The objective of this study was to assess the impact of certolizumab pegol (CZP) treatment on health-related quality of life (HRQoL), fatigue and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA).
Patients with active RA (N = 982) were randomized 2:2:1 to subcutaneous CZP (400 mg at weeks 0, 2 and 4; followed by CZP 200 mg or 400 mg) plus methotrexate (MTX) every other week, or placebo (PBO) plus MTX. PRO assessments included HRQoL, fatigue, physical function, arthritis pain and disease activity. Adjusted mean changes from baseline in all PROs were obtained using analysis of covariance (ANCOVA) applying last observation carried forward (LOCF) imputation. The proportion of patients achieving clinically meaningful improvements in each PRO was obtained using logistic regression and by applying non-responder imputation to missing values after rescue medication or withdrawal. The correlations between PRO responses and clinical responses were also assessed by tetrachoric correlation using non-responder imputation.
Patients treated with CZP plus MTX reported significant (P < 0.001), clinically meaningful improvements in HRQoL at the first assessment (week 12); reductions in fatigue, disease activity and pain and improvements in physical function were reported at week 1. In particular, CZP-treated patients reported improvements in mental health. Mean changes from baseline in the SF-36 Mental Component Summary (MCS) at week 52 for CZP 200 mg and 400 mg plus MTX, and PBO plus MTX were 6.4, 6.4 and 2.1, respectively (P < 0.001). In addition, mental health and vitality scores in CZP-treated patients approached age- and gender-adjusted US population norms. Improvements in all PROs were sustained. Similar benefits were reported with both CZP doses. Changes in SF-36 MCS scores had the lowest correlation with disease activity scores (DAS28) and American College of Rheumatology 20% improvement (ACR20) response rates, while improvements in pain showed the highest correlation.
Treatment with CZP plus MTX resulted in rapid and sustained improvements in all PROs, indicating that the benefits of CZP extend beyond clinical efficacy endpoints into areas that are more relevant and meaningful for patients on a daily basis.
Objectives. To evaluate the association between improvements in physical function, fatigue and pain and improvements in productivity at work and at home in patients treated with certolizumab pegol (CZP) in combination with MTX.
Methods. Physical function, fatigue and pain were assessed in two CZP clinical trials (Rheumatoid Arthritis PreventIon of structural Damage 1 and 2) using the HAQ-Disability Index (HAQ-DI), Fatigue Assessment Scale (FAS) and Patient Assessment of Pain, with minimal clinically important differences (MCIDs) defined as ≥0.22, ≥1 and ≥10 points, respectively. Work and home productivity were evaluated using the RA-specific Work Productivity Survey (WPS-RA). The odds of achieving an HAQ-DI, FAS or pain ‘response’ at Week 12, defined as improvements ≥MCID, were compared between CZP and control groups. Improvements in productivity at Week 12 were compared between CZP-treated HAQ-DI, FAS or pain responders and non-responders.
Results. The odds of achieving improvements ≥MCID were five times higher for pain, and two to three times higher for physical function and fatigue, in patients receiving CZP vs control. Per month, responders reported significantly greater improvements in productivity at work and reduced interference of RA with their work productivity than non-responders. Responders also reported significantly greater improvements in productivity at home and participation in family, social and leisure activities.
Conclusions. This study demonstrated a clear association between patient-reported improvements in physical function, fatigue and pain, and improvements in productivity both at work and home.
