Afsaneh Shirani

Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

CONTEXT Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. OBJECTIVE To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. DESIGN, SETTING, AND PATIENTS Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. MAIN OUTCOME MEASURES The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. RESULTS The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. CONCLUSION Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada

Objective To examine mortality and factors associated with survival in a population based multiple sclerosis (MS) cohort. Methods Clinical and demographic data of MS patients registered with the British Columbia MS clinics (1980–2004) were linked to provincial death data, and patients were followed until death, emigration or study end (31 December 2007). Absolute survival and the influence of patient characteristics (sex, disease course (primary progressive (PPMS) vs relapsing onset (R-MS)) and onset age) were estimated by Kaplan–Meier analyses (from birth and disease onset). Mortality relative to the general population was examined using standardised mortality ratios. Excess mortality associated with patient characteristics and time period of cohort entry was assessed by relative survival modelling. Results Of 6917 patients, 1025 died. Median survival age was 78.6 years (95% CI 77.5 to 79.7) for women and 74.3 years (95% CI 73.1 to 75.4) for men. Survival from onset was longer for R-MS (49.7 years; 95% CI 47.9 to 51.5) than for PPMS (32.5 years; 95% CI 29.5 to 35.7); however, survival age was similar. The overall standardised mortality ratios was 2.89 (95% CI 2.71 to 3.07), and patients survived approximately 6 years less than expected, relative to the general population. PPMS had a higher relative mortality risk compared with R-MS (relative mortality ratio (RMR) 1.52; 95% CI 1.30 to 1.80). Women with PPMS had a relative survival disadvantage compared with men with PPMS (RMR 1.55; 95% CI 1.19 to 2.01). Relative survival within 10 years of cohort entry was similar between time periods. Conclusions Some of the longest MS survival times are reported here but the risk of death was still greater than in the age, sex and calendar year matched general population. No evidence of increased survival over time was found when improved survival in the general population was taken into consideration.

Outcomes and recurrence rates in chronic subdural haematoma

The object of this study was to determine the relationship between outcome (assessed by Glasgow Outcome Scale) and recurrence in chronic subdural haematoma (CSDH). Eighty-two consecutive patients who underwent surgery for CSDH were included in this study. The relationship between the following variables and CSDH recurrence was studied: sex; age; history of trauma; Glasgow Coma Scale (GCS) at the time of admission (stage 1: GCS > 12, stage 2: GCS: 8 – 12, stage 3: GCS < 8); interval between head injury (when a history of trauma was present) and surgery; presence of a midline shift on CT scans; presence of intracranial air 7 days after surgery; haematoma density; haematoma width; presence of brain atrophy; and Glasgow Outcome Scale (GOS, both quantitative and non-quantitative) at the time of discharge. Throughout the analysis, p < 0.05 was considered statistically significant. The results showed lower GCS (p < 0.001), higher GOS (p < 0.001), presence of intracranial air 7 days after surgery (p = 0.002), and a high density haematoma (p < 0.001) were significantly associated with recurrence of CSDH. It was concluded that GOS is related with recurrence in CSDH.

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis.

Identifying effective therapies for the treatment of progressive forms of multiple sclerosis (MS) is a highly relevant priority and one of the greatest challenges for the global MS community. Better understanding of the mechanisms involved in progression of the disease, novel trial designs, drug repurposing strategies, and new models of collaboration may assist in identifying effective therapies. In this review, we discuss various therapies under study in phase II or III trials, including antioxidants (idebenone); tyrosine kinase inhibitors (masitinib); sphingosine receptor modulators (siponimod); monoclonal antibodies (anti-leucine-rich repeat and immunoglobulin-like domain containing neurite outgrowth inhibitor receptor-interacting protein-1, natalizumab, ocrelizumab, intrathecal rituximab); hematopoetic stem cell therapy; statins and other possible neuroprotective agents (amiloride, riluzole, fluoxetine, oxcarbazepine); lithium; phosphodiesterase inhibitors (ibudilast); hormone-based therapies (adrenocorticotrophic hormone and erythropoietin); T-cell receptor peptide vaccine (NeuroVax); autologous T-cell immunotherapy (Tcelna); MIS416 (a microparticulate immune response modifier); dopamine antagonists (domperidone); and nutritional supplements, including lipoic acid, biotin, and sunphenon epigallocatechin-3-gallate (green tea extract). Given ongoing and planned clinical trial initiatives, and the largest ever focus of the global research community on progressive MS, future prospects for developing targeted therapeutics aimed at reducing disability in progressive forms of MS appear promising.

Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975–2009)

Background: Recent natural history studies suggest that multiple sclerosis (MS) is a more slowly progressing disease than previously thought. These observations are from studies separated by time, geography and methodological approach. Objectives: We investigated whether MS disease progression has changed over time in British Columbia, Canada. Methods: The British Columbia MS database was queried for relapsing-onset MS patients with symptom onset from 1975 to <1995, first assessed within 15 years from onset and with at least two Expanded Disability Status Scale (EDSS) scores. Latest follow-up was to 2009. Patients were grouped by 5-year onset intervals (1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995). Outcome was defined as time to reach sustained and confirmed EDSS 6 within 15 years of disease duration. Kaplan–Meier analysis was used to compare: the proportion of patients reaching EDSS 6 (primary analysis) and the time to EDSS 6 (secondary analysis) across the time-period groups. Results: A total of 2236 relapsing-onset MS patients (73.4% female; mean age at onset: 32.3 ± 8.8 years) were included. No significant temporal trend was found in the proportion of patients reaching EDSS 6 within 15 years from onset (28.5%, 26.4%, 27.7%, 22.3% for intervals 1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995, respectively; p = 0.09) or in survival curves for time to reach the outcome (p = 0.14). Conclusions: Rates of disease progression remained relatively stable over two decades of MS onset in British Columbia, Canada. Our results suggest that differences in disease progression findings between natural history studies may be related to factors other than time period.

