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Abstract
Objectives Very limited data are available regarding the efficacy of abatacept (ABA) in real life. The aims of this study were to determine the efficacy of ABA in rheumatoid arthritis and predicting factors of efficacy in common practice.
Methods The Orencia and Rheumatoid Arthritis” (ORA) prospective registry, promoted by the French Society of Rheumatology, has included 1003 patients with RA.
Results 773 patients had already fulfilled the 6-month follow-up visit. Only 21.3% of patients would have fulfilled inclusion criteria used in pivotal controlled trials. The European League Against Rheumatism (EULAR) response, was observed in 330 (59.1%) of the 558 assessed patients (good response: 20.4%, moderate response: 38.7%) and was similar in patients who did and in patients who did not fulfill inclusion criteria of controlled trials. Among EULAR responders, initial 28-joint disease activity score (5.4 (4.7-6.5) in responders vs 4.9 (4.0-6.0) in non responders, p< 0.0001), the proportion of rheumatoid factor (75.6% vs 66.7%, p= 0.03) and the proportion of anti-cyclic citrullinated peptide antibody (anti-CCP)-positivity (75.9% vs 62.2%, p= 0.001) were significantly higher. In multivariate analysis adjusted on initial 28-joint disease activity score and CRP, anti-CCP positivity was associated with EULAR response (OR=1.9;95% CI=1.2 to 2.9, p=0.007), but not rheumatoid factor (OR=1.0;95% CI=0.6 to 1.6, p=0.9). Anti-CCP positivity was also significantly associated with a higher ABA retention rate at 6 months.
Conclusions Real life efficacy of ABA in the ORA registry was similar as that reported in clinical trials. Anti-CCP positivity was associated with a better response to ABA, independently from disease activity.
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Introduction
The knowledge on the efficacy of biological agents in rheumatoid arthritis (RA) is mostly derived from controlled trials. However, due to inclusion criteria and co-medications used in trials, the results may sometimes differ in common practice. In addition, the homogeneity of the populations studied, notably regarding high disease activity and rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) positivity, makes it difficult to analyse the potential predicting factors of efficacy. In addition, the short-term follow-up and the trial protocols do not allow to determine whether a corticosteroid-sparing effect can be observed, which is an important surrogate marker of efficacy in real life. The analysis of efficacy using registries can overcome most of these shortcomings, although registries have other limitations: absence of control arm, missing data and heterogeneity of patient populations and of follow ups. In registries, the number of patients analysed, the use of solid efficacy outcome such as drug retention rate, helped to obtain very interesting and relevant results concerning anti-tumour necrosis factor (anti-TNF) drugs.1,–,5 While recent data on other biologic agents were obtained from registries, very little or no registry data are available on the efficacy of abatacept (ABA).6 The aims of this study were to determine the real-life efficacy of ABA in RA and predicting factors of efficacy using data from the Orencia and Rheumatoid Arthritis (ORA) registry, promoted by the French Society of Rheumatology.
Patients and methods
The ORA registry
The ORA registry is an ongoing nationwide prospective cohort study for investigating the long-term safety and efficacy of ABA for treating RA, using the same design and protocol as the AutoImmunity and Rituximab registry.7,–,9 It was set up in 2008 by the French Society of Rheumatology and receives financial support (unrestricted educational grant) from Bristol-Myers-Squibb. However, Bristol-Myers-Squibb was not involved in the design, protocol, data collection or statistical analysis of the study. Written informed consent was obtained from all patients. Details regarding the methodology of ORA registry are available in the online supplementary text. All patients who had already reached their 6-month follow-up visit were included.
Statistical analysis
The European League Against Rheumatism (EULAR) (either good or moderate) response was selected as primary outcome of efficacy. To take into account the potential impact of missing data, characteristics of patients for whom 28-joint disease activity score (DAS28) at enrolment or at 6 months was missing were first compared with those of patients for whom these data were available. Details regarding the statistical analysis are available in the online supplementary text.
Statistical analysis was performed with SAS V.9.2 (Cary, North Carolina, USA).
