Abstract
Objective To analyze the long-term survival of subcutaneous biosimilar tumor necrosis factor inhibitors compared to the originator molecules in patients with rheumatic diseases, as well as the factors associated with drug discontinuation.
Methods Retrospective analysis of BIOBADASER, the Spanish multicenter prospective registry of patients with rheumatic disease receiving biologic and targeted disease-modifying antirheumatic drugs. Patients who started etanercept (ETN) or adalimumab (ADA) from January 2016 to October 2023 were included. The survival probabilities of biosimilars and originators were compared using Kaplan-Meier estimating curves. To identify factors associated with differences in the retention rates, hazard ratios (HR) were estimated using Cox regression models for all and specific causes (inefficacy or adverse events [AEs]) of discontinuation.
Results A total of 4162 patients received 4723 treatment courses (2991 courses of ADA and 1732 courses of ETN), of which 722 (15.29%) were with originator molecules and 4001 (84.71%) were with biosimilars. The originators were more frequently discontinued than biosimilars (53.32% vs 33.37%, respectively). The main reason for discontinuation was inefficacy (60.35% of the treatments). The risk of overall discontinuation was lower for biosimilars (adjusted HR 0.84, 95% CI 0.75-0.95). Female sex, obesity, and second or later treatment lines increased the risk of discontinuation, whereas disease duration and the use of concomitant methotrexate were associated with a greater survival. When assessing cause-specific reasons of discontinuation, excluding nonmedical switching, the results from the crude and adjusted analyses showed no significant differences in the retention rate between biosimilars and originators.
Conclusion No significant differences were found between treatments in long-term survival due to inefficacy or AEs.
Adalimumab (ADA) and etanercept (ETN) are subcutaneous biologic disease-modifying antirheumatic drugs (bDMARDs) that have been used in the treatment of rheumatic disease for over 2 decades. In recent years, several biosimilar alternatives to these originator molecules have been approved for patients with rheumatic diseases. The European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of rheumatic diseases consider the use of biosimilars from the point of view of economic savings and states a preference for therapies with a lower cost in a situation of equal efficacy and safety.1 However, there are no recommendations regarding the interchangeability or replacement of an originator by biosimilar molecules. Similar efficacy, safety, and immunology data have been consistently reported with different biosimilars compared to their original molecules,2-5 although some observational studies have reported lower retention rates for biosimilars after nonmedical switching.6,7 Drug survival in patients with rheumatic diseases is an important outcome and can be influenced by many different factors related to efficacy and adverse events (AEs), among others. A real-world study identified an increase in AEs in patients receiving biosimilars, which could be related to a possible nocebo effect, thus affecting survival rates.8 Recently, observational data from large North European cohorts showed similar retention rates in patients with different rheumatic conditions treated with originator vs biosimilar molecules, indicating comparable effectiveness in clinical practice.9,10
In Spain, the use of bDMARDs is supported by the tax-funded healthcare system. The first ETN biosimilar has been available since 2016, and an ADA biosimilar since 2018.11 Whereas the switch to biosimilar infliximab (IFX) and rituximab (RTX) was made by the authorities several years ago for economic reasons, the use of subcutaneous biosimilar tumor necrosis factor inhibitors (TNFi) has been thoroughly encouraged but not imposed. Although the survival of the different bDMARDs in Spanish patients with rheumatic diseases in clinical practice has been recently analyzed,12 we do not know if there are differences in treatment survival depending on whether patients receive an originator or a biosimilar molecule. Lower retention rates of biosimilars in a real-world clinical setting might raise concerns about safety issues or suggest that biosimilars are less effective than originators. The main objective of this study was to compare the overall and cause-specific drug discontinuations between subcutaneous biosimilar TNFi (ETN and ADA) and their originators in a prospective cohort of patients with rheumatic diseases in clinical practice in Spain. The secondary objective was to identify the factors that influenced drug survival.
METHODS
Setting. This study is a retrospective analysis of BIOBADASER, the Spanish multicenter prospective observational registry of patients with rheumatic diseases receiving bDMARDs and targeted synthetic DMARDs (tsDMARDs). It was established in 2000 and has been comprehensively described in previous reports.13,14 BIOBADASER 3.0 is the third phase of the registry, adapted in December 201514 by adding to its objectives the systematic assessment of drug effectiveness using commonly accepted disease activity indexes. The BIOBADASER registry is promoted by the Spanish Society of Rheumatology and supported by the Spanish Agency of Drugs and Medical Devices and several pharmaceutical companies. For the assessment of data consistency and quality, strict measures are implemented. The full database is monitored online; additionally, a random sample of patients is selected and audited in situ annually in all 28 participating centers. The recruitment of new patients is dynamic and remains indefinitely open. Further details about the design and inclusion criteria of BIOBADASER 3.0 are available on the registry website.15
Ethics. All procedures and materials comply with the principles of the Declaration of Helsinki and with Spanish regulations on data protection and research. The project has the approval of the Research Ethics Committee of the Complejo Hospitalario Universitario de Canarias acting as reference committee (approval code FER-ADA-2015-01). All patients signed informed consent to be included in the BIOBADASER registry, covering subsequent analyses such as the present study. Patients’ information was managed as anonymized data and as approved by the Research Ethics Committee, specific informed consent for this analysis was not required.