Rheumatoid arthritis; Certolizumab pegol; Physical function; Fatigue; Pain; TNF; Work productivity; Household productivity; Daily activities
Biological agents, including TNF inhibitors, have revolutionized the treatment of RA in recent years. Certolizumab pegol (CZP) is a novel pegylated anti-TNF approved for the treatment of adult patients with moderately to severely active RA. This article provides an overview of three published clinical trials of CZP in RA in patients with active disease who have shown an inadequate response to DMARDs, including MTX: RA prevention of structural damage (RAPID) 1 and 2, which evaluated the efficacy and safety of CZP added to MTX when dosed every 2 weeks, and efficacy and safety of CZP – 4 weekly dosage in rheumatoid arthritis (FAST4WARD), which evaluated CZP monotherapy when dosed every 4 weeks. In the trials, CZP plus MTX or as monotherapy significantly improved the signs and symptoms of RA and RA disease activity, and CZP plus MTX significantly inhibited the progression of radiographic joint damage as early as Week 16 of the treatment. In addition, CZP treatment significantly improved patient-reported outcome measures, providing significant reductions in pain and fatigue and improvements in physical function as early as Week 1 of treatment; improvements in health-related quality of life were evident at the first assessment at Week 12. CZP treatment improved productivity at work, significantly reducing the number of days of missed work as well as the number of days with reduced productivity, and also increased productivity within the home and improved participation in family, social and leisure activities. CZP was generally well tolerated when used either as monotherapy or added to MTX; most adverse events were mild or moderate. Taken together, the results of these trials suggest that CZP is an effective new option for the treatment of RA.
Certolizumab pegol; Methotrexate; Monotherapy; Rheumatoid arthritis; TNF-α inhibitor
Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor.
To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA).
An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function.
Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p⩽0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4, respectively, versus 1.2 for placebo (rank analysis p⩽0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50, respectively, versus −0.14 for placebo (p⩽0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis.
Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression.
Trial registration number:
The ACR hybrid (a modified mean percent response to treatment) was officially recommended by the ACR as a revision to ACR20/50/70 scores but has not been tested in clinical trials. We performed a post hoc analysis of a phase III study of certolizumab pegol (RAPID 1) using the ACR hybrid.
Patients with active RA were randomized to certolizumab pegol (200 mg or 400 mg every other week) plus methotrexate or placebo plus methotrexate. ACR hybrid scores were compared with ACR20/50/70 outcomes.
Differences between active treatment and placebo were significant throughout the study using the ACR20 and ACR hybrid outcomes. In the certolizumab pegol 200 mg group, the median ACR hybrid score at Week 52 (LOCF) was 49.99. 258/392 (65.8%) and 172/392 (43.9%) patients had ACR20 and ACR50 responses, respectively. An additional 55 (14.0%) and 59 (15.1%) patients had mean improvements in ACR core measures of ≥20% and ≥50%, respectively, and therefore had positive ACR hybrid scores, despite lacking ACR20 and ACR50 responses, respectively. In the placebo group, median ACR hybrid scores were <10 at most time points; unlike other measures, the ACR hybrid measure indicated worsening scores for many patients.
ACR hybrid analysis had greater sensitivity than traditional ACR20/50/70 criteria, demonstrating improvements in ACR20 nonresponders treated with certolizumab pegol. Negligible benefit was observed with placebo using ACR hybrid analysis.
To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA).
Patients were randomised 1:1:1 to placebo, 200 mg CZP every 2 weeks (Q2W) or 400 mg CZP every 4 weeks (Q4W). Patients could have had exposure to one previous tumour necrosis factor (TNF) inhibitor therapy. Primary endpoints were American College of Rheumatology 20% (ACR20) response at week 12 and modified Total Sharp Score change from baseline at week 24. Secondary endpoints included; Psoriatic Arthritis Response Criteria (PsARC) score, Health Assessment Questionnaire Disability Index (HAQ-DI), Psoriasis Area and Severity Index, Leeds Enthesitis Index, Leeds Dactylitis Index, and Modified Nail Psoriasis Severity Index.
Of 409 patients randomised, 368 completed 24 weeks of treatment. ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1. There was a statistically significant improvement in physical function from baseline, measured by HAQ-DI in CZP patients compared with placebo (−0.50 vs −0.19, p<0.001) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo (78.3% and 77.0% vs 33.1% (p<0.001)). Sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis and nail disease. Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure. No new safety signals were observed.
