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A 8-year retrospective cohort study comparing Interferon-β formulations for relapsing‐remitting multiple sclerosis
Multiple Sclerosis and Related Disorders 19 (2018) 50–54
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
A 8-year retrospective cohort study comparing Interferon-β formulations for relapsing‐remitting multiple sclerosis
MARK
⁎
Marcello Mocciaa, , Raffaele Palladinob,c, Antonio Carotenutoa, Francesco Saccàa, Cinzia Valeria Russoa, Roberta Lanzilloa, Vincenzo Brescia Morraa a
Multiple Sclerosis Clinical Care and Research Centre, Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Via Sergio Pansini, 5 – Building 17, Ground floor, Naples, Italy b Department of Primary Care and Public Health, Imperial College, London, United Kingdom c Department of Public Health, Federico II University, Naples, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple sclerosis Interferon Long-term Relapsing Progression Disability
Background: Interferon-β has been approved for the treatment of relapsing-remitting (RR) multiple sclerosis (MS), whereas its efficacy in preventing long-term disability and conversion to secondary progressive (SP) MS is still debated. We aim to compare long-term clinical evolution of newly-diagnosed RRMS patients treated with different Interferon-β formulations. Methods: 507 patients were included in the analysis and followed-up for 8.5 ± 3.9 years. 37.6% were treated with subcutaneous Interferon-β1a 44 mcg, 33.4% with intramuscular Interferon-β1a 30 mcg, and 29.0% with subcutaneous Interferon-β1b 250 mcg. Relapse occurrence, 1-point EDSS progression, reaching of EDSS 4.0 and conversion to SP were recorded as outcome measures. To reduce the selection bias, we calculated the propensity score of receiving the specific treatment considering age (32.7 ± 8.3 years), gender (female 63.1%), disease duration (2.7 ± 2.8 years), and baseline EDSS (1.5, range 1.0–3.5). Propensity score and covariates (age, gender, disease duration and EDSS) were included in the statistical models. Results: At Cox regression models, the reaching of EDSS 4.0 was not-significantly higher for Interferon-β1b 250 mcg (HR = 1.207; p = 0.063) and for Interferon-β1a 30 mcg (HR = 1.363; p = 0.095), when compared with Interferon-β1a 44 mcg. The rate of SP conversion was higher for Interferon-β1b 250 mcg (HR = 2.054; p = 0.042), and not-significantly higher for Interferon-β1a 30 mcg (HR = 1.884; p = 0.081), when compared with Interferon-β1a 44 mcg. Conclusions: Patients treated with Interferon-β1a 44 mcg presented with a marginally reduced risk of disability accrual in the long-term, when compared with Interferon-β1b 250 mcg and, at least in part, with Interferon-β1a 30 mcg. Formulation, frequency of administration and dose of Interferon-β might affect the long-term clinical evolution of RRMS.
1. Introduction Multiple sclerosis (MS) usually starts with a relapsing-remitting (RR) course, and eventually converts to a phase of progressive disability accrual, namely secondary progressive (SP) MS (Lublin et al., 2014). Currently available disease modifying treatments (DMT) have proven to reduce amount and severity of relapses in RRMS (Agenzia Italiana, 2016; Goodin et al., 2012a). However, natural history studies showed a dissociation between relapses and disability progression in the longterm (Scalfari et al., 2010; Río et al., 2017), and, accordingly, the benefit of DMTs on disability progression is still uncertain (Fogarty et al., 2016; Zhang et al., 2015). Evidence of DMT efficacy is based on
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randomized clinical trials conducted during relatively short observation time, not detecting long-term disease outcomes (Goodin et al., 2012a). Their long-term extension has shed light on the importance of early and continuous treatment, but failed to show any definite comparative result on clinical efficacy, as being open-label (Goodin et al., 2012b; Ebers et al., 2010). Interferon-β is one of the oldest and still frequently prescribed medications for the treatment of RRMS. Meta-analytic studies found different Interferon-β formulations being similar in efficacy on relapses, whereas no definite results were presented for disability progression (Fogarty et al., 2016; Mendes et al., 2016; Einarson et al., 2017; Kalincik et al., 2015; Newsome et al., 2017). A pooled analysis
Corresponding author. E-mail address: [email protected] (M. Moccia).
https://doi.org/10.1016/j.msard.2017.11.006 Received 23 August 2017; Received in revised form 13 October 2017; Accepted 5 November 2017 2211-0348/ © 2017 Elsevier B.V. All rights reserved.