Patients. For this analysis, the inclusion criteria were as follows: patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS) and other nonpsoriatic spondyloarthritis (SpA), or psoriatic arthritis (PsA) who had started original or biosimilar molecules of ETN or ADA. Participants needed to have been receiving treatment for ≥ 3 months and to have started therapy from January 2016 (for ETN) or January 2018 (for ADA), when first subcutaneous biosimilars were available, until October 2023 (date of the data lock for the analysis).
For patients who switched between ADA and ETN, or between originator and biosimilar, each treatment course contributed to the corresponding treatment group; therefore, a patient could be counted in both groups.
Variables. The following demographic and clinical data were analyzed: diagnosis, age at the moment of ETN or ADA initiation, sex, BMI (calculated as weight in kilograms divided by height in meters squared [kg/m2]), tobacco use, disease duration at treatment initiation (years since diagnosis), follow-up time, concomitant treatment with conventional synthetic DMARDS (csDMARDs) and corticosteroids (CS), line of treatment (first, second, and third or subsequent), and reason for drug withdrawal.
Statistical analyses. Summary statistics were described as frequencies and percentages for qualitative variables and as means and SDs or medians and IQRs for continuous variables. To analyze differences in the baseline characteristics between originator molecules and biosimilars, t tests and chi-square tests were used. Different models were used to calculate the drug retention rates using Kaplan-Meier survival curves, first considering all treatment discontinuations as completion events, and then cause-specific reasons for discontinuation (inefficacy, AEs, or remission). In the survival analyses for cause-specific drug discontinuation, other reasons for discontinuation were considered as competing events, and were thus censored. To identify factors associated with differences in the retention rates of biosimilar compared to originator molecules, hazard ratios (HRs) were estimated using a Cox regression model, adjusting for sex, age at therapy initiation, disease duration, diagnosis, type of molecule (ADA or ETN), line of treatment, BMI, tobacco use, and the use of concomitant csDMARDs and CS. Statistical significance was set at P < 0.05. All analyses were performed using Stata version 13.1 (Stata Corp.).
RESULTS
Demographic and clinical characteristics. A total of 4723 courses of treatment (2991 courses of ADA and 1732 courses of ETN) and 4162 patients were included, of whom 683 (16.41%) received originator molecules and 3630 (87.22%) received biosimilars. There were 151 patients (3.6%) who received both biosimilar and originator molecules and 256 (6.2%) were treated with both ADA and ETN. The most common condition was RA (45.99%), and 60.31% of the patients were women. Regarding treatment, biosimilars were prescribed in 84.71% of the courses and were used as first-line treatment in 62.18% of cases. Concomitant methotrexate (MTX) was used at baseline in 41.01% of the treatments, other csDMARDs (antimalarials, azathioprine, cyclophosphamide, cyclosporine, intravenous immunoglobulin, leflunomide, mesalazine, mofetil mycophenolate, gold salts, and sulfasalazine) were used in 22.23%, and CS were used in 35.59%. Baseline demographic and clinical characteristics of the cohort are shown in Table 1, and treatment characteristics are displayed in Table 2.
Baseline demographic and clinical characteristics of the 4162 included patients.
Characteristics of 4723 treatment courses.
Compared to the originator courses of treatment, biosimilars were more frequently prescribed as a first-line treatment (62.18% vs 47.78%, P < 0.001). Biosimilars were also used more often in combination with MTX (41.94% vs 35.87%, P = 0.001), other csDMARDs (22.99% vs 18.01%, P = 0.003), and CS (36.32% vs 31.58%, P = 0.01) than originators. Patients in the biosimilar group started therapy at an older age (52.2 vs 48.4 years, P < 0.001) but had shorter disease duration at treatment start (8.3 vs 9.3 years, P = 0.01). No other significant differences regarding the clinical characteristics between the patients within the originator or biosimilar treatment groups were identified (Table 2).