Rapid improvements in the signs and symptoms of PsA, including joints, skin, enthesitis, dactylitis and nail disease were observed across both CZP dosing regimens.
Anti-TNF; Treatment; Psoriatic Arthritis
To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-axSpA (NCT01087762), an ongoing Phase 3 trial in patients with axial spondyloarthritis (axSpA), including patients with ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA).
Patients with active axSpA were randomised 1:1:1 to placebo, CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg every 4 weeks (Q4W). In total 325 patients were randomised. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society 20) response at week 12. Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) linear.
Baseline disease activity was similar between AS and nr-axSpA. At week 12, ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (57.7 and 63.6 vs 38.3, p≤0.004). At week 24, combined CZP arms showed significant (p<0.001) differences in change from baseline versus placebo in BASFI (−2.28 vs −0.40), BASDAI (−3.05 vs −1.05), and BASMI (−0.52 vs −0.07). Improvements were observed as early as week 1. Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA subpopulations. Adverse events were reported in 70.4% vs 62.6%, and serious adverse events in 4.7% vs 4.7% of All CZP versus placebo groups. No deaths or malignancies were reported.
CZP rapidly reduced the signs and symptoms of axSpA, with no new safety signals observed compared to the safety profile of CZP in RA. Similar improvements were observed across CZP dosing regimens, and in AS and nr-axSpA patients.
To determine the prognostic significance of data collected early after starting certolizumab pegol (CZP) to predict low disease activity (LDA) at Week 52.
Data through Week 12 from 703 CZP-treated patients in the RA PreventIon of structural Damage (RAPID 1) trial were used as variables to predict LDA (DAS28 [ESR] ≤3.2) at Week 52. We identified variables, developed prediction models using classification trees, and tested performance using training and testing datasets. Additional prediction models were constructed using CDAI and an alternate outcome definition (composite of LDA or ACR50).
Using Week 6 and 12 data and across several different prediction models, response (LDA) and nonresponse at 1 year was predicted with relatively high accuracy (70–90%) for most patients. The best performing model predicting nonresponse by 12 weeks was 90% accurate and applied to 46% of the population. Model accuracy for predicted responders (30% of the RAPID1 population) was 74%. The area under the receiver operator curve was 0.76. Depending on the desired certainty of prediction at 12 weeks, ~12–24% of patients required >12 weeks of treatment to be accurately classified. CDAI-based models, and those evaluating the composite outcome (LDA or ACR50), achieved comparable accuracy.
We could accurately predict within 12 weeks of starting CZP whether most established RA patients with high baseline disease activity would likely achieve/not achieve LDA at 1 year. Decision trees may be useful to guide prospective management for RA patients treated with CZP and other biologics.
Objective. To investigate the effect of tocilizumab on patient-reported outcomes (PROs) in RA patients with inadequate responses to TNF inhibitors (TNFis).
Methods. In a Phase III randomized controlled trial, 489 patients received 4 or 8 mg/kg tocilizumab or placebo every 4 weeks plus MTX for 24 weeks. Mean changes from baseline over time and proportions of patients reporting improvements greater than or equal to minimum clinically important differences (MCIDs) in PROs were analyzed.
Results. At week 24, 8 mg/kg resulted in significantly greater improvements vs placebo in pain, global assessment of disease activity (P = 0.001), Health Assessment Questionnaire-Disability Index (HAQ-DI; P < 0.0001), Functional Assessment of Chronic Illness Therapy-Fatigue (P = 0.0150) and Medical Outcomes Survey Short Form 36 (SF-36 v2) Physical Component Summary (PCS; P = 0.0003) scores, all greater than MCID; 4 mg/kg resulted in greater improvements in pain (P = 0.0100), HAQ-DI (P = 0.0030) and SF-36 PCS (P = 0.0020) scores. Tocilizumab-associated improvements were evident as early as week 2. At week 24, more tocilizumab-treated than control patients reported improvements greater than or equal to MCID in SF-36 domain scores and related PROs (50.9–84.9% vs 35.0–51.7%) and achieved ACR50 responses and/or Disease Activity Score 28 (DAS28) remission with PRO improvements greater than or equal to MCID (36.2–51.2% vs 10–20.7% and 10.7–37.5% vs 0.0–3.4%, respectively).