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– Occurrence of clinical relapses (time to the first relapse on treatment and annualized relapse rate -ARR- during the whole observation period were calculated); – 1-point expanded disability status scale (EDSS) progression (independently from relapses and sustained for 12 months); – Reaching of EDSS 4.0 (independently from relapses and sustained for 12 months); – Transition from RR to SP course (MS was considered SP when a progressive accumulation of disability occurred after an initial relapsing course, and was associated with a worsening of the same functional system, independently from relapse activity) (Lublin et al., 2014).
suggested a reduction of the risk of disability progression for the use of Interferon-β, compared with no treatment (Signori et al., 2016), but long-term studies directly comparing the three main Interferon-β formulations have never been conducted so far. Therefore, the present propensity score-adjusted cohort study evaluated the clinical evolution of newly diagnosed RRMS patients during 8-year treatment with different Interferon-β formulations. 2. Methods 2.1. Study design The present mono-centric retrospective observational cohort study has been conducted on prospectively collected data, recorded in the clinical database of the Multiple Sclerosis Clinical Care and Research Centre at the “Federico II” University of Naples, Italy. Data were entered by physicians specifically trained in MS and were checked in terms of quality by senior physicians. In compliance with current Italian applicable laws and regulations, considering that all clinical assessments were part of clinical practice in a university setting and that the retrospective analysis included anonymized data, specific ethics approval was not required. All subjects signed the general informed consent form, authorizing the use of personal data for research purposes, as approved by the Ethics Committee of the “Federico II” University of Naples, Italy. The study was performed in accordance with good clinical practice and Declaration of Helsinki.
Observation period was extended to 12 months in order to confirm the reaching of disability outcomes independently from clinical relapses that, if occurring within the period of interest, were required to involve a functional system different from that being involved by progression. 2.5. Statistical analyses Means and proportions of demographic features and clinical findings were calculated for the MS population, and were compared among DMT subgroups (Interferon-β1a 44 mcg, Interferon-β1a 30 mcg, and Interferon-β1b 250 mcg) with χ2 test, or analysis of variance (ANOVA) with post-hoc Bonferroni Correction, as appropriate. The group of patients treated with Interferon-β1a 44 mcg was considered the reference for statistical analysis. Time-to-event Cox proportional hazard regression models were performed to estimate differences in rates of relapse occurrence (time to the first relapse), 1-point EDSS progression, reaching of EDSS 4.0, and conversion to SP, in different treatment groups. Hazard ratio (HR) and 95% confidence intervals (95%CI) are presented. Poisson regression model was used to measure differences in ARR between treatments. Coefficient (Coeff) and 95%CI are presented. Covariates included in the statistical models were demographic characteristics (age, gender), disease duration (time occurring from first reported symptom to diagnosis and subsequent DMT start), and baseline EDSS. In order to reduce this source of bias, we estimated three sets of propensity score variables based on the probability of patients being selected for a specific treatment. The propensity score variables were developed using three logistic regression models (Interferon-β1a 44 mcg vs Interferon-β1a 30 mcg; Interferon-β1a 44 mcg vs Interferonβ1b 250 mcg; Interferon-β1a 30 mcg vs Interferon-β1b 250 mcg), entering the following variables in the models: age, gender, disease duration, and baseline EDSS. The propensity score variables were used as additional covariates in the regression models for each study outcome. Considering that we included newly-diagnosed patients, no reliable data were available before baseline visit. Results have been considered statistically significant if p < 0.05. Stata 14.0 has been used for data processing and analysis. Statistician was blind to treatment codes.
2.2. Population Inclusion criteria were: 1) new diagnosis of clinically-definite RRMS from January 2001 to January 2010 (McDonald et al., 2001); 2) use of Interferon-β as first prescribed DMT after diagnosis, in accordance with the indications for clinical practice of the Italian regulatory agency (Agenzia Italiana, 2016). Exclusion criteria were: 1) progressive forms of MS at baseline (Lublin et al., 2014); 2) age at diagnosis < 18 years; 3) incomplete clinical records; 4) previous use of DMTs. 2.3. Treatment variables Newly diagnosed RRMS patients eligible for Interferon-β treatment, received their first medication supply with instructions for the administration from a trained nurse within one month from the diagnosis. No specific criteria were applied in selecting the formulation; patients had the opportunity to discuss pros and cons of available treatments with physicians and nurses, and were given a prescription for the preferred. Clinical evaluations were scheduled according to clinical practice (every 3–6 months). Patients were included in the study up to their last moment of continuous treatment with the same Interferon-β formulation, in order to evaluate the separate contribution of each regimen on the clinical evolution. Patients were grouped in relation to the prescribed Interferon-β: 1) high-dose high-frequency subcutaneous Interferon-β1a 44 mcg (Rebif 44®) (Interferon-β1a 44 mcg sc); 2) low-dose low-frequency intramuscular Interferon-β1a 30 mcg (Avonex®) (Interferon-β1a 30 mcg); 3) high-dose high-frequency subcutaneous Interferon-β1b 250 mcg (Betaferon®) (Interferon-β1b 250 mcg).
