calculated in a cohort of patients with RA receiving care within the national Veterans Health Administration from 1998 to 2011. Cox proportional hazard models were used to examine the association between these outcomes and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as time-varying variables, divided into quintiles. Results There were 37 568 patients with RA in the cohort with mean age of 63 years (SD 12.1); 90% were men. There was a no clear association between LDL-C and CHD/stroke. Compared with lower HDL-C (<34 mg/dL), higher HDL-C (≥54 mg/dL) was inversely associated with MI (hazard ratio (HR)=0.68, 95% CI 0.55 to 0.85) and stroke (HR=0.69, 95% CI 0.50 to 0.96). Higher CRP >2.17 mg/dL (vs CRP <0.26 mg/dL) was associated with increased risk (HR=2.43, 95% CI 1.77 to 3.33) for MI and 2.02 (95% CI 1.32 to 3.08) for stroke. ESR >47 mm/h compared with <8 mm/h had an HR 1.87 (95% CI 1.39 to 2.52) for MI and 2.00 (95% CI 1.26 to 3.18) for stroke. The association between MI was significant for RA seropositivity (HR=1.23, 95% CI 1.03 to 1.48). Conclusions In this predominantly older male RA cohort, there was no clear association between LDL-C and CHD, whereas higher HDL-C was inversely associated with MI and stroke. CRP and ESR were similarly associated with increase MI risk and stroke, reflecting the prominent role of inflammation in CHD risk in RA.

Newest clinical trial results with antitumor necrosis factor and nonantitumor necrosis factor biologics for rheumatoid arthritis.

Purpose of reviewTo highlight recent evidence from the clinical trials of anti-tumor necrosis factor (TNF) and non anti-TNF biologics for rheumatoid arthritis (RA) focused on comparative clinical efficacy including safety outcomes and medication discontinuation. Recent findingsPatients with RA are sometimes able to attain low disease activity or remission since the introduction of biologic therapy for RA. Biologics like anti-TNF, anti-interleukin-6 (IL-6), anti-CD20 and those that modulate T-cell co-stimulation have consistently shown good efficacy in patients with RA. Preliminary data from comparative efficacy studies to evaluate the potential differences between anti-TNF and non anti-TNF biologics have shown little differences among these. There is ongoing work in comparative efficacy to answer this question further. SummaryBiologic therapy in RA has significantly changed the course of RA in the last decade. Recently published clinical trials have been focused on comparative efficacy, cardiovascular safety of biologics and potential anti-TNF therapy discontinuation in patients with RA.

Clinical Response Within 12 Weeks as a Predictor of Future Low Disease Activity in Patients with Early RA: Results from the TEAR Trial

Objective. Rapidly predicting future outcomes based on short-term clinical response would be helpful to optimize rheumatoid arthritis (RA) management in early disease. Our aim was to derive and validate a clinical prediction rule to predict low disease activity (LDA) at 1 year among patients participating in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial escalating RA therapy by adding either etanercept or sulfasalazine + hydroxychloroquine [triple therapy (TT)] after 6 months of methotrexate (MTX) therapy. Methods. Eligible subjects included in the derivation cohort (used for model building, n = 186) were participants with moderate or higher disease activity [Disease Activity Score 28-erythrocyte sedimentation rate (DAS-ESR) > 3.2] despite 24 weeks of MTX monotherapy who added either etanercept or sulfasalazine + hydroxychloroquine. Clinical characteristics measured within the next 12 weeks were used to predict LDA 1 year later using multivariable logistic regression. Validation was performed in the cohort of TEAR patients randomized to initially receive either MTX + etanercept or TT. Results. The derivation cohort yielded 3 prediction models of varying complexity that included age, DAS28 at various timepoints, body mass index, and ESR (area under the receiver-operator characteristic curve up to 0.83). Accuracy of the prediction models ranged between 80% and 95% in both derivation and validation cohorts, depending on the complexity of the model and the cutpoints chosen for response and nonresponse. About 80% of patients could be predicted to be responders or nonresponders at Week 12. Conclusion. Clinical data collected early after starting or escalating disease-modifying antirheumatic drug/biologic treatment could accurately predict LDA at 1 year in patients with early RA. For patients predicted to be nonresponders, treatment could be changed at 12 weeks to optimize outcomes.

Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two‐Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial

To evaluate long‐term changes in cholesterol levels in patients with early rheumatoid arthritis (RA) who were randomized to begin treatment with methotrexate (MTX) monotherapy, MTX plus etanercept, or triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial.

Improvement of High-Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial.

Abnormal function of high‐density lipoprotein (HDL) has been implicated as a potential mechanism for the increased incidence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). This study was undertaken to evaluate changes in HDL function and HDL‐associated proteins over 2 years of follow‐up in patients with early RA receiving either methotrexate (MTX) monotherapy, MTX + etanercept (ETN) combination therapy, or MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ) triple therapy in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial.

Dose escalation of certolizumab pegol from 200 mg to 400 mg every other week provides no additional efficacy in rheumatoid arthritis: An analysis of individual patient‐level data

OBJECTIVE To determine whether certolizumab pegol (CZP) dosage escalation from 200 mg to 400 mg every other week benefits some patients with rheumatoid arthritis (RA). METHODS In the extension of the Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) study into an open-label study, all patients received CZP 400 mg every other week in combination with methotrexate (MTX). Before the open-label phase of the study, patients had received CZP 200 mg or 400 mg every other week, or placebo every other week, as add-on therapy to MTX. The open-label study included those who had completed the RAPID 1 study (to week 52) and also those who had been withdrawn from the study (at week 16, due to inadequate response). At 12 weeks and 48 weeks after enrollment in the open-label study, changes in the Disease Activity Score in 28 joints (DAS28) were compared in dose-escalation patients (200 mg increased to 400 mg every other week) versus stable-dosage patients (400 mg every other week), using cumulative probability plots of individual patient-level data. RESULTS In the group of patients who had completed the RAPID 1 study and had moderate or severe disease activity at entry into the open-label study, and in those who had been withdrawn early from the RAPID 1 study, the median DAS28 improvements 12 weeks after enrollment into the open-label study were similar in the dose-escalation and stable-dose groups. Individual patient-level data revealed no greater likelihood of response in the group of patients who received an increased dosage of CZP versus those in whom a stable dosage was maintained, whether they had completed the RAPID 1 study or had been withdrawn early. CONCLUSION Although patient heterogeneity in clinical settings is acknowledged, the present results indicate that increasing the dose of CZP from 200 mg to 400 mg offers little additional benefit in RA, even for selected patients.