Results
Characteristics of the patients
At the time of analysis, among the 1003 patients included in the ORA registry and at the time of analysis, 773 patients (77.1%) had already been followed up for at least 6 months without any patients lost to follow up, with a follow up of 384 patient-years. Median age and median disease duration were 58.0 (49.0; 68.0) and 14.0 (8.0; 21.0) years, respectively. There were 35.2% who had previous severe or recurrent infections, 5.6% had a history of cancer and 11.5% had diabetes mellitus. In addition, 72.5% of patients were RF-positive and 70.2% were anti-CCP-positive (11.6% and 20.1% of missing data, respectively). Median number of previous synthetic disease-modifying anti-rheumatic drugs (DMARDs) was 3.0 (2.0; 4.0); 11.4%, 21.6%, 37.7% and 29.3% of patients had been previously given 0, 1, 2 and 3 anti-TNFα drugs, respectively. 30.1% had received rituximab (RTX) previous to ABA; 75.8% of patients received comedication with corticosteroids at onset of ABA (median dosage of 8.0 mg/day (2.0; 10.0)); 35.2% were not treated concomitantly with a DMARD, whereas 64.8% were (methotrexate: 76.3%; leflunomide: 14.6%; other/combination of DMARDs: 9.1%).
Among the 773 patients, data on inclusion criteria used in the pivotal ABA randomised trials10,–,14 could be collected in 649 patients (83.9%), and 138 patients (21.3%) fulfilled the criteria for being included in at least one of these trials.
Safety
Eighteen serious infections occurred (seven broncho-pulmonary infections, four genito-urinary, three articular, two skin, one digestive and one septicaemia), resulting in 4.7 serious infections/100 patient-years, four of them leading to ABA discontinuation. No opportunistic infection and no death occurred. Two cancers (one basal cell skin cancer, one colon cancer) occurred (0.5/100 patient/years). Four serious infusion reactions (0.5% of the patients, resulting in ABA discontinuation after 2, 3, 4 and 6 infusions) occurred within the first 6 months of treatment with ABA.
Efficacy and drug retention rate
DAS28 erythrocyte sedimentation rate data were available in 680 patients (87.9%) before ABA, in 626 (80.9%) at 6 months, and in 558 (72.2%) both at baseline and at 6 months. Median baseline DAS28 was 5.4 (4.5–6.3). Median baseline DAS28 was similar in patients with/without RF (5.5 vs 5.3, p=0.2) or with/without anti-CCP (5.4 in both groups, p=0.3).
Among the 558 patients for whom an EULAR response could be evaluated, a response was observed in 330 (59.1%) (moderate in 38.7%, good response in 20.4%). No significant difference in baseline characteristics was observed between these 558 patients and the 215 other patients for whom a EULAR response could not be evaluated, except for number of previous synthetic DMARDs (table 1).
Characteristics of the study population
Treatment with ABA was maintained in 78.2% of patients at the 6-month follow-up visit. Inefficacy, observed in 72.5% of the patients who discontinued ABA, was the main reason for stopping ABA. Adverse events resulted in ABA discontinuation in 11.5%, and other reasons (ie, patient's wish, combination of adverse events and inefficacy) in 16.0% patients.
Baseline predictors of efficacy
Age, number of previous synthetic DMARDs or of biologics, previous use of RTX, concomitant treatment with synthetic DMARD or corticosteroids and baseline erythrocyte sedimentation rate were similar in the 330 EULAR (either good or moderate) responders and in the 228 EULAR non-responders (table 2). The proportion of EULAR responders, after adjustment on baseline DAS28, was similar in patients who did not fulfil inclusion criteria of pivotal controlled trials (good response: 22.7%, moderate response: 35.7%) as in patients who did (good response: 11.0%, moderate response: 49.2%, p=0.60). Factors associated with EULAR response in univariate analysis are indicated in table 2. RF-positivity (75.6% vs 66.7%, p=0.03 in univariate analysis) and anti-CCP positivity (75.9% vs 62.2, p=0.001) were more frequent among EULAR responders than non-responders. Levels of anti-CCP (92.0 (0–250.0) vs 5.1 (0–212.0) U/l, p=0.01) but not those of RF (57.8 (0–153.0) vs 27.7 (0–157) IU/l, p=0.3) were significantly higher in EULAR responders than in non-responders. In multivariate logistic regression analysis adjusted on DAS28, only anti-CCP positivity (OR=1.9; 95% CI=1.3 to 2.8, p=0.001) and initial DAS28 (OR=1.4; 95% CI=1.2 to 1.6, p<0.0001 were associated with EULAR response. In a second multivariate logistic regression, RF and initial C reactive protein were forced into the model. Confirming the results of the previous model, anti-CCP positivity was associated with EULAR response (OR=1.9; 95% CI=1.2 to 2.9, p=0.007) but not RF (OR=1.0; 95% CI=0.7 to 1.6, p=0.9) (table 2). In a third multivariate logistic regression analysis, age, sex and use of previous biologics were forced into the model and only anti-CCP positivity was similarly associated with EULAR response (OR 1.9 (1.2–3.10), p=0.009).