3. Results 685 subjects received a new diagnosis of MS during the study period. Among them, 507 RRMS patients were included in the analysis, and followed-up for 8.5 ± 3.9 years. Reasons for exclusion were: first DMT different from Interferon-β (n = 91), progressive disease course at diagnosis (n = 42), age < 18 years (n = 21), incomplete records (n = 23). Demographic features, clinical findings and treatment variables are presented in Table 1. At diagnosis, treatment groups were similar in gender distribution (p = 0.884), disease duration (p = 0.522), and EDSS (p = 0.320), but were different in age (p = 0.007). Interferon-β1a 44 mcg patients were
2.4. Clinical outcomes Clinical assessments were performed by physicians specifically trained in MS and qualified for expanded disability status scale (EDSS) assessments. During the study period, following endpoints of MS evolution were recorded (Runmarker and Andersen, 1993): 51
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Table 1 Demographic features and clinical findings. Demographic features and clinical findings are reported for different treatment groups. HR, 95%CI and p-values are shown from propensity score-adjusted Cox regression models (*: p < 0.05).
Age, years Gender, female (%) Disease duration at diagnosis, years EDSS at diagnosis, median (min-max) Study duration, years Annualized relapse rate Relapse occurrence (%) Time to first relapse, years 1-point EDSS progression (%) Time to 1-point EDSS progression, years Reaching of EDSS 4.0 (%) Time to reaching of EDSS 4.0, years SP conversion (%) Time to SP conversion, years
Interferon-β1a 44 mcg (reference) (n = 191, 37.6%)
Interferon-β1a 30 mcg (n = 168, 33.4%)
31.4 ± 8.3 123 (64.4%) 2.7 ± 2.8
32.3 ± 7.8 104 (61.9%) 2.8 ± 2.7
34.2 ± 8.5 93 (62.8%) 2.5 ± 2.7
1.5 (1.0–3.5)
1.5 (1.0–3.5)
1.5 (1.0–3.5)
9.0 ± 4.3 0.32 ± 0.59 131 (68.5%) 4.3 ± 4.2
8.8 ± 3.6 0.35 ± 0.43 120 (71.0%) 4.1 ± 3.4
8.4 ± 3.7 0.34 ± 0.47 93 (62.8%) 3.9 ± 3.2
154 (81.0%)
135 (80.3%)
6.6 ± 3.4
5.8 ± 3.2
60 (31.4%) 8.5 ± 3.9
65 (38.5%) 7.1 ± 3.4
1.363
0.947
1.963
0.095
16 (8.3%) 9.3 ± 4.1
22 (13.0%) 7.9 ± 3.4
1.884
0.925
3.834
0.081
HR
95%CI Lower
p-values Upper
1.138
0.885
1.464
0.312
1.084
0.827
1.369
0.070
Interferon-β1b 250 mcg (n = 148, 29.0%)
HR
95%CI
p-values
Lower
Upper
0.878
0.671
1.149
0.345
1.064
0.827
1.369
0.628
51 (34.6%) 7.1 ± 3.7
1.207
0.828
1.761
0.063
17 (11.5%) 7.3 ± 3.5
2.054
1.026
4.110
0.042*
104 (70.2) 5.5 ± 2.7
HR: hazard ratio; 95%CI: 95% confidence intervals; IFN: Interferon; EDSS: Expanded Disability Status Scale; SP: secondary progressive.