Oligoclonal bands and cerebrospinal fluid markers in multiple sclerosis: associations with disease course and progression

Background: The use of oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) parameters are established in the diagnosis of MS, but poorly as markers of disease. Objective: To investigate the role of OCBs in disease course and progression. Methods: CSF data for 1120 patients with MS were analyzed for associations between OCBs and CSF parameters and clinical data (disease course [relapsing-onset MS (ROMS) vs primary-progressive MS (PPMS)]), disability progression (proportion reaching Expanded Disability Status Scale 6 within 10 years of onset and progression index) and ethnicity. Results: Of patients with MS, 72.5% had detectable OCBs. For patients with detectable OCBs, 84.6% had ROMS and 15.4% PPMS versus 89.7% and 10.3%, respectively for those without detectable OCBs (p=0.04). Total CSF IgG and protein levels were higher in PPMS compared with ROMS (p<0.001). Disease progression appeared independent of OCB status. Patients with CSF (vs without) data were more likely to be male, older at onset, have PPMS and lack optic neuropathy at onset (p<0.001). Conclusions: OCB positivity and elevated total CSF IgG and protein were moderately associated with a PPMS disease course, but not disease progression. Patients with atypical clinical presentations were more likely to have had CSF work-up, suggesting a testing bias.

Characterising aggressive multiple sclerosis

Objective To explore the occurrence and characteristics of aggressive multiple sclerosis (AMS) in adult-onset multiple sclerosis (MS) patients. Methods Prospectively collected data (1980–2009) from British Columbia, Canada, were retrospectively analysed. AMS was defined in three different ways (AMS1, 2 and 3): ‘AMS1’—confirmed Expanded Disability Status Scale (EDSS) ≥6 within 5 years of MS onset; ‘AMS2’—confirmed EDSS ≥6 by age 40; and ‘AMS3’—secondary progressive MS within 3 years of a relapsing-onset course. Three respective ‘non-aggressive’ MS comparison cohorts were selected. Patients’ characteristics were compared between aggressive and non-aggressive cohorts using multivariable logistic regression, with findings expressed as adjusted OR (AOR) and 95% CI. Results Application of the three definitions to the source population of 5891 patients resulted in 235/4285 (5.5%) patients fulfilling criteria for AMS1 (59.6% were female; 74.5% had relapsing-onset MS), 388/2762 (14.0%) for AMS2 (65.2% were female; 92.8% had relapsing-onset MS) and 195/4918 (4.0%) patients for AMS3 (61.0% were female). Compared to the respective control cohorts, those with AMS were more likely to be male (AOR=1.5, 95% CI 1.1 to 2.0 (AMS1); 1.6, 95% CI 1.3 to 2.1 (AMS2); 1.8, 95% CI 1.3 to 2.4 (AMS3)), older at MS symptom onset (AOR=1.1; 95% CI 1.1 to 1.1 (AMS1 and AMS3)) and have primary progressive MS (AOR=2.3, 95% CI 1.6 to 3.3 (AMS1); 2.7, 95% CI 1.7 to 4.4 (AMS2)). Conclusions AMS was identified in 4–14% of patients, depending on the definition used. Although there was a relative preponderance of men and primary progressive MS presenting with AMS, the majority of patients were still women and those with relapsing-onset MS.

Comparison of Statistical Approaches for Dealing With Immortal Time Bias in Drug Effectiveness Studies

In time-to-event analyses of observational studies of drug effectiveness, incorrect handling of the period between cohort entry and first treatment exposure during follow-up may result in immortal time bias. This bias can be eliminated by acknowledging a change in treatment exposure status with time-dependent analyses, such as fitting a time-dependent Cox model. The prescription time-distribution matching (PTDM) method has been proposed as a simpler approach for controlling immortal time bias. Using simulation studies and theoretical quantification of bias, we compared the performance of the PTDM approach with that of the time-dependent Cox model in the presence of immortal time. Both assessments revealed that the PTDM approach did not adequately address immortal time bias. Based on our simulation results, another recently proposed observational data analysis technique, the sequential Cox approach, was found to be more useful than the PTDM approach (Cox: bias = -0.002, mean squared error = 0.025; PTDM: bias = -1.411, mean squared error = 2.011). We applied these approaches to investigate the association of β-interferon treatment with delaying disability progression in a multiple sclerosis cohort in British Columbia, Canada (Long-Term Benefits and Adverse Effects of Beta-Interferon for Multiple Sclerosis (BeAMS) Study, 1995-2008).

Beta-interferon exposure and onset of secondary progressive multiple sclerosis.

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).

Multiple Sclerosis in Older Adults: The Clinical Profile and Impact of Interferon Beta Treatment

Background. We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, ≥50 years at symptom onset) versus adult-onset (AOMS, 18–<50 years) MS and (2) the association between interferon-beta (IFNβ) and disability progression in older relapsing-onset MS adults (≥50 years). Methods. This retrospective study (1980–2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFNβ-treated relapsing-onset MS patients aged ≥50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFNβ eligibility were examined using survival analyses. Results. LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFNβ. Among older relapsing-onset MS adults, no significant association between IFNβ exposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18–1.22) or historical controls (HR: 0.54; 95% CI: 0.20–1.42) were considered. Conclusion. LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFNβ exposure was not significantly associated with reduced disability in older MS patients.