Univariate and multivariate analysis of predicting factors of efficacy
Anti-CCP antibodies were more frequently positive among patients still treated with ABA at the 6-month follow-up visit than in patients who discontinued ABA (72.5% vs 62.4%, p=0.02) without any significant difference observed regarding RF positivity.
In responders versus non-responders, the median decrease of corticosteroid dosage was higher (−1.0 (−5;0) mg vs 0 (−4;0 mg)), p=0.02). Among responders, the decrease of corticosteroid dosage was higher in patient with RF than without (−1.0 (−6;0) vs 0 (−3;0) mg, p=0.03) and in patients with anti-CCP than without (−1.0 (−5;0) vs 0 (−2.5;0) mg, p=0.02).
Discussion
These data from the ORA registry demonstrate comparable efficacy rates in real life to those reported in clinical trials and show a better response of patients with anti-CCP autoantibodies. Limitations of this study include the risk of selection bias in such an observational setting, the short follow-up and the missing data.
The first result of the present study is the assessment of efficacy in unselected patients treated in common practice with ABA, for whom very little data is available in the literature. The population included in the ORA is definitively different from that included in controlled trials: longer disease duration, more frequent comorbidities and previous use of biological agents, less frequent use of concomitant methotrexate (49%) and lower initial disease activity. Thus, only approximately 20% of the patients would have fulfilled all the inclusion criteria of at least one of the pivotal controlled trials. However, the rate of responders was similar, irrespective of the fulfilment of such inclusion criteria, conversely to what was reported in some studies in patients treated with anti-TNF.15 ,16
The main result of the present study is the identification of predicting factors of response to ABA. In multivariate analysis, after adjustment for DAS28, only anti-CCP positivity was associated with EULAR response. Drug retention rate and the decrease of corticosteroid dosage were also significantly higher in patients with anti-CCP.
Association of autoantibody status and response to ABA has hardly been studied in controlled studies since most of the patients were RF/anti-CCP positive. Regarding the association between response and autoantibodies, the only clear data concerns RTX, which is more efficient in autoantibody-positive patients on signs and symptoms and structural progression in different types of studies.17,–,22 Data are much more controversial with anti-TNF, but several studies suggested, conversely, a lower response in autoantibody-positive patients.23 To understand this association between response to ABA and autoantibodies, 3 hypotheses could be proposed. First, it could be speculated that some anti-CCP-negative patients may not have RA, or at least that anti-CCP-positive RA patients represent a more homogeneous RA population, thus more prone to response to drugs targeting the pathogenesis of RA. This might explain why anti-CCP antibodies, but not RF, a less specific marker of RA, were associated with better response in multivariate analysis. Second, since B lymphocytes express CD80 and CD86, which bind CTLA-4, it could be hypothesised that action of CTLA4-Ig could also result from the inhibition of autoreactive B-cells-mediated T-cell activation. This may result in a better efficacy in patients for whom the contribution of B cells in RA pathogenesis is more pronounced. Of note, ABA results in a decrease of synovial B cells24 and in decreased secretion of autoantibodies.25 Last, in mice, ABA decreases the differentiation of follicular T helper cells,26 which play a major role in B-cell activation.
Detailed analysis of tolerance, which is the primary objective in the ORA registry, will be performed when the follow-up of patients is longer. Current preliminary results indicated that the rate of serious infections was a little higher in these real-life patients with comorbidities than in controlled trials, which was also reported with other biologic agents,9 and that no case of opportunistic infection had occurred as yet.
In conclusion, real-life efficacy of ABA in the ORA registry was similar as that reported in clinical trials although the characteristics of patients included were different from those of patients in controlled trials. Anti-CCP positivity was associated with a better response to ABA, independently of disease activity. These results demonstrate for the first time that modulation of Tcell,- B cell co-stimulatory pathways using ABA is more effective in patients with autoantibodies.
Acknowledgments
We thank all the investigators of the ORA registry, the French Society of Rheumatology, E Boccard (BMS), the 14 research study nurses (A Bourgeois, E Braychenko, F Carmet, MH Da Silva, S Delmas, D Guinement, R Lefebure, C Lehning, N Minot, FMA Ouattara, V Pinosa, M Reau, H Thibault and E Wallet), L Dongmo and V Martin (Euraxipharma) for their contributions.
References
Supplementary materials
Supplementary Data
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