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Interferon-beta and disability progression in relapsing-remitting multiple sclerosis
Clinical Neurology and Neurosurgery, pages S65 - S69
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.
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.
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).
This observational study further supports the notion that IFN-beta could have potential beneficial effect on disease progression in RRMS.
Keywords: Disease progression, Interferon-beta, Multiple sclerosis, Observational study, Prognosis.
Multiple sclerosis (MS) is a chronic neurological disease which affects approximately 2.5 million people around the world  . The natural history of MS is characterized by a marked variation when it comes to the gradual development of disability  . 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  and .
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)  . 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 resonance imaging  . However, RCTs which last only 2–3 years, and their continuous extensions up to 5 years, are primarily focused on short-term outcomes , , , , and . Evidence from RCTs and extension open-label IFN-beta studies for preventing or delaying long-term neurologic disability is less consistent and incomplete  and . 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 long-term impact of IFN-beta , , and .
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  . The date of the first visit corresponded to the date of the first IFN-beta administration for 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  , maximum Expanded Disability Status Scale (EDSS) score  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., IFN-beta 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  . 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  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 χ2 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.
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-beta-treated 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).
|Variable||IFN-beta-treated group||Untreated control group||All patients||p|
|Age at first visit (years)|
|Mean ± SD||31.1 ± 7.7||32.2 ± 8.5||31.6 ± 8.1||0.185|
|Median (range)||31.0 (22.0–56.0)||32.0 (22.0–66.0)||31.0 (21.0–66.0)|
|Age at onset (years)|
|Mean ± SD||27.4 ± 7.3||28.0 ± 8.1||27.7 ± 7.6||0.432|
|Median (range)||27.0 (13.0–57.0)||27.0 (12.0–57.0)||27.0 (12.0–57.0)|
|Male||69 (29.2)||54 (29.5)||123 (29.4)||0.952|
|Female||167 (70.8)||129 (70.5)||296 (70.6)|
|Disease duration (years)|
|Mean ± SD||11.1 ± 5.0||10.7 ± 5.7||10.9 ± 5.4||0.428|
|Median (range)||9.0 (0.2–31.0)||10.0 (0.3–24.0)||10.0 (0.2–32.0)|
|EDSS score at first visit|
|Mean ± SD||1.9 ± 0.8||1.8 ± 0.7||1.9 ± 0.8||0.337|
|Median (range)||2.0 (0.0–3.5)||2.0 (1.0–4.5)||2.0 (0.0–4.5)|
|Number of relapses in the last year before first visit|
|Mean ± SD||1.6 ± 0.9||0.5 ± 0.7||1.1 ± 1.0||<0.001|
|Median (range)||1.0 (0.0–5.0)||0.0 (0.0–4.0)||1.0 (0.0–5.0)|
a Number (%).
EDSS-Expanded Disability Status Scale, SD-standard deviation.
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 (Fig 1, Fig 2, and Fig 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 IFN-beta-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-beta-treated group showed a highly significant reduction (p < 0.001) in the risk of SP when compared with untreated patients after adjustment by number of relapses in the last year before first visit. For the end point EDSS score of 4, there was a significant (p = 0.001) difference of at least 50% in favor of the IFN-beta-treated group. For the end point EDSS score of 6, there was a significant difference (p = 0.007) in risk of at least 66% reduction in favor of the IFN-beta-treated group.
|Clinical end points|
|SP||EDSS score 4||EDSS score 6|
|HR (95%CI) a||p||HR (95%CI) a||p||HR (95%CI) a||p|
|IFN-beta treatment||0.34 (0.19–0.61)||<0.001||0.45 (0.28–0.73)||0.001||0.34 (0.16–0.75)||0.007|
a Adjusted by number of relapses in the last year before first visit.
SP-secondary progression, EDSS-Expanded Disability Status Scale, HR-hazard ratio, 95%CI-confidence interval.
In our study, cohort of patients receiving two high-dose IFN-beta therapies has been followed for up to 7 years, and time and probability of conversion from RR disease course to SP as a measure of disability progression were assessed. Additionally, in order to assess the impact of treatment on the development of unremitting irreversible disability, we evaluated the time and likelihood of reaching sustained and confirmed EDSS 4 and 6 in this cohort in order to assess the impact of treatment on the development of unremitting irreversible disability. We compared group of 236 IFN-beta-treated patients with a group of 183 untreated patients and demonstrated beneficial effect of therapy related to all three clinical end points.
