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Volume 83, Issue 6, December 2016, Pages 721-725
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Early clinical response predicts low disease activity at one year in rheumatoid arthritis patients on treatment with certolizumab in real-life settings. An appraisal of the Italian registry GISEA

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Abstract

Objectives

The aim of this study was to assess whether good EULAR response assessed at 3 months may predict the achievement of low disease activity (LDA) at 1 year in rheumatoid arthritis (RA) patients on treatment with certolizumab pegol (CZP).

Methods

From the nationwide Italian registry, we analysed 278 RA patients (age 54.8 ± 12 years, duration of disease 9.8 ± 8 years, female 84%) initiating CZP as first line (68%) or  second line (32%) of biological treatment because of their active disease. Assessment of disease activity was based on 28 joint Disease Activity Score (DAS28). A reduction of DAS28 > 1.2 (good EULAR response) was assessed at 3 months, and the achievement of LDA (DAS28  3.2) was evaluated at 1 year. Multiple regression models were used to estimate predictors of early good EULAR response or LDA.

Results

The percentages of patients attaining good EULAR response were 52% at 3, 65% at 6, and 66% at 12 months. Furthermore, 51.2% (98/192) of the patients reached LDA at 12 months. Patients taking CZP as first biological treatment had adjusted odds ratios (OR) of good EULAR response at 3 months 6 folds higher than in those with  1 prior biological drug (OR 6.7, 95% CI 1.97–23.1). While, the strongest variable correlating with 12 months LDA was the achievement of good EULAR response at 3 months (OR 11.3, 95% CI 13.1–34.8).

Conclusions

Our findings showed that attaining good EULAR response at 3 months strongly predicted 1 year LDA in RA patients treated with CZP in real-life settings.

Introduction

Searching for possible predictors of long-term response in patients with rheumatoid arthritis (RA) is becoming always more demanding. There are clues that bone erosions, HLA-DRB1 aplotype, and positivity for rheumatoid factor (RF) and/or ACPA (anti-citrullinated protein antibodies antibodies) predict a worse disease course and need an intensive therapy [1]. There are also some evidence that high body mass index (BMI) may hinder the clinical outcomes of anti-TNF biological therapies [2], [3], [4], [5]. However, predictors of the clinical response to a specific drug are lacking. A pragmatic approach usually applied in settings of standard of care by physicians is to envisage a long-term good clinical response if an initial response already occurs early in the first months. Indeed, randomized clinical trials (RCTs) have shown that clinical response within the first 3 months is related to the level of disease activity at 1 year in RA patients taking adalimumab, infliximab, etanercept, regardless of the disease duration [6].

Certolizumab pegol (CZP) is a PEGylated Fab’ fragment anti-TNF agent approved in Europe and the US for the treatment of adult patients with moderate to severe active RA either in combination with methotrexate (MTX) or as monotherapy. Several RCTs have shown the capability of CZP to act quite early and that the clinical response achieved in the first months after the start of the treatment is sustained over time [7], [8], [9], [10], [11]. Patients reported outcomes, such as fatigue, mental health, pain, vitality, have been reported to ameliorate by 12 weeks, further improved by 24 weeks, and stable up to 52 weeks in RA patients randomized to receive CZP 200 mg or 400 mg (after the standard loading dose) plus MTX, irrespective of the treatment regimen [12]. Work place and home productivity, assessed by Work Productivity Survey improved even as early as 4 weeks and maintained until 12 months [13]. A post hoc analysis of the RAPID-1 trial in which RA patients were randomized to MTX and either CZP 200 mg or placebo has shown that the kinetics of clinical response within the first 3 months was highly predictive of low disease activity (LDA) and progression of structural damage at 1 year, and the earlier the improvement was achieved, the better the late clinical and radiological responses were [7]. Thereby, the failure to achieve a meaningful clinical response within 12 weeks was predictive of low odds to obtain LDA at 1 year [10]. More recently, it has been shown a significant reduction of MRI synovitis and bone oedema in RA patients on CZP by weeks 16, [11]. Instead, data from the real-life on the kinetics of responses in unselected RA patients are missing and we aimed at assessing whether early response at 3 months could foresee a state of low disease activity (LDA) at 12 months in patients on treatment with CZP in the settings of standard of medical care.

Section snippets

Methods

We screened 323 patients with RA [14], from the Italian national registry GISEA, starting CZP because of an inadequate response to conventional DMARDs or failure of a prior biological drug. The local Ethics Committee approved the GISEA registry (Trial registry no NCT01543594) and prior written informed consent to take part was obtained from all patients in compliance with the Helsinki declaration. Patient data were recorded at baseline and every six months thereafter, while 3 months data were

Statistical analysis

Continuous variables were reported as means and standard deviations, while counts and percentages were calculated for categorical variables. Differences in means were compared by one-way analysis of variance or paired t-tests. Differences in the distribution of frequencies were assessed by chi-squared test. Multivariate logistic regression analysis was used to analyse predictors of clinical outcomes. In a first model, the response variable was the achievement of EULAR good response at 3 months

Baseline data

To the purpose of this analysis, complete data were available from 278 patients. Clinical and demographics data are shown in Table 1. CZP was the first biological drug for 68%, whilst 32% of the patients had taken  1 prior biological drug. Their mean age was 54.8 ± 12, and they had active (DAS28 5.1 ± 1.0) and established (9.8 ± 8.8 years) disease. RF or ACPA were detected in 79%, and mean BMI (available in 162 patients) was 25.5 ± 4.6 kg/m2. CZP was given as per loading schedule (400 mg at week 0, 2, 4)

Discussion

In this study, we retrospectively analysed 278 RA patients on treatment with CZP to search for possible predictors of LDA at 12 months. LDA was reached in about 52% of patients and the strongest predictor was the achievement of the good EULAR response by 3 months. Furthermore, patients more likely to attain an early good EULAR response were those naïve for biological treatments.

Beside the need to profile each RA patient by searching for bone erosions, HLA-DRB1, autoimmunity, BMI before devising a

Funding

This work has not received financial support.

ClinicalTrials.gov Identifier NCT01543594.

Disclosure of interest

Florenzo Iannone has received consulting fees, speaking fees or honoraria (less than € 10,000) from Pfizer, Merck, Abbott, Bristol-Myers Squibb outside this work.

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