use of long-term outcomes, with prolonged clinical observation being required to obtain clinically meaningful results. This should be accounted when interpreting data on disability progression not only on Interferon-β, but also on newer medications. Differences across Interferon-β formulations might be a consequence of the dose and frequency of administration (Mitsikostas and Goodin, 2017). Indeed, higher levels of cumulative exposure to subcutaneous Interferon-β1a have been associated with a more positive disease evolution after 15 years, compared with lower exposure (Kappos et al., 2015). Bioavailability and peak serum concentration of Interferon-β are dose-dependent (Hegen et al., 2015), and biological effects can be mediated, at least in part, by the dose and the frequency of the administration (Kieseier, 2011). The present study has different limitations, mainly related to its observational non-randomized design, with the risk of unmeasurable confounders (e.g. MRI activity at baseline). Sample size could have been larger with more balanced distribution across treatment groups, although we applied a double-adjustment method (propensity and covariate adjustment), in order to reduce possible bias. Also, recruitment period was relatively long, but patient inclusion was based on homogenous diagnostic criteria. Follow-up duration was different across treatment groups; however, in order to reduce the risk of attrition bias, we applied survival models accounting for the time each patient spent in the cohort. Discontinuation rates to different Interferon-β formulations have already been reported elsewhere (Moccia et al., 2016, 2015). A control group without treatment would have been useful as reference in the analysis, but is hard to realize in the real word; however our objective was comparing different Interferon-β formulation, rather than showing overall efficacy in the long term. Outcomes of disease evolution were clinical, as newer outcomes (e.g. MRI, cognition or patient-reported outcomes) were not routinely recorded in the database and, so, were not available for the whole population in a standard fashion (Uher et al., 2017). Presence of neutralizing antibodies might have also affected present results (Lanzillo et al., 2011; Paolicelli et al., 2013), but it is unlikely being different across different treatment groups. In conclusion, the present study compared the clinical efficacy of different labeled formulations of Interferon-β, and showed that patients treated with Interferon-β1a 44 mcg presented with a marginally
younger, compared with Interferon-β1b 250 mcg (p = 0.007) but not with Interferon-β1a 30 mcg (p = 0.077) (Table 1). Interferon-β1b 250 mcg presented with shorter follow-up time, compared with Interferon-β1a 44 mcg (p < 0.001) and with Interferon-β1a 30 mcg (p = 0.001) (Table 1). At propensity score-adjusted Cox regression models, patients treated with Interferon-β1b 250 mcg presented with a higher rate of SP conversion (HR = 2.054; p = 0.042), and with a not-significant higher rate of reaching of EDSS 4.0 (HR = 1.207; p = 0.063), when compared with Interferon-β1a 44 mcg. Patients treated with Interferon-β1a 30 mcg presented with a not-significant higher rate of 1-point EDSS progression (HR = 1.084; p = 0.070), of reaching of EDSS 4.0 (HR = 1.363; p = 0.095), and of SP conversion (HR = 1.884; p = 0.081), when compared with Interferon-β1a 44 mcg (Table 1) (Fig. 1). Results from unadjusted and partially-adjusted models are reported in the Supplementary Table 1. At propensity score-adjusted Poisson regression models, the ARR of patients treated with Interferon-β1a 44 mcg was not different from Interferon-β1b 250 mcg (Coeff = −0.008; 95%CI = −0.087–0.629; p = 0.139), and from Interferon-β1a 30 mcg (Coeff = 0.002; 95%CI = −0.389-0.372; p = 0.964). 4. Discussion The present propensity score-adjusted cohort study compared the 8year clinical evolution of newly-diagnosed RRMS patients treated with different Interferon-β formulations. Long-term disease evolution was marginally different across treatment groups, pointing towards a trend for higher risk of reaching of EDSS 4.0 and of converting to SP for Interferon-β1b 250 mcg and for Interferon-β1a 30 mcg, when compared with Interferon-β1a 44 mcg. In line with this study, previous meta-analyses showed that the use of Interferon-β1a 44 mcg during the RR phase might mitigate the risk of disability progression, compared with other Interferon-β formulations (Fogarty et al., 2016; Mendes et al., 2016; Einarson et al., 2017; Mitsikostas and Goodin, 2017), despite no differences in relapse risk (Fogarty et al., 2016; Mendes et al., 2016; Einarson et al., 2017), and lack of efficacy after SP conversion (Kuhle et al., 2016). Noteworthy, our findings on disability progression increased in significance with the 52
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Fig. 1. Kaplan-Meier curves for study outcomes. Kaplan-Meier plots estimating the probability of relapse occurrence (A), of 1-point EDSS progression (B), of reaching of EDSS 4.0 (C), and of SP conversion (D), in patients treated with Interferon-β1a 44 mcg (green), Interferon-β1a 30 mcg (red), and Interferon-β1b 250 mcg (blue). HR and p-values are shown from propensity score-adjusted Cox regression models. The group of patients treated with Interferon-β1a 44 mcg (green) was used as reference in statistical analyses. Mean follow-up was 8.5 ± 3.9 years (ranging from 0.6 to 15.8 years). EDSS: expanded disability status scale; SP: secondary progressive; HR: hazard ratio. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
reduced risk of disability accrual in the long-term, when compared with Interferon-β1a 30 mcg and Interferon-β1b 250 mcg. Formulation, frequency of administration and dose of Interferon-β might affect the longterm clinical evolution of RRMS. Therefore, in the clinical practice, MS physicians, patients and caregivers have to balance the more convenient and possibly better tolerated low-dose low-frequency regimen, with the long-term risk of disease evolution.