The IFN-beta-treated group showed a highly significant reduction in the risk of reaching SP (HR = 0.34, p < 0.001), EDSS score of 4 (HR = 0.45, p = 0.001), and EDSS score of 6 (HR = 0.34, p = 0.007), when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from MS onset (4.0, 4.4, and 2.2 years) in favor of treated patients.
Well designed observational studies have made important contributions to our understanding of the risks and benefits of drug treatment, since they facilitate evaluation of treatment effects in “real-world” settings, outside the strongly controlled conditions of RCTs. Since observational studies are, on the other hand, burdened with a number of biases, several methodological improvements (adjustment, stratification, matching, restriction, etc.) have been recently suggested in order to overcome lack of randomization as the major issue  .
Propensity-score analysis is the most common technique currently used in observational studies in order to reduce biases when comparing outcomes between groups of treated and untreated patients  . In the first large observational study  which used propensity-score adjusted analysis to evaluate whether IFN-beta treatment have an impact on disability progression in MS, 1504 RRMS patients were recruited by two Italian MS Centers (Bari and Florence) and followed for up to 7 years. Similar to our findings, authors of this study have demonstrated that the SP, and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years, respectively) in favor of IFN-beta-treated patients compared with untreated group. Additionally, IFN-beta-treated group showed a highly significant reduction in the incidence of SP after the first visit (HR = 0.38, p < 0.0001), EDSS score of 4 (HR = 0.70, p < 0.02), and EDSS score of 6 (HR, 0.60, p < 0.03) when compared with untreated patients. Authors performed sensitivity analysis which confirmed these findings.
Recently, second large observational study which used propensity score adjusted method to investigate the association between IFN-beta exposure and disability was performed in British Columbia, Canada  . IFN-treated RRMS patients (n = 868) were compared retrospectively with patients from 2 control groups (contemporary untreated and historical untreated, comprising 829 and 959 patients, respectively). The main outcome measure was time from IFN-beta treatment eligibility to a confirmed and sustained EDSS of 6. After adjustment, it has been demonstrated that IFN-beta therapy was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 compared with both the contemporary cohort (HR = 1.30, p = 0.140) and the historical control cohort (HR = 0.77, p = 0.070). These results were not significantly changed after sensitivity analysis, various additional adjustments and propensity score analysis. Based on these findings, Shirani et al. concluded that IFN-beta therapy does not prevent sustained disability in patients with MS  .
Although RCTs have proven short-term efficacy of IFN-beta in relapsing MS, its impact on long-term disability is not clearly elucidated yet. Therefore, despite all well-known limitations, observational studies could potentially offer helpful supportive data to complement evidence-based medicine. In addition to above mentioned investigations  and , several more postmarketing studies have suggested the effectiveness of IFN-beta, implying that one of the beneficial effects could be a potential positive association between IFN-beta therapy and MS disability , , , , , and .
In patients with relapsing forms of MS, accumulation of disability may occur by incomplete recovery from acute exacerbations, and in progressive forms, by gradual deterioration of functional ability outside of a relapse  . It has been demonstrated that the relapses prevented by interferon lead to disability accumulation  . Additionally, pathological studies have shown that MS inflammation is closely associated with axonal damage that starts early with the first manifestations of the disease  , and therefore, anti-inflammatory effect of IFN-beta in the early phase of MS should lead to a reduced amount of tissue damage and potentially less disability during long-term follow-up.
Precise mechanisms of action of IFN-beta are still not completely understood. Numerous evidence suggest effects which include regulation of pro-inflammatory and anti-inflammatory cytokines, inhibition of T-cell proliferation, and reduction of the trafficking of leukocytes into the CNS  . Additionally, some recent studies indicate that IFN-beta may have indirect neuroprotective effects, via increasing nerve growth factor production and decreasing oxidative stress in MS  and .
In our study, the treatment and control groups were balanced for all of the baseline covariates, except for number of relapses in the last year before first visit. Therefore, in statistical analysis, we adjusted all proportional hazard models by this variable. This study has certain limitations related to small sample size, relatively short follow-up and hidden bias due to potential unmeasured confounders which were not assessed. Additionally, we have not sufficiently considered immortal time bias.
In conclusion, this observational study, despite above mentioned limitations, further support the results obtained in previous larger studies , , and  that strongly suggest that IFN-beta could have potential beneficial effect on disease progression in RRMS patients.
This study was supported by the Ministry of Education and Science of the Republic of Serbia (grant numbers 175031 and 175087).
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a Clinic of Neurology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotica 6, 11129 Belgrade, Serbia
b Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Visegradska 26A, 11129 Belgrade, Serbia
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