Conclusion. Tocilizumab treatment in patients with inadequate responses to TNFis resulted in rapid and sustained improvements in multiple PROs that were statistically significant and clinically meaningful, consistent with previous efficacy reports.
Trial Registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00106522.
rheumatoid arthritis; tocilizumab; health-related quality of life; patient-reported outcomes; randomized controlled trial
To evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD).
This phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in ≥2 intestinal segments with a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≥8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score <6), complete remission (CDEIS score <3) and mucosal healing (no ulcer) at weeks 10 and 54.
In the intention-to-treat population (n=89) the mean±SD CDEIS score was 14.5±5.3 at baseline; the mean decrease in CDEIS score at week 10 was 5.7 (95% CI 4.6 to 6.8, p<0.0001). Rates of endoscopic response, endoscopic remission, complete endoscopic remission and mucosal healing at week 10 were 54%, 37%, 10% and 4%, respectively. At week 54 the corresponding rates were 49%, 27%, 14% and 8%, respectively. The safety profile was consistent with that of previous CZP trials.
Following CZP treatment in patients with active CD, endoscopic lesions were improved as shown by the decrease in mean CDEIS score and by endoscopic response and remission rates. These benefits were achieved as early as week 10 and were generally maintained through week 54.
Clinical Trial Registration Number
Certolizumab pegol; mucosal healing; endoscopic response; Crohn's disease; anti-TNF agent
The goal of this study was to compare the efficacy in terms of Health Assessment Questionnaire change from baseline (HAQ CFB), 50% improvement in American College of Rheumatology criterion (ACR-50) and Disease Activity Score in 28 joints (DAS28) defined remission (< 2.6) between abatacept and other biologic disease modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX-IR).
A systematic literature review identified controlled trials investigating the efficacy of abatacept (three studies), etanercept (two studies), infliximab (two), adalimumab (two), certolizumab pegol (two) ritixumab (three), and tocilizumab (two) in MTX-IR patients with RA. The clinical trials included in this analysis were similar with respect to trial design, baseline patient characteristics and background therapy (MTX). The key clinical endpoints of interest were HAQ CFB, ACR-50 and DAS28 < 2.6 measured at 24 and 52 weeks. The results were analysed using network meta-analysis methods that enabled calculation of an estimate for expected relative effect of comparative treatments. Analysis results were expressed as the difference in HAQ CFB score and odds ratio (OR) of achieving an ACR-50 and DAS28 response and associated 95% credible intervals (CrI).
The analysis of HAQ CFB at 24 weeks and 52 weeks showed that abatacept in combination with MTX is expected to be more efficacious than MTX monotherapy and is expected to show a comparable efficacy relative to other biologic DMARDs in combination with MTX. Further, abatacept showed comparable ACR-50 and DAS28 < 2.6 response rates with other biologic DMARDs at 24 and 52 weeks, except for ACR-50 compared to certolizumab pegol at 52 weeks and for DAS28 < 2.6 compared to tocilizumab at 24 weeks. Sensitivity analyses confirmed the robustness of the findings.
Abatacept in combination with MTX is expected to result in a comparable change from baseline in HAQ score and comparable ACR-50 and DAS28 < 2.6 response rates in MTX-IR patients compared to other approved biologic agents.
abatacept; rheumatoid arthritis; biologic DMARDs; network meta-analysis; health assessment questionnaire
Tumour necrosis factor α (TNFα) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). Treatment with TNFα inhibitors reduces disease activity and improves outcomes for patients with RA. This study evaluated the efficacy and safety of certolizumab pegol 400 mg, a novel, poly-(ethylene glycol) (PEG)ylated, Fc-free TNFα inhibitor, as monotherapy in patients with active RA.