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Acknowledgments and conflict of interest This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors have no conflict of interest to report. Appendix A. Supplementary material Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.msard.2017.11.006. References Lublin, F.D., Reingold, S.C., Cohen, J.A., et al., 2014. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83, 278–286. http://dx.doi.org/10. 1212/WNL.0000000000000560. Agenzia Italiana, 2016. del Farmaco. Banca Dati Farmaci dell’AIFA.〈https://www. farmaci.agenziafarmaco.gov.it/〉 (Accessed 23 August 2017). Goodin, D.S., Traboulsee, A., Knappertz, V., et al., 2012a. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon-1b trial in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 83, 282–287. http://dx.doi.org/10.1136/jnnp-2011-301178. Scalfari, A., Neuhaus, A., Degenhardt, A., et al., 2010. The natural history of multiple sclerosis, a geographically based study: relapses and long-term disability. Brain 133, 1914–1929. http://dx.doi.org/10.1093/brain/awq118.
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Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
A 8-year retrospective cohort study comparing Interferon-β formulations for relapsing‐remitting multiple sclerosis
MARK
⁎
Marcello Mocciaa, , Raffaele Palladinob,c, Antonio Carotenutoa, Francesco Saccàa, Cinzia Valeria Russoa, Roberta Lanzilloa, Vincenzo Brescia Morraa a
Multiple Sclerosis Clinical Care and Research Centre, Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Via Sergio Pansini, 5 – Building 17, Ground floor, Naples, Italy b Department of Primary Care and Public Health, Imperial College, London, United Kingdom c Department of Public Health, Federico II University, Naples, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Multiple sclerosis Interferon Long-term Relapsing Progression Disability
Background: Interferon-β has been approved for the treatment of relapsing-remitting (RR) multiple sclerosis (MS), whereas its efficacy in preventing long-term disability and conversion to secondary progressive (SP) MS is still debated. We aim to compare long-term clinical evolution of newly-diagnosed RRMS patients treated with different Interferon-β formulations. Methods: 507 patients were included in the analysis and followed-up for 8.5 ± 3.9 years. 37.6% were treated with subcutaneous Interferon-β1a 44 mcg, 33.4% with intramuscular Interferon-β1a 30 mcg, and 29.0% with subcutaneous Interferon-β1b 250 mcg. Relapse occurrence, 1-point EDSS progression, reaching of EDSS 4.0 and conversion to SP were recorded as outcome measures. To reduce the selection bias, we calculated the propensity score of receiving the specific treatment considering age (32.7 ± 8.3 years), gender (female 63.1%), disease duration (2.7 ± 2.8 years), and baseline EDSS (1.5, range 1.0–3.5). Propensity score and covariates (age, gender, disease duration and EDSS) were included in the statistical models. Results: At Cox regression models, the reaching of EDSS 4.0 was not-significantly higher for Interferon-β1b 250 mcg (HR = 1.207; p = 0.063) and for Interferon-β1a 30 mcg (HR = 1.363; p = 0.095), when compared with Interferon-β1a 44 mcg. The rate of SP conversion was higher for Interferon-β1b 250 mcg (HR = 2.054; p = 0.042), and not-significantly higher for Interferon-β1a 30 mcg (HR = 1.884; p = 0.081), when compared with Interferon-β1a 44 mcg. Conclusions: Patients treated with Interferon-β1a 44 mcg presented with a marginally reduced risk of disability accrual in the long-term, when compared with Interferon-β1b 250 mcg and, at least in part, with Interferon-β1a 30 mcg. Formulation, frequency of administration and dose of Interferon-β might affect the long-term clinical evolution of RRMS.
1. Introduction Multiple sclerosis (MS) usually starts with a relapsing-remitting (RR) course, and eventually converts to a phase of progressive disability accrual, namely secondary progressive (SP) MS (Lublin et al., 2014). Currently available disease modifying treatments (DMT) have proven to reduce amount and severity of relapses in RRMS (Agenzia Italiana, 2016; Goodin et al., 2012a). However, natural history studies showed a dissociation between relapses and disability progression in the longterm (Scalfari et al., 2010; Río et al., 2017), and, accordingly, the benefit of DMTs on disability progression is still uncertain (Fogarty et al., 2016; Zhang et al., 2015). Evidence of DMT efficacy is based on
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randomized clinical trials conducted during relatively short observation time, not detecting long-term disease outcomes (Goodin et al., 2012a). Their long-term extension has shed light on the importance of early and continuous treatment, but failed to show any definite comparative result on clinical efficacy, as being open-label (Goodin et al., 2012b; Ebers et al., 2010). Interferon-β is one of the oldest and still frequently prescribed medications for the treatment of RRMS. Meta-analytic studies found different Interferon-β formulations being similar in efficacy on relapses, whereas no definite results were presented for disability progression (Fogarty et al., 2016; Mendes et al., 2016; Einarson et al., 2017; Kalincik et al., 2015; Newsome et al., 2017). A pooled analysis
Corresponding author. E-mail address: [email protected] (M. Moccia).
https://doi.org/10.1016/j.msard.2017.11.006 Received 23 August 2017; Received in revised form 13 October 2017; Accepted 5 November 2017 2211-0348/ © 2017 Elsevier B.V. All rights reserved.
