Clinical Neurology and Neurosurgery 115S (2013) S65–S69
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Interferon-beta and disability progression in relapsing-remitting multiple sclerosis Jelena Drulovic a,∗ , Jelena Kostic a , Sarlota Mesaros a , Irena Dujmovic Basuroski a , Nebojsa Stojsavljevic a , Darija Kisic-Tepavcevic b , Tatjana Pekmezovic b a b
Clinic of Neurology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotica 6, 11129 Belgrade, Serbia Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Visegradska 26A, 11129 Belgrade, Serbia
a r t i c l e Keywords: Disease progression Interferon-beta Multiple sclerosis Observational study Prognosis
i n f o
a b s t r a c t Objective: To assess the impact of interferon (IFN)-beta treatment on the progression of unremitting disability in IFN-beta treated and untreated relapsing-remitting (RR) patients with multiple sclerosis (MS) using prospective cohort study. Methods: A cohort of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients was followed for up to 7 years. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points: secondary progression (SP), and sustained Expanded Disability Status Scale (EDSS) score 4 and 6. Time from disease onset was used as survival time variable. Results: The IFN-beta-treated group showed a highly significant reduction (hazard ratio [HR], 0.34, 95% confidence interval [CI] 0.19–0.61, p < 0.001) in the risk of SP when compared with untreated patients. There were significant differences in favor of the IFN-beta-treated group for the end point EDSS score of 4 (HR = 0.45, 95%CI 0.28–0.73, p = 0.001) and EDSS score of 6 (HR = 0.34, 95%CI 0.16–0.75, p = 0.007). Conclusion: This observational study further supports the notion that IFN-beta could have potential beneficial effect on disease progression in RRMS. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a chronic neurological disease which affects approximately 2.5 million people around the world [1]. The natural history of MS is characterized by a marked variation when it comes to the gradual development of disability [2]. Up to 85% of patients present with a relapsing form of MS, and studies suggest that 2–3% of patients per year convert to secondary progressive (SP) phase of the disease [3,4]. In 1993 IFN-beta 1b (Betaseron in the US, Betaferon in Europe) was the first disease modifying therapy (DMT) to be approved for the treatment of relapsing-remitting (RR) MS, and additional IFN-beta preparations have since become available for clinical use: IFN-beta 1a for intramuscular (im) or subcutaneous (sc) use (Avonex and Rebif, respectively) [5]. Up to now, several randomized clinical trials (RCTs) which have been considered as the gold standard for assessment of drug efficacy, have shown that INF-beta reduced relapse frequency, relapse-related progression of disability, and new inflammatory lesions as demonstrated by magnetic
∗ Corresponding author. Tel.: +381 11 2685662; fax: +381 11 2685662. E-mail address: [email protected] (J. Drulovic). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.024
resonance imaging [6]. However, RCTs which last only 2–3 years, and their continuous extensions up to 5 years, are primarily focused on short-term outcomes [7–11]. Evidence from RCTs and extension open-label IFN-beta studies for preventing or delaying long-term neurologic disability is less consistent and incomplete [12,13]. In contrast to RCTs, observational studies, which can be used for long-term outcomes, are affected by considerable biases. However, well-designed observational studies are currently recognized as a design which could provide significant information on the longterm impact of IFN-beta [14–16]. In this study, we conducted a 7-year survival analysis on a cohort of IFN beta treated and untreated RRMS patients, in order to assess the impact of treatment on the progression of unremitting disability, under “real world” conditions.
