Beta-interferon exposure and onset of secondary progressive multiple sclerosis

Abstract

Background and purpose: Beta-interferons (IFNβ) are the most widely prescribed drugs for patients with multiple sclerosis (MS). However, whether or not treatment with IFNβ can delay secondary progressive MS (SPMS) onset remains unknown. Our aim was to examine the association between IFNβ exposure and SPMS onset in patients with relapsing-remitting MS (RRMS).

Methods: A retrospective cohort study using British Columbia (Canada) population-based clinical and health administrative data (1985-2008) was conducted. RRMS patients treated with IFNβ (n = 794) were compared with untreated contemporary (n = 933) and historical (n = 837) controls. Cohort entry was the first clinic visit during which patients became eligible for IFNβ treatment (baseline). The outcome was time from baseline to SPMS onset. Cox regression models with IFNβ as a time-dependent exposure were adjusted for sex, and baseline age, disease duration, disability, *socioeconomic status and *comorbidities (*available for the contemporary cohorts only). Additional analyses included propensity score adjustment.

Results: The median follow-up for the IFNβ-treated, untreated contemporary and historical controls were 5.7, 3.7 and 7.3 years, and the proportions of patients reaching SPMS were 9.2%, 11.8% and 32.9%, respectively. After adjustment for confounders, IFNβ exposure was not associated with the risk of reaching SPMS when either the contemporary or the historical untreated cohorts were considered (hazard ratio 1.07; 95% confidence interval 0.93-1.48, and hazard ratio 1.04; 95% confidence interval 0.74-1.46, respectively). Further adjustments and the propensity score yielded results consistent with the main analysis.

Conclusions: Amongst patients with RRMS, use of IFNβ was not associated with a delayed onset of SPMS.

Keywords: beta-interferon; cohort study; multiple sclerosis; progression.

Figure 1

Selection of IFNβ‐treated and untreated cohorts from the BCMS database for the main analysis. BCMS, British Columbia Multiple Sclerosis; IMDs, immunomodulatory drugs; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; IFNβ, beta‐interferons; SPMS, secondary progressive multiple sclerosis. ^aThe sum of the individual reasons for exclusion exceeds the total number of patients because some patients met more than 1 condition.

Figure 2

Multivariable time‐dependent Cox regression analysis of potential factors associated with time to SPMS ^a onset for IFNβ‐treated versus untreated cohorts. (a) IFNβ‐treated (n = 794) versus the contemporary untreated (n = 933) group. (b) IFNβ‐treated (n = 794) versus the historical untreated (n = 873) group. ^a SPMS, secondary progressive multiple sclerosis. ^b IFNβ, beta‐interferons; IFNβ exposure was modelled as a time‐dependent variable. ^c EDSS, Expanded Disability Status Scale score which ranged from 0 to 6.5 at baseline.

Figure 3

Time‐dependent Cox regression analysis of potential factors associated with time to SPMS ^a onset for IFNβ‐treated versus the contemporary untreated cohort^b (with additional adjustments for socioeconomic status and the Charlson comorbidity index). ^a SPMS, secondary progressive multiple sclerosis. ^b IFNβ, beta‐interferons; IFNβ‐treated patients, n = 794; contemporary untreated patients, n = 933. ^cIFNβ exposure was modelled as a time‐dependent variable. ^d EDSS, Expanded Disability Status Scale score which ranged from 0 to 6.5 at baseline. ^eDeyo adaptation of the Charlson comorbidity index 24, based on hospital admissions or physician visits in the 2 years prior to baseline and derived from the International Classification of Diseases, 9th Revision, Clinical Modification (ICD‐9‐CM) codes, excluding hemiplegia, paraplegia and dementia to avoid misclassifying complications of MS as comorbidity. All relevant comorbidities are aggregated into a single variable theoretically ranging from 0 to 33; higher scores indicate greater burden of comorbidity.

Figure 4

Association between IFNβ exposure and onset of SPMS amongst IFNβ‐treated patients and untreated patients according to each baseline characteristic. (a) IFNβ‐treated (n = 794) versus the contemporary untreated (n = 933) group. (b) IFNβ‐treated (n = 794) versus the historical untreated (n = 873) group. ^aBaseline was considered as the first clinic visit when a patient became eligible for beta interferon (IFNβ) treatment. ^b EDSS, Expanded Disability Status Scale; ARR, annualized relapse rate. ^cThe hazard ratio of IFNβ exposure for the corresponding baseline characteristics level estimated using Cox regression models adjusting for the main effects of all the baseline characteristics, the IFNβ exposure as well as the interaction term between IFNβ exposure and the baseline characteristic of interest. ^d P values for testing the interaction between IFNβ exposure and the baseline characteristic of interest based on the likelihood ratio test which compares the models with and without the interaction term. ^eIf this period included the onset attack, this was not counted as a relapse. ^fOutcome rates indicate how many patients were observed to reach the outcome (onset of SPMS) for each level of the baseline characteristic.