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– Occurrence of clinical relapses (time to the first relapse on treatment and annualized relapse rate -ARR- during the whole observation period were calculated); – 1-point expanded disability status scale (EDSS) progression (independently from relapses and sustained for 12 months); – Reaching of EDSS 4.0 (independently from relapses and sustained for 12 months); – Transition from RR to SP course (MS was considered SP when a progressive accumulation of disability occurred after an initial relapsing course, and was associated with a worsening of the same functional system, independently from relapse activity) (Lublin et al., 2014).
suggested a reduction of the risk of disability progression for the use of Interferon-β, compared with no treatment (Signori et al., 2016), but long-term studies directly comparing the three main Interferon-β formulations have never been conducted so far. Therefore, the present propensity score-adjusted cohort study evaluated the clinical evolution of newly diagnosed RRMS patients during 8-year treatment with different Interferon-β formulations. 2. Methods 2.1. Study design The present mono-centric retrospective observational cohort study has been conducted on prospectively collected data, recorded in the clinical database of the Multiple Sclerosis Clinical Care and Research Centre at the “Federico II” University of Naples, Italy. Data were entered by physicians specifically trained in MS and were checked in terms of quality by senior physicians. In compliance with current Italian applicable laws and regulations, considering that all clinical assessments were part of clinical practice in a university setting and that the retrospective analysis included anonymized data, specific ethics approval was not required. All subjects signed the general informed consent form, authorizing the use of personal data for research purposes, as approved by the Ethics Committee of the “Federico II” University of Naples, Italy. The study was performed in accordance with good clinical practice and Declaration of Helsinki.
Observation period was extended to 12 months in order to confirm the reaching of disability outcomes independently from clinical relapses that, if occurring within the period of interest, were required to involve a functional system different from that being involved by progression. 2.5. Statistical analyses Means and proportions of demographic features and clinical findings were calculated for the MS population, and were compared among DMT subgroups (Interferon-β1a 44 mcg, Interferon-β1a 30 mcg, and Interferon-β1b 250 mcg) with χ2 test, or analysis of variance (ANOVA) with post-hoc Bonferroni Correction, as appropriate. The group of patients treated with Interferon-β1a 44 mcg was considered the reference for statistical analysis. Time-to-event Cox proportional hazard regression models were performed to estimate differences in rates of relapse occurrence (time to the first relapse), 1-point EDSS progression, reaching of EDSS 4.0, and conversion to SP, in different treatment groups. Hazard ratio (HR) and 95% confidence intervals (95%CI) are presented. Poisson regression model was used to measure differences in ARR between treatments. Coefficient (Coeff) and 95%CI are presented. Covariates included in the statistical models were demographic characteristics (age, gender), disease duration (time occurring from first reported symptom to diagnosis and subsequent DMT start), and baseline EDSS. In order to reduce this source of bias, we estimated three sets of propensity score variables based on the probability of patients being selected for a specific treatment. The propensity score variables were developed using three logistic regression models (Interferon-β1a 44 mcg vs Interferon-β1a 30 mcg; Interferon-β1a 44 mcg vs Interferonβ1b 250 mcg; Interferon-β1a 30 mcg vs Interferon-β1b 250 mcg), entering the following variables in the models: age, gender, disease duration, and baseline EDSS. The propensity score variables were used as additional covariates in the regression models for each study outcome. Considering that we included newly-diagnosed patients, no reliable data were available before baseline visit. Results have been considered statistically significant if p < 0.05. Stata 14.0 has been used for data processing and analysis. Statistician was blind to treatment codes.
2.2. Population Inclusion criteria were: 1) new diagnosis of clinically-definite RRMS from January 2001 to January 2010 (McDonald et al., 2001); 2) use of Interferon-β as first prescribed DMT after diagnosis, in accordance with the indications for clinical practice of the Italian regulatory agency (Agenzia Italiana, 2016). Exclusion criteria were: 1) progressive forms of MS at baseline (Lublin et al., 2014); 2) age at diagnosis < 18 years; 3) incomplete clinical records; 4) previous use of DMTs. 2.3. Treatment variables Newly diagnosed RRMS patients eligible for Interferon-β treatment, received their first medication supply with instructions for the administration from a trained nurse within one month from the diagnosis. No specific criteria were applied in selecting the formulation; patients had the opportunity to discuss pros and cons of available treatments with physicians and nurses, and were given a prescription for the preferred. Clinical evaluations were scheduled according to clinical practice (every 3–6 months). Patients were included in the study up to their last moment of continuous treatment with the same Interferon-β formulation, in order to evaluate the separate contribution of each regimen on the clinical evolution. Patients were grouped in relation to the prescribed Interferon-β: 1) high-dose high-frequency subcutaneous Interferon-β1a 44 mcg (Rebif 44®) (Interferon-β1a 44 mcg sc); 2) low-dose low-frequency intramuscular Interferon-β1a 30 mcg (Avonex®) (Interferon-β1a 30 mcg); 3) high-dose high-frequency subcutaneous Interferon-β1b 250 mcg (Betaferon®) (Interferon-β1b 250 mcg).