2. Materials and methods Cohort of the RRMS patients was recruited consecutively from January 2004 at the MS Center of the Clinic of Neurology, Clinical Center of Serbia, Belgrade. MS-related clinical data were obtained from hospital database. A diagnosis of MS was established according to the McDonald criteria [17]. The date of the first visit corresponded to the date of the first IFN-beta administration for
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J. Drulovic et al. / Clinical Neurology and Neurosurgery 115S (2013) S65–S69
the IFN-beta-treated patients. For untreated patients, the date of the first admission to the MS center was used as the date of the first visit. In our prospective cohort study, median follow-up time was 6.0 years in both groups. The IFN-beta-treated cohort comprised patients who were exposed to IFN-beta therapy for up to 7 years. In January 2004, the Serbian Health Insurance Fund began to consider reimbursement of IFN-beta (IFN-beta 1a, 44 mcg, Rebif, and IFN-beta 1b, 250 mcg, Betaferon) for the treatment of RRMS patients in our country, and during the whole study follow-up period (January 2004–December 2010), only these two preparations of IFN-beta were available for therapy: IFN-beta-1b (250 mcg, subcutaneously, every other day) and IFN-beta-1a (44 mcg, subcutaneously, three times weekly). Because of the poor economic situation in Serbia, limited number of relapsing MS patients is treated according to the Serbian Health Insurance Fund reimbursement scheme. Because of the high cost of IFN-beta, government decided that this therapy can be obtained exclusively in four University MS centers in Serbia, ours having the largest cohort of IFN-beta treated MS patients in our country. Patients eligible to start IFN-beta treatment had to fulfil following criteria: diagnosis of MS established according to the Mc Donald criteria [17], maximum Expanded Disability Status Scale (EDSS) score [18] 3.5, a RR form of the disease and active course, with at least two functionally relevant relapses within the last two years, age 18 years or older. Having in mind that it is extremely difficult to define beneficial response to treatment in each individual patient, the following scenarios had been considered for treatment discontinuation according to the scheme: (1) The development of at least two aggressive clinical relapses or increased frequency compared to pre-treatment levels; (2) The development of sustained EDSS progression for more than 1.0 point at 12 months. Periods of treatment with IFN-beta in our MS center were recorded for each patient, including the start and stop dates. The majority of IFN-beta treated patients had a short break (less than 3 months), which we considered not to influence the benefit from therapy. We considered transient combination therapy (e.g., IFNbeta and mitoxantrone or azathioprine) to be equal to IFN-beta therapy alone. In this study, we assumed that both IFN-beta products or transient combinations had equivalent impacts on disability progression [19]. Thus, no adjustment by specific therapeutic interventions was performed. The untreated cohort comprised equivalent time period RRMS patients. Majority of those patients were untreated because of the poor economic situation in Serbia and restrictive eligibility criteria for IFN-beta therapy (above mentioned). Additionally, remaining subjects were not treated because they: voluntarily refused this therapy, planned to get pregnant, had concomitant diseases (i.e. liver diseases, hematological disorders or severe depression), or had low MS activity. The main outcome measure was time from MS onset to the development of SP. The secondary progressive phase was defined as initial RR disease course followed by progression with or without relapses [20] and additionally characterized by deterioration which lead to an increase in the EDSS score for at least 1.0 point for at least one year. The secondary outcomes were time from MS onset to a confirmed and sustained EDSS score of 4 and 6. The date of onset is defined as the appearance of the first symptoms. A score of EDSS 4 corresponds to limited walking ability for greater than 500 m without the need for a walking aid or rest. An EDSS score of 6 indicates intermittent or unilateral constant assistance required to walk about 100 m with or without resting. A disability score was defined as irreversible when persisted for at least 6 months, and all the subsequent scores assessed during the follow-up of the patient were either equal to or higher than that score. The EDSS score was