Drug discontinuation and retention rates. At the end of the study, 1720 (36.42%) courses of treatment had been discontinued, and 3003 (63.58%) were still ongoing. The originators were more frequently discontinued than biosimilars (53.32% and 33.37%, respectively). The main reason for discontinuation was inefficacy (60.35%), followed by AEs (17.85%). When comparing the reasons for discontinuation across groups, significant differences were found in the distribution (P < 0.001). Biosimilars were more frequently discontinued because of inefficacy and AEs, whereas discontinuation for remission was more frequent in the originator group. Results are shown in Table 2.
The survival curves and log-rank tests revealed greater retention rate among biosimilars for overall drug discontinuation (P = 0.003) but not for cause-specific discontinuations. The survival curves comparing biosimilars with originators are shown in the Figure (inefficacy, AE, inefficacy or AE).
Kaplan-Meier survival curves for drug survival, stratified by reasons for discontinuation (A) due to any reason (overall), (B) due to inefficacy or AEs, (C) due to inefficacy, and (D) due to AEs. P values were calculated using log-rank test. AE: adverse event.
In the Cox regression model, the risk of overall discontinuation was lower for biosimilars compared to originators (adjusted HR 0.84, 95% CI 0.75-0.95, P = 0.01). Among the factors that increased the risk of discontinuation were female sex (P = 0.001), obesity (P = 0.03), second-line treatment (P = 0.03), and third or subsequent lines of treatment (P < 0.001). The use of concomitant MTX—but not the use of other csDMARDs—and disease duration were associated with a lower risk of discontinuation (P = 0.001 and P < 0.001, respectively). Compared to patients with RA, those with SpA had lower risk of discontinuation (P = 0.03). Results are shown in Table 3. No interaction was found between biosimilar/originator and the type of molecule (ETN or ADA).
Cox regression model for overall drug discontinuation.
When assessing cause-specific reasons for discontinuation (Table 4), there were no statistically significant differences in the risk of discontinuation between biosimilars and originators in the crude nor in the adjusted analyses from the Cox regression models, in accordance with the log-rank test. The fully adjusted regression models are available in Supplementary Table S1 (available with the online version of this article).
Cox regression model for cause-specific drug discontinuation due to inefficacy and/or AEs.
DISCUSSION
In this study, we have analyzed the treatment survival rates of subcutaneous TNFi therapies in patients from the BIOBADASER cohort, comparing originators and biosimilars of ETN and ADA. Our results revealed that there is no difference in discontinuation due to inefficacy or AEs between subcutaneous biosimilars and originators.
The European Medicines Agency and the Heads of Medicines Agencies have issued a joint statement confirming that biosimilar medicines approved in the European Union are interchangeable with their reference medicine or with an equivalent biosimilar.16 Although the use of subcutaneous biosimilars has been previously encouraged but not systematically imposed by health administrations in Spain, our results show that rheumatologists already prescribe them more frequently in clinical practice, especially as a first-line treatment. Recently, cooperative agreements to treat every bDMARD-naïve patient with biosimilar molecules when available are being reached in some health departments. In others, an automatic nonmedical switching for all subcutaneous bDMARDs has already been established. Therefore, a potential increase in the use of biosimilars can be further expected.
A previous study of the BIOBADASER cohort in patients with RA, AS, and PsA showed that the line of treatment was the factor that most influenced the discontinuation of bDMARDs or tsDMARDs due to lack of efficacy, for all conditions.12 The concomitant use of MTX was associated with greater risk of discontinuation due to inefficacy only in the group of patients with AS. In our study, the use of MTX was associated with better survival overall, similar to what has been previously reported.17-20 On the contrary, the concomitant use of CS at baseline seemed to be associated with lower drug survival, whereas other csDMARDs did not affect the drug survival. The percentage of all the concomitant treatments was slightly higher among the patients in the biosimilar group. Hypothetically, prescribers might feel less confident with biosimilars and may tend to use concomitant treatments more frequently, but as no differences in survival between groups were observed, this tendency as well as other significant differences in the basal characteristics do not seem to influence drug survival so far. Another factor associated with lower risk of discontinuation was disease duration. Although similar results have been previously reported,21 we do not have a definite explanation for it. Theoretically, baseline disease activity or variations in the concomitant treatment over time may have had some effect on this result. The retention rate was lower for women and second or subsequent lines of treatment, as has already been described in other studies.17,20 Whereas ADA combined with MTX was associated with the longest drug survival compared to ETN-based regimens in a series of patients with enthesitis-related arthritis,17 we did not find any difference in survival between molecules.