3. Results 685 subjects received a new diagnosis of MS during the study period. Among them, 507 RRMS patients were included in the analysis, and followed-up for 8.5 ± 3.9 years. Reasons for exclusion were: first DMT different from Interferon-β (n = 91), progressive disease course at diagnosis (n = 42), age < 18 years (n = 21), incomplete records (n = 23). Demographic features, clinical findings and treatment variables are presented in Table 1. At diagnosis, treatment groups were similar in gender distribution (p = 0.884), disease duration (p = 0.522), and EDSS (p = 0.320), but were different in age (p = 0.007). Interferon-β1a 44 mcg patients were
2.4. Clinical outcomes Clinical assessments were performed by physicians specifically trained in MS and qualified for expanded disability status scale (EDSS) assessments. During the study period, following endpoints of MS evolution were recorded (Runmarker and Andersen, 1993): 51
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Table 1 Demographic features and clinical findings. Demographic features and clinical findings are reported for different treatment groups. HR, 95%CI and p-values are shown from propensity score-adjusted Cox regression models (*: p < 0.05).
Age, years Gender, female (%) Disease duration at diagnosis, years EDSS at diagnosis, median (min-max) Study duration, years Annualized relapse rate Relapse occurrence (%) Time to first relapse, years 1-point EDSS progression (%) Time to 1-point EDSS progression, years Reaching of EDSS 4.0 (%) Time to reaching of EDSS 4.0, years SP conversion (%) Time to SP conversion, years
Interferon-β1a 44 mcg (reference) (n = 191, 37.6%)
Interferon-β1a 30 mcg (n = 168, 33.4%)
31.4 ± 8.3 123 (64.4%) 2.7 ± 2.8
32.3 ± 7.8 104 (61.9%) 2.8 ± 2.7
34.2 ± 8.5 93 (62.8%) 2.5 ± 2.7
1.5 (1.0–3.5)
1.5 (1.0–3.5)
1.5 (1.0–3.5)
9.0 ± 4.3 0.32 ± 0.59 131 (68.5%) 4.3 ± 4.2
8.8 ± 3.6 0.35 ± 0.43 120 (71.0%) 4.1 ± 3.4
8.4 ± 3.7 0.34 ± 0.47 93 (62.8%) 3.9 ± 3.2
154 (81.0%)
135 (80.3%)
6.6 ± 3.4
5.8 ± 3.2
60 (31.4%) 8.5 ± 3.9
65 (38.5%) 7.1 ± 3.4
1.363
0.947
1.963
0.095
16 (8.3%) 9.3 ± 4.1
22 (13.0%) 7.9 ± 3.4
1.884
0.925
3.834
0.081
HR
95%CI Lower
p-values Upper
1.138
0.885
1.464
0.312
1.084
0.827
1.369
0.070
Interferon-β1b 250 mcg (n = 148, 29.0%)
HR
95%CI
p-values
Lower
Upper
0.878
0.671
1.149
0.345
1.064
0.827
1.369
0.628
51 (34.6%) 7.1 ± 3.7
1.207
0.828
1.761
0.063
17 (11.5%) 7.3 ± 3.5
2.054
1.026
4.110
0.042*
104 (70.2) 5.5 ± 2.7
HR: hazard ratio; 95%CI: 95% confidence intervals; IFN: Interferon; EDSS: Expanded Disability Status Scale; SP: secondary progressive.