recorded at baseline and at least every 6 months subsequently to determine the level of disability, based on the neurological examination performed by experienced MS neurologists (JD, SM, IDB, NS) who were not blinded to patients treatment status. The study was approved by the Ethics Committee of the Faculty of Medicine University of Belgrade. 2.1. Statistical analysis Baseline characteristics for the IFN-beta-treated group and the untreated control group were compared with 2 and Mann–Whitney U tests for categorical and continuous variables, respectively. We used Kaplan–Meier method to draw curves for each of three clinical endpoints (times to reach SP, EDSS 4, EDSS 6), and the log-rank test to assess the difference between the two groups investigated. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points. Results are expressed as hazard ratios (HR) and 95% confidence intervals. P-values less than 0.05 were considered significant. The SPSS 17.0 statistical software package (SPSS Inc., Chicago, IL, U.S.A.) was used in the statistical analysis. 3. Results A total of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients participated in the study. Fifty six percent (n = 133) of 236 IFN-beta-treated patients were treated with Rebif 44 mcg, and 44% (n = 103) received Betaferon. Only 3 out of 236 (1.3%) IFN-betatreated patients were also treated with mitoxantrone. Table 1 shows the baseline characteristics of both treated and untreated RRMS cohort. There were no significant differences between the IFN-beta-treated and untreated MS patients for all baseline variables except for number of relapses in the last year before the visit. The IFN-beta-treated group had a greater number of relapses during the year before the first visit compared with the untreated control group (p < 0.001). The sample size for the EDSS score of 4 end point was 399 since we excluded patients with EDSS ≥ 4 at first visit from untreated group. IFN-beta treatment significantly delayed the time to each of the three clinical end points (Figs. 1–3). Time from disease onset to SP was reached with a delay of 4 years in IFN-beta-treated patients (12.9 years for IFN-beta-treated vs. 8.9 years for untreated patients). The percentage of patients that reached SP after 6 years of follow-up was 30.1% for the untreated patients versus 9.3% for IFNbeta-treated patients. The percentage of untreated patients who had reached a sustained and confirmed EDSS score of 4 was 33.9% compared with 15.7% of the IFN-beta-treated group. The delay for the development of EDSS score of 4 from the disease onset was 4.4 years (12.2 years for IFN-beta-treated vs. 7.8 years for untreated patients). The percentage of patients that reached sustained and confirmed EDSS 4 after 6 years of follow-up was 33.9% for the untreated patients versus 13.7% for IFN-beta-treated patients. For the end point EDSS score of 6, 18% of untreated patients compared with 5.1% of IFN-beta-treated group reached an EDSS score of 6. Time from the disease onset to EDSS score of 6 was reached with a delay of 2.2 years (12.4 years for IFN-beta-treated vs. 10.2 years for untreated patients). The results of the Cox proportional hazard models for risk of each of the three end points are summarized in Table 2. The IFN-betatreated group showed a highly significant reduction (p < 0.001) in the risk of SP when compared with untreated patients after
J. Drulovic et al. / Clinical Neurology and Neurosurgery 115S (2013) S65–S69
S67
Table 1 Baseline characteristics of relapsing-remitting multiple sclerosis patients according to the treatment group (n = 419). Variable
IFN-beta-treated group
236 No Age at first visit (years) Mean ± SD 31.1 ± 7.7 Median (range) 31.0 (22.0–56.0) Age at onset (years) Mean ± SD 27.4 ± 7.3 27.0 (13.0–57.0) Median (range) a Gender Male 69 (29.2) Female 167 (70.8) Disease duration (years) 11.1 ± 5.0 Mean ± SD 9.0 (0.2–31.0) Median (range) EDSS score at first visit 1.9 ± 0.8 Mean ± SD 2.0 (0.0–3.5) Median (range) Number of relapses in the last year before first visit 1.6 ± 0.9 Mean ± SD Median (range) 1.0 (0.0–5.0)