Data on survival of biosimilars compared to their originators in patients with rheumatic inflammatory conditions are scarce. In an observational study of bDMARD-naïve patients with SpA from 5 Nordic countries, similar 1-year retention rates were found in patients treated with originators vs biosimilars of IFX and ETN.9 In this cohort, there was a higher proportion of patients using concomitant csDMARDs in the originator groups of both IFX and ETN, whereas in our study we found a higher percentage of MTX and other csDMARDs among biosimilar users. In the large observational cohort study from the Swedish Rheumatology Quality Register,10 similar crude 1-year survival was found for ADA, ETN, IFX, and RTX originators and their respective different biosimilars. After adjusting for age and sex, they found a slightly increased retention for only 1 of the biosimilar brands compared with the originator ETN, and a slightly lower retention for 1 biosimilar brand of IFX compared with its originator. In a secondary analysis of the treatment retention after nonmedical switch, researchers did not find any differences in the crude 1-year retention rate among originator and biosimilars, showing no evidence of a nocebo effect bias for the biosimilars. In contrast with prior literature, our study found not only 1-year but long-term survival results, in which retention rates do not differ between subcutaneous biosimilars and originators. In a recent retrospective multicenter French study comparing originator ETN and ADA and their biosimilars, retention rate was significantly higher for subcutaneous biosimilar TNFi. When specific causes were analyzed, a higher retention rate for biosimilars was only observed for RA, ETN, and when used as second-line agents.21 However, no regression models were applied to better study these differences, and authors did not provide definite explanations for those results. In our study, even when the percentage of discontinuations was higher for originators, the regression models showed no real differences in the drug retention due to inefficacy or AEs.
To our knowledge, this is the first study comparing survival of both ADA and ETN biosimilars and originators that included JIA. A retrospective study of the German Biologics JIA Registry (BIKER) showed that, in patients with JIA who required treatment with ETN, the biosimilars were equivalent to the originator in efficacy and side effects.22 Together with these results, our data, which show a similar retention rate, suggest that in pediatric patients, either a subcutaneous biosimilar or originator TNFi may be used.
Among the strengths of our study, we highlight the multicenter nationwide setting, the long-term design, and the large number of patients from daily clinical practice that were included. Real-world data are necessary to improve clinical practice, and the present study provides information on subcutaneous TNFi molecules in a coordinated and unified registry that is periodically monitored to ensure better data quality. Thus, the results are representative of a wide spectrum of patients attending rheumatology outpatient clinics and show that survival is not different between subcutaneous biosimilar TNFi molecules and their originators in real practice. On the other hand, as the treatments switching from originator to biosimilar were excluded in the cause-specific discontinuation models, the nonmedical reasons have not affected the survival results.
Our study also had several limitations. First, the encouraging administrative environment may have potentially biased clinicians in support of using biosimilars. Second, we have not discriminated among originator commercial brands. As slight variability in composition and manufacturing is allowed, future research could assess whether it correlates with survival differences in real life. Last, although we accounted for differences in the risk of drug discontinuation through adjusted HRs in the multivariate regression models, there might still be residual confounding due to other factors not included. An example would be changes in concomitant csDMARDs over time or baseline disease activity, which could not be incorporated in the model because of the heterogeneity in disease activity scores for each condition.
In conclusion, in this Spanish multicenter prospective observational registry of patients with rheumatic diseases, there was no difference in long-term survival due to inefficacy or AEs between subcutaneous biosimilar TNFi and the originator TNFi molecules. In real-world practice, this can be reassuring when deciding to start a biosimilar. Concomitant MTX was associated with higher retention rate, and its use should be considered when appropriate.
ACKNOWLEDGMENT
The authors thank all the rheumatologists and investigators involved in the BIOBADASER registry.
Footnotes
BIOBADASER is supported by the Spanish Society of Rheumatology and the Spanish Agency of Medicines and Healthcare Products. Grants in approximately equal amounts from AbbVie, Biogen, BMS, Celltrion, Galapagos, Janssen, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and Samsung Bioepis have contributed to the support of the registry.
MPMV has received lecture fees from AbbVie, Janssen, Lilly, Novartis, Roche, Sanofi, and UCB, unrelated to the present work. CFC has received lecture fees from AbbVie, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and UCB, and has worked as a paid consultant for AbbVie, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, unrelated to the present work. SMA has received lecture fees from AbbVie, Janssen, Lilly, Novartis, Pfizer, and GSK, and has received consultancy fees from AbbVie, Janssen, and Novartis, unrelated to the present work. The remaining authors declare no conflicts of interest relevant to this article.
- Accepted for publication May 10, 2024.
- Copyright © 2024 by the Journal of Rheumatology
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