use of long-term outcomes, with prolonged clinical observation being required to obtain clinically meaningful results. This should be accounted when interpreting data on disability progression not only on Interferon-β, but also on newer medications. Differences across Interferon-β formulations might be a consequence of the dose and frequency of administration (Mitsikostas and Goodin, 2017). Indeed, higher levels of cumulative exposure to subcutaneous Interferon-β1a have been associated with a more positive disease evolution after 15 years, compared with lower exposure (Kappos et al., 2015). Bioavailability and peak serum concentration of Interferon-β are dose-dependent (Hegen et al., 2015), and biological effects can be mediated, at least in part, by the dose and the frequency of the administration (Kieseier, 2011). The present study has different limitations, mainly related to its observational non-randomized design, with the risk of unmeasurable confounders (e.g. MRI activity at baseline). Sample size could have been larger with more balanced distribution across treatment groups, although we applied a double-adjustment method (propensity and covariate adjustment), in order to reduce possible bias. Also, recruitment period was relatively long, but patient inclusion was based on homogenous diagnostic criteria. Follow-up duration was different across treatment groups; however, in order to reduce the risk of attrition bias, we applied survival models accounting for the time each patient spent in the cohort. Discontinuation rates to different Interferon-β formulations have already been reported elsewhere (Moccia et al., 2016, 2015). A control group without treatment would have been useful as reference in the analysis, but is hard to realize in the real word; however our objective was comparing different Interferon-β formulation, rather than showing overall efficacy in the long term. Outcomes of disease evolution were clinical, as newer outcomes (e.g. MRI, cognition or patient-reported outcomes) were not routinely recorded in the database and, so, were not available for the whole population in a standard fashion (Uher et al., 2017). Presence of neutralizing antibodies might have also affected present results (Lanzillo et al., 2011; Paolicelli et al., 2013), but it is unlikely being different across different treatment groups. In conclusion, the present study compared the clinical efficacy of different labeled formulations of Interferon-β, and showed that patients treated with Interferon-β1a 44 mcg presented with a marginally
younger, compared with Interferon-β1b 250 mcg (p = 0.007) but not with Interferon-β1a 30 mcg (p = 0.077) (Table 1). Interferon-β1b 250 mcg presented with shorter follow-up time, compared with Interferon-β1a 44 mcg (p < 0.001) and with Interferon-β1a 30 mcg (p = 0.001) (Table 1). At propensity score-adjusted Cox regression models, patients treated with Interferon-β1b 250 mcg presented with a higher rate of SP conversion (HR = 2.054; p = 0.042), and with a not-significant higher rate of reaching of EDSS 4.0 (HR = 1.207; p = 0.063), when compared with Interferon-β1a 44 mcg. Patients treated with Interferon-β1a 30 mcg presented with a not-significant higher rate of 1-point EDSS progression (HR = 1.084; p = 0.070), of reaching of EDSS 4.0 (HR = 1.363; p = 0.095), and of SP conversion (HR = 1.884; p = 0.081), when compared with Interferon-β1a 44 mcg (Table 1) (Fig. 1). Results from unadjusted and partially-adjusted models are reported in the Supplementary Table 1. At propensity score-adjusted Poisson regression models, the ARR of patients treated with Interferon-β1a 44 mcg was not different from Interferon-β1b 250 mcg (Coeff = −0.008; 95%CI = −0.087–0.629; p = 0.139), and from Interferon-β1a 30 mcg (Coeff = 0.002; 95%CI = −0.389-0.372; p = 0.964). 4. Discussion The present propensity score-adjusted cohort study compared the 8year clinical evolution of newly-diagnosed RRMS patients treated with different Interferon-β formulations. Long-term disease evolution was marginally different across treatment groups, pointing towards a trend for higher risk of reaching of EDSS 4.0 and of converting to SP for Interferon-β1b 250 mcg and for Interferon-β1a 30 mcg, when compared with Interferon-β1a 44 mcg. In line with this study, previous meta-analyses showed that the use of Interferon-β1a 44 mcg during the RR phase might mitigate the risk of disability progression, compared with other Interferon-β formulations (Fogarty et al., 2016; Mendes et al., 2016; Einarson et al., 2017; Mitsikostas and Goodin, 2017), despite no differences in relapse risk (Fogarty et al., 2016; Mendes et al., 2016; Einarson et al., 2017), and lack of efficacy after SP conversion (Kuhle et al., 2016). Noteworthy, our findings on disability progression increased in significance with the 52
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Fig. 1. Kaplan-Meier curves for study outcomes. Kaplan-Meier plots estimating the probability of relapse occurrence (A), of 1-point EDSS progression (B), of reaching of EDSS 4.0 (C), and of SP conversion (D), in patients treated with Interferon-β1a 44 mcg (green), Interferon-β1a 30 mcg (red), and Interferon-β1b 250 mcg (blue). HR and p-values are shown from propensity score-adjusted Cox regression models. The group of patients treated with Interferon-β1a 44 mcg (green) was used as reference in statistical analyses. Mean follow-up was 8.5 ± 3.9 years (ranging from 0.6 to 15.8 years). EDSS: expanded disability status scale; SP: secondary progressive; HR: hazard ratio. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
reduced risk of disability accrual in the long-term, when compared with Interferon-β1a 30 mcg and Interferon-β1b 250 mcg. Formulation, frequency of administration and dose of Interferon-β might affect the longterm clinical evolution of RRMS. Therefore, in the clinical practice, MS physicians, patients and caregivers have to balance the more convenient and possibly better tolerated low-dose low-frequency regimen, with the long-term risk of disease evolution.
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