Untreated control group
All patients
183
419
p
32.2 ± 8.5 32.0 (22.0–66.0)
31.6 ± 8.1 31.0 (21.0–66.0)
0.185
28.0 ± 8.1 27.0 (12.0–57.0)
27.7 ± 7.6 27.0 (12.0–57.0)
0.432
54 (29.5) 129 (70.5)
123 (29.4) 296 (70.6)
0.952
10.7 ± 5.7 10.0 (0.3–24.0)
10.9 ± 5.4 10.0 (0.2–32.0)
0.428
1.8 ± 0.7 2.0 (1.0–4.5)
1.9 ± 0.8 2.0 (0.0–4.5)
0.337
0.5 ± 0.7 0.0 (0.0–4.0)
1.1 ± 1.0 1.0 (0.0–5.0)
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Interferon-beta and disability progression in relapsing-remitting multiple sclerosis Jelena Drulovic a,∗ , Jelena Kostic a , Sarlota Mesaros a , Irena Dujmovic Basuroski a , Nebojsa Stojsavljevic a , Darija Kisic-Tepavcevic b , Tatjana Pekmezovic b a b
Clinic of Neurology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotica 6, 11129 Belgrade, Serbia Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Visegradska 26A, 11129 Belgrade, Serbia
a r t i c l e Keywords: Disease progression Interferon-beta Multiple sclerosis Observational study Prognosis
i n f o
a b s t r a c t Objective: To assess the impact of interferon (IFN)-beta treatment on the progression of unremitting disability in IFN-beta treated and untreated relapsing-remitting (RR) patients with multiple sclerosis (MS) using prospective cohort study. Methods: A cohort of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients was followed for up to 7 years. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points: secondary progression (SP), and sustained Expanded Disability Status Scale (EDSS) score 4 and 6. Time from disease onset was used as survival time variable. Results: The IFN-beta-treated group showed a highly significant reduction (hazard ratio [HR], 0.34, 95% confidence interval [CI] 0.19–0.61, p < 0.001) in the risk of SP when compared with untreated patients. There were significant differences in favor of the IFN-beta-treated group for the end point EDSS score of 4 (HR = 0.45, 95%CI 0.28–0.73, p = 0.001) and EDSS score of 6 (HR = 0.34, 95%CI 0.16–0.75, p = 0.007). Conclusion: This observational study further supports the notion that IFN-beta could have potential beneficial effect on disease progression in RRMS. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a chronic neurological disease which affects approximately 2.5 million people around the world [1]. The natural history of MS is characterized by a marked variation when it comes to the gradual development of disability [2]. Up to 85% of patients present with a relapsing form of MS, and studies suggest that 2–3% of patients per year convert to secondary progressive (SP) phase of the disease [3,4]. In 1993 IFN-beta 1b (Betaseron in the US, Betaferon in Europe) was the first disease modifying therapy (DMT) to be approved for the treatment of relapsing-remitting (RR) MS, and additional IFN-beta preparations have since become available for clinical use: IFN-beta 1a for intramuscular (im) or subcutaneous (sc) use (Avonex and Rebif, respectively) [5]. Up to now, several randomized clinical trials (RCTs) which have been considered as the gold standard for assessment of drug efficacy, have shown that INF-beta reduced relapse frequency, relapse-related progression of disability, and new inflammatory lesions as demonstrated by magnetic
∗ Corresponding author. Tel.: +381 11 2685662; fax: +381 11 2685662. E-mail address: [email protected] (J. Drulovic). 0303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.09.024
resonance imaging [6]. However, RCTs which last only 2–3 years, and their continuous extensions up to 5 years, are primarily focused on short-term outcomes [7–11]. Evidence from RCTs and extension open-label IFN-beta studies for preventing or delaying long-term neurologic disability is less consistent and incomplete [12,13]. In contrast to RCTs, observational studies, which can be used for long-term outcomes, are affected by considerable biases. However, well-designed observational studies are currently recognized as a design which could provide significant information on the longterm impact of IFN-beta [14–16]. In this study, we conducted a 7-year survival analysis on a cohort of IFN beta treated and untreated RRMS patients, in order to assess the impact of treatment on the progression of unremitting disability, under “real world” conditions.