In this 24-week, multicentre, randomised, double-blind, placebo-controlled study, 220 patients previously failing ⩾1 disease-modifying antirheumatic drug (DMARD) were randomised 1:1 to receive subcutaneous certolizumab pegol 400 mg (n = 111) or placebo (n = 109) every 4 weeks. The primary endpoint was 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 24. Secondary endpoints included ACR50/70 response, ACR component scores, 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 (DAS28(ESR)3), patient-reported outcomes (including physical function, health-related quality of life (HRQoL), pain and fatigue) and safety.
At week 24, the ACR20 response rates were 45.5% for certolizumab pegol 400 mg every 4 weeks vs 9.3% for placebo (p<0.001). Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 (p<0.001). Significant improvements in ACR50, ACR components, DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study. Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported.
Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing ⩾1 DMARD compared with placebo, and demonstrated an acceptable safety profile.
Trial registration number:
To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials.
The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated.
409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses.
Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.
Anti-TNF; Psoriatic Arthritis; Outcomes research
Crohn’s disease (CD) is a chronic inflammatory bowel disease characterized by a relapsing/remitting course with transmural inflammation of potentially any section of the digestive tract. Certolizumab pegol (CZP) is a pegylated Fc-free Fab’ fragment of a humanized anti-TNF-alfa monoclonal antibody that is in development for clinical use in CD.
To review the available data with CZP in CD, to investigate its possible place in therapy.
Available studies suggest that CZP has the potential to achieve and maintain clinical response and remission in moderate to severe CD, and to improve quality of life compared with placebo. Further studies with CZP are also ongoing.
Place in therapy:
Although only suggested by currently available studies, successive clinical practice and further ongoing trials may confirm a positive role for CZP as a new anti-TNF treatment in CD. The impact on clinical management or on resources cannot be estimated until the results from all phase III clinical trials are available and the price is determined.
anti-TNF; biological therapy; certolizumab pegol; Crohn’s disease
Tumour necrosis factor inhibition plus methotrexate is believed to inhibit radiographic progression independent of inflammation. This analysis assessed whether these protective effects are exerted on bone (joint erosion; JE) and/or cartilage (joint space narrowing; JSN), and what the independent effects of JE/JSN progression are on longer-term patient-reported outcomes.
PREMIER was a 2-year, randomised, controlled trial of adalimumab plus methotrexate (ADA+MTX) versus the monotherapies. The impact of treatment on the relationships between time-averaged disease activity (TA-DAS28(CRP)) and changes in JE/JSN and associations of JE/JSN with the disability index of the health assessment questionnaire (HAQ-DI) at baseline and weeks 52 and 104 were assessed through non-parametric approaches of analysis of variance and quantile regression. JE/JSN association with employment status was evaluated at baseline and weeks 52 and 104 through logistic regression.
Increasing tertiles of TA-DAS28(CRP) were associated with JE and JSN progression in the monotherapy groups, a phenomenon largely absent in ADA+MTX-treated patients. Although JSN was not associated with HAQ-DI at baseline, it was at 52 and 104 weeks. In contrast, JE was not associated with HAQ-DI at any time point examined. Odds of being employed at baseline, 52 weeks and 104 weeks were significantly associated with lower JSN, but not JE, scores.
ADA+MTX inhibited both JE and JSN progression independently of disease activity. JSN played a more prominent role in patient-reported outcomes than JE. Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients.
Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied.
Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used.
Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores.
Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region.
clintrials.gov # NCT00422227
Patient reported outcomes; Etanercept; Rheumatoid arthritis; Asia-Pacific; Health outcomes assessments
Background and Objectives
Five-tumour necrosis factor (TNF)-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA) and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT).
A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE), Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX), in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias.
Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo.
No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.
Whereas many patients respond quickly to treatment with tumour necrosis factor (TNF) inhibitors, some patients may experience significant but delayed responses.
To evaluate the clinical response between 12 and 24 weeks in subjects with rheumatoid arthritis from the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes.
Clinical response was assessed at 24 weeks in 12-week non-responders, according to American College of Rheumatology (ACR) response criteria. The proportion of subjects who successfully maintained response to 52 weeks was analysed, as were radiographic outcomes.
Data from 682 subjects were included in the analysis. Non and partial responders in all three groups (etanercept, methotrexate and etanercept plus methotrexate) at week 12 showed an improvement in responses at week 24. Over 80% of the week 24 ACR20/50/70 responders in the etanercept plus methotrexate arm sustained their response to 52 weeks. In the etanercept arms, a delayed clinical response was not associated with increased radiographic progression at week 52.
A significant proportion of non and partial responders to etanercept with or without methotrexate therapy at week 12 achieved a good clinical response or improved their overall clinical response at week 24. Discontinuing TNF inhibitor therapy at 12 weeks may be premature in some rheumatoid arthritis patients.
In the IMAGE study, rituximab plus methotrexate (MTX) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis.
The aim of this study was to assess joint damage progression and clinical outcomes over 2 years.
Patients (n=755) were randomised to receive rituximab 2×500 mg+MTX, 2×1000 mg+MTX or placebo+MTX. The placebo-controlled period continued to week 104. Two-year end points were defined as secondary or exploratory and included change in total Genant-modified Sharp score (mTSS), total erosion score and joint space narrowing score from baseline to week 104. Clinical efficacy and physical function end points were also assessed.
At 2 years, rituximab 2×1000 mg+MTX maintained inhibition of progressive joint damage versus MTX alone (mTSS change 0.41 vs 1.95; p<0.0001 (79% inhibition)), and a higher proportion of patients receiving rituximab 2×1000 mg+MTX had no radiographic progression over 2 years compared with those receiving MTX alone (57% vs 37%; p<0.0001). Contrary to 1-year results, exploratory analysis of rituximab 2×500 mg+MTX at 2 years showed that progressive joint damage was slowed by ∼61% versus placebo+MTX (mTSS, exploratory p=0.0041). Improvements in clinical signs and symptoms and physical function seen after 1 year in rituximab-treated patients versus those receiving placebo were maintained at year 2. Safety profiles were similar between groups.
Treatment with rituximab 2×1000 mg+MTX was associated with sustained improvements in radiographic, clinical and functional outcomes over 2 years.
Clinical trials.gov identifier NCT00299104.
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO). PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab’ fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-α agents tested for the treatment of Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-α efficacy in Crohn’s disease. As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.
psoriatic arthritis; certolizumab pegol; biological therapies; anti-TNF
A new anti-tumor necrosis factor alpha (TNF-α) inhibitor with a novel mechanism of action has entered phase 3 trials in rheumatoid arthritis (RA). Certolizumab pegol (Cimzia®) is a humanized Fab′ antibody fragment against TNF-α with a polyethylene glycol tail that prevents complement-dependent and antibody-dependent cell-mediated cytotoxicity or apoptosis. Four randomized clinical trials have been published so far. Reported results are similar to those published in previous studies with other TNF-α inhibitors, with ACR20, ACR50, and ACR70 responses of around 60%, 40%, and 20%, respectively, when combined with methotrexate and slightly lower when used as monotherapy. Safety was shown to be similar to that seen with TNF-α blockers and some cases of tuberculosis were seen in the trials, stressing the importance of a complete screening in these patients. Although we still need effectiveness and safety data in larger numbers of patients and longer follow-up, this new TNF inhibitor is a welcome addition to our current armamentarium for the treatment of RA.
certolizumab pegol; rheumatoid arthritis therapy; biologic therapies
To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP)) <3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA).
1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP) <3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission.
Among patients completing 6 months, 44% (207/466) ADA+MTX versus 24% (112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect.
Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.
This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo. The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score (based on erythrocyte sedimentation rates; DAS28 (ESR)) for the abatacept vs placebo groups at day 197.
Patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) were randomised 3:3:2 to abatacept (∼10 mg/kg every 4 weeks, n = 156), infliximab (3 mg/kg every 8 weeks, n = 165), or placebo (every 4 weeks, n = 110) and background MTX. Safety and efficacy were assessed throughout the study.
Similar patient demographics and clinical characteristics were present at baseline between groups, with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 (ESR). At 6 months, mean changes in DAS28 (ESR) were significantly greater for abatacept vs placebo (–2.53 vs –1.48, p<0.001) and infliximab vs placebo (–2.25 vs –1.48, p<0.001). For abatacept vs infliximab treatment at day 365, reductions in the DAS28 (ESR) were –2.88 vs –2.25. At day 365, the following response rates were observed for abatacept and infliximab, respectively: American College of Rheumatology (ACR) 20, 72.4 and 55.8%; ACR 50, 45.5 and 36.4%; ACR 70, 26.3 and 20.6%; low disease activity score (LDAS), 35.3 and 22.4%; DAS28-defined remission, 18.7 and 12.2%; good European League Against Rheumatism (EULAR) responses, 32.0 and 18.5%; and Health Assessment Questionnaire Disability Index (HAQ-DI), 57.7 and 52.7%. Mean changes in physical component summary (PCS) were 9.5 and 7.6, and mental component summary (MCS) were 6.0 and 4.0, for abatacept and infliximab, respectively. Over 1 year, adverse events (AEs) (89.1 vs 93.3%), serious AEs (SAEs) (9.6 vs 18.2%), serious infections (1.9 vs 8.5%) and discontinuations due to AEs (3.2 vs 7.3%) and SAEs (2.6 vs 3.6%) were lower with abatacept than infliximab.
In this study, abatacept and infliximab (3 mg/kg every 8 weeks) demonstrated similar efficacy. Overall, abatacept had a relatively more acceptable safety and tolerability profile, with fewer SAEs, serious infections, acute infusional events and discontinuations due to AEs than the infliximab group.
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Subcutaneous self-injection of medication has benefits for the patient and healthcare system, but there are barriers such as dexterity problems and injection anxiety that can prevent self-injection being used effectively. An accurate method of evaluating patients' experiences with self-injection would enable assessment of their success in giving self-injections and the likelihood of them adhering to a self-injection regimen. The aim of this study was to develop a questionnaire to measure overall patient experience with subcutaneous self-injection (the Self-Injection Assessment Questionnaire [SIAQ]), and to investigate its psychometric properties.
The construct validity and reliability of the SIAQ were tested in patients with rheumatoid arthritis who volunteered to inject certolizumab pegol using a standard syringe during an open-label multinational extension trial of the long-term safety and efficacy of this drug. The SIAQ PRE module was self-completed before the first self-injection, and the POST module was self-completed following each of three fortnightly self-injections.
Ninety-seven patients completed the SIAQ. All items correlated well with their respective domains in confirmatory factor analysis. As predicted, compared with other participants, patients with very low scores (less than 3 out of 10) in PRE causal domains (Feelings about injections and Self-confidence) were significantly less satisfied with their first self-injection, as were patients with a very low score in any POST causal domain (Self-confidence, Feelings about injections, Injection-site reactions and Ease of use), demonstrating known-groups validity. Causal domain scores generally correlated most strongly with the Satisfaction with self-injection domain, supporting convergent validity. The SIAQ demonstrated internal consistency and reproducibility; Cronbach's α and the test-retest coefficient were > 0.70 for all domains. Sensitivity and responsiveness were also shown, where measurable. Each language version showed structural validity.
The SIAQ was demonstrated to be a valid, reliable tool in patients with rheumatoid arthritis.
Objective: To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA).
Methods: Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group.
Results: The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet.
Conclusions: Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.