2. Materials and methods Cohort of the RRMS patients was recruited consecutively from January 2004 at the MS Center of the Clinic of Neurology, Clinical Center of Serbia, Belgrade. MS-related clinical data were obtained from hospital database. A diagnosis of MS was established according to the McDonald criteria [17]. The date of the first visit corresponded to the date of the first IFN-beta administration for
S66
J. Drulovic et al. / Clinical Neurology and Neurosurgery 115S (2013) S65–S69
the IFN-beta-treated patients. For untreated patients, the date of the first admission to the MS center was used as the date of the first visit. In our prospective cohort study, median follow-up time was 6.0 years in both groups. The IFN-beta-treated cohort comprised patients who were exposed to IFN-beta therapy for up to 7 years. In January 2004, the Serbian Health Insurance Fund began to consider reimbursement of IFN-beta (IFN-beta 1a, 44 mcg, Rebif, and IFN-beta 1b, 250 mcg, Betaferon) for the treatment of RRMS patients in our country, and during the whole study follow-up period (January 2004–December 2010), only these two preparations of IFN-beta were available for therapy: IFN-beta-1b (250 mcg, subcutaneously, every other day) and IFN-beta-1a (44 mcg, subcutaneously, three times weekly). Because of the poor economic situation in Serbia, limited number of relapsing MS patients is treated according to the Serbian Health Insurance Fund reimbursement scheme. Because of the high cost of IFN-beta, government decided that this therapy can be obtained exclusively in four University MS centers in Serbia, ours having the largest cohort of IFN-beta treated MS patients in our country. Patients eligible to start IFN-beta treatment had to fulfil following criteria: diagnosis of MS established according to the Mc Donald criteria [17], maximum Expanded Disability Status Scale (EDSS) score [18] 3.5, a RR form of the disease and active course, with at least two functionally relevant relapses within the last two years, age 18 years or older. Having in mind that it is extremely difficult to define beneficial response to treatment in each individual patient, the following scenarios had been considered for treatment discontinuation according to the scheme: (1) The development of at least two aggressive clinical relapses or increased frequency compared to pre-treatment levels; (2) The development of sustained EDSS progression for more than 1.0 point at 12 months. Periods of treatment with IFN-beta in our MS center were recorded for each patient, including the start and stop dates. The majority of IFN-beta treated patients had a short break (less than 3 months), which we considered not to influence the benefit from therapy. We considered transient combination therapy (e.g., IFNbeta and mitoxantrone or azathioprine) to be equal to IFN-beta therapy alone. In this study, we assumed that both IFN-beta products or transient combinations had equivalent impacts on disability progression [19]. Thus, no adjustment by specific therapeutic interventions was performed. The untreated cohort comprised equivalent time period RRMS patients. Majority of those patients were untreated because of the poor economic situation in Serbia and restrictive eligibility criteria for IFN-beta therapy (above mentioned). Additionally, remaining subjects were not treated because they: voluntarily refused this therapy, planned to get pregnant, had concomitant diseases (i.e. liver diseases, hematological disorders or severe depression), or had low MS activity. The main outcome measure was time from MS onset to the development of SP. The secondary progressive phase was defined as initial RR disease course followed by progression with or without relapses [20] and additionally characterized by deterioration which lead to an increase in the EDSS score for at least 1.0 point for at least one year. The secondary outcomes were time from MS onset to a confirmed and sustained EDSS score of 4 and 6. The date of onset is defined as the appearance of the first symptoms. A score of EDSS 4 corresponds to limited walking ability for greater than 500 m without the need for a walking aid or rest. An EDSS score of 6 indicates intermittent or unilateral constant assistance required to walk about 100 m with or without resting. A disability score was defined as irreversible when persisted for at least 6 months, and all the subsequent scores assessed during the follow-up of the patient were either equal to or higher than that score. The EDSS score was
recorded at baseline and at least every 6 months subsequently to determine the level of disability, based on the neurological examination performed by experienced MS neurologists (JD, SM, IDB, NS) who were not blinded to patients treatment status. The study was approved by the Ethics Committee of the Faculty of Medicine University of Belgrade. 2.1. Statistical analysis Baseline characteristics for the IFN-beta-treated group and the untreated control group were compared with 2 and Mann–Whitney U tests for categorical and continuous variables, respectively. We used Kaplan–Meier method to draw curves for each of three clinical endpoints (times to reach SP, EDSS 4, EDSS 6), and the log-rank test to assess the difference between the two groups investigated. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points. Results are expressed as hazard ratios (HR) and 95% confidence intervals. P-values less than 0.05 were considered significant. The SPSS 17.0 statistical software package (SPSS Inc., Chicago, IL, U.S.A.) was used in the statistical analysis. 3. Results A total of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients participated in the study. Fifty six percent (n = 133) of 236 IFN-beta-treated patients were treated with Rebif 44 mcg, and 44% (n = 103) received Betaferon. Only 3 out of 236 (1.3%) IFN-betatreated patients were also treated with mitoxantrone. Table 1 shows the baseline characteristics of both treated and untreated RRMS cohort. There were no significant differences between the IFN-beta-treated and untreated MS patients for all baseline variables except for number of relapses in the last year before the visit. The IFN-beta-treated group had a greater number of relapses during the year before the first visit compared with the untreated control group (p < 0.001). The sample size for the EDSS score of 4 end point was 399 since we excluded patients with EDSS ≥ 4 at first visit from untreated group. IFN-beta treatment significantly delayed the time to each of the three clinical end points (Figs. 1–3). Time from disease onset to SP was reached with a delay of 4 years in IFN-beta-treated patients (12.9 years for IFN-beta-treated vs. 8.9 years for untreated patients). The percentage of patients that reached SP after 6 years of follow-up was 30.1% for the untreated patients versus 9.3% for IFNbeta-treated patients. The percentage of untreated patients who had reached a sustained and confirmed EDSS score of 4 was 33.9% compared with 15.7% of the IFN-beta-treated group. The delay for the development of EDSS score of 4 from the disease onset was 4.4 years (12.2 years for IFN-beta-treated vs. 7.8 years for untreated patients). The percentage of patients that reached sustained and confirmed EDSS 4 after 6 years of follow-up was 33.9% for the untreated patients versus 13.7% for IFN-beta-treated patients. For the end point EDSS score of 6, 18% of untreated patients compared with 5.1% of IFN-beta-treated group reached an EDSS score of 6. Time from the disease onset to EDSS score of 6 was reached with a delay of 2.2 years (12.4 years for IFN-beta-treated vs. 10.2 years for untreated patients). The results of the Cox proportional hazard models for risk of each of the three end points are summarized in Table 2. The IFN-betatreated group showed a highly significant reduction (p < 0.001) in the risk of SP when compared with untreated patients after
J. Drulovic et al. / Clinical Neurology and Neurosurgery 115S (2013) S65–S69
S67
Table 1 Baseline characteristics of relapsing-remitting multiple sclerosis patients according to the treatment group (n = 419). Variable
IFN-beta-treated group
236 No Age at first visit (years) Mean ± SD 31.1 ± 7.7 Median (range) 31.0 (22.0–56.0) Age at onset (years) Mean ± SD 27.4 ± 7.3 27.0 (13.0–57.0) Median (range) a Gender Male 69 (29.2) Female 167 (70.8) Disease duration (years) 11.1 ± 5.0 Mean ± SD 9.0 (0.2–31.0) Median (range) EDSS score at first visit 1.9 ± 0.8 Mean ± SD 2.0 (0.0–3.5) Median (range) Number of relapses in the last year before first visit 1.6 ± 0.9 Mean ± SD Median (range) 1.0 (0.0–5.0)
Untreated control group
All patients
183
419
p
32.2 ± 8.5 32.0 (22.0–66.0)
31.6 ± 8.1 31.0 (21.0–66.0)
0.185
28.0 ± 8.1 27.0 (12.0–57.0)
27.7 ± 7.6 27.0 (12.0–57.0)
0.432
54 (29.5) 129 (70.5)
123 (29.4) 296 (70.6)
0.952
10.7 ± 5.7 10.0 (0.3–24.0)
10.9 ± 5.4 10.0 (0.2–32.0)
0.428
1.8 ± 0.7 2.0 (1.0–4.5)
1.9 ± 0.8 2.0 (0.0–4.5)
0.337
0.5 ± 0.7 0.0 (0.0–4.0)
1.1 ± 1.0 1.0 (0.0–5.0)
