Yinshan Zhao

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.

New perspectives in the natural history of multiple sclerosis

Multiple sclerosis (MS) has entered an era of immunomodulatory drug treatment, the impact of which on long-term disease progression remains controversial. The increasing use of these therapies has intensified our need to understand the true natural history of MS. The MS community is poised to establish whether the immunomodulatory drugs exhibit long-term benefits, with a suitable untreated natural history cohort likely the most practical and ethical comparator group. Thus, a thorough understanding of the natural history of MS is fundamental. In this review, we highlight recent advances in MS natural history over the last 5 years, with a focus on long-term population-based cohorts and factors associated with disease progression. Survival in MS has increased and longer times to irreversible disability have been reported in contemporary studies, indicating a slower accumulation of disability. Wide variation in the MS disease trajectory is evident within and between natural history studies, reflecting both methodologic considerations related to data collection and heterogeneity of disease activity. Recent publications have indicated that a younger age at disease onset is no longer indicative of a favorable outcome and further evidence supports the dissociation between relapses and long-term disability, although windows of opportunity may exist for some patients. We are now perhaps faced with our last chance to examine the true natural history of MS, so whether the reader is a practicing physician, health care provider, or researcher, or engaged in the pharmaceutical industry or in clinical trial design, recent advances in our understanding of the natural history of MS are of key significance.

Impact of multiple sclerosis relapses on progression diminishes with time.

Objective: The relationship between relapses and long-term disability in multiple sclerosis (MS) remains to be fully elucidated. Current literature is conflicting and focused on early relapses. We investigated the effects of relapses at different stages on disability progression. Methods: We conducted a retrospective review of 2,477 patients with definite relapsing-onset MS followed until July 2003 in British Columbia, Canada. Time-dependent Cox proportional hazards models examined the effect of relapses at different time periods (0–5; >5–10; >10 years postonset) on time to cane (Expanded Disability Status Scale [EDSS]) and secondary progressive MS (SPMS). Findings were derived from hazard ratios with 95% confidence intervals (CIs), adjusted for sex, onset age, and symptoms. Results: Mean follow-up was 20.6 years; 11,722 postonset relapses were recorded. An early relapse (within 5 years postonset) was associated with an increased hazard in disease progression over the short term, by 48%; 95% CI 37%–60% for EDSS 6 and 29%; 95% CI 20%–38% for SPMS. However, this substantially lessened to 10%; 95% CI 4%–16% (EDSS 6) and 2%; 95% CI −2%–7% (SPMS) after 10 years postonset. The impact of later relapses (>5–10 years postonset) also lessened over time. Effects were modulated by age, impact being greatest in younger (<25 years at onset) and least in older (≥35 years) patients where relapses beyond 5–years postonset typically failed to reach significance. Relapses during SPMS had no measurable impact on time to EDSS 6 from SPMS. Conclusion: Relapses within the first 5 years of disease impacted on disease progression over the short term. However, the long-term impact was minimal, either for early or later relapses. Long-term disease progression was least affected by relapses in patients with an extended disease duration (>10 years) or already in the secondary progressive phase.

Relapses in multiple sclerosis are age- and time-dependent

Objectives: To examine the relative relapse-rate patterns over time in a relapsing multiple sclerosis (MS) cohort and to investigate potential predictors of relapse rates and periods of low-relapse activity. Methods: This retrospective cohort study followed 2477 relapsing-remitting (RR) MS patients from onset to 1 July 2003. Annualised relapse rates were examined according to sex, age at onset, the patient’s current age and disease duration. The relationship between relapse rates and baseline characteristics (sex, onset age and onset symptoms) were examined using Poisson regression. Time to the first 5 years relapse-free was examined using Kaplan–Meier survival analysis. Results: The mean follow-up time (from onset of MS symptoms) was 20.6 years, during which time 11,722 post-onset relapses were recorded. The relapse rate decreased by 17% every 5 years (between years 5 to 30 post-onset), but this decline increased in magnitude with increasing onset age. Women and those with onset sensory symptoms exhibited a higher relapse rate (p⩽0.001). More than three-quarters of patients (1692/2189) experienced a 5-year relapse-free period during the RR phase. Conclusion: Relapse rates were age- and time-dependent. Our observations have clinical implications: 1) any drug able to modify relapse rates has the greatest potential for a population impact in patients <40 years old and within the first few demi-decades of disease; 2) continuation of drug beyond these times may be of limited value; 3) long-term follow-up studies must consider that relapse rates probably decline at different rates over time according to the patient’s onset age; 4) a relapse-quiescent period in MS is not uncommon.

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.

Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study

BACKGROUND Chronic cerebrospinal venous insufficiency has been proposed as a unique combination of extracranial venous blockages and haemodynamic flow abnormalities that occurs only in patients with multiple sclerosis and not in healthy people. Initial reports indicated that all patients with multiple sclerosis had chronic cerebrospinal venous insufficiency. We aimed to establish the prevalence of venous narrowing in people with multiple sclerosis, unaffected full siblings, and unrelated healthy volunteers. METHODS We did an assessor-blinded, case-control, multicentre study of people with multiple sclerosis, unaffected siblings, and unrelated healthy volunteers. We enrolled the study participants between January, 2011 and March, 2012, and they comprised 177 adults: 79 with multiple sclerosis, 55 siblings, and 43 unrelated controls, from three centres in Canada. We assessed narrowing of the internal jugular and azygous veins with catheter venography and ultrasound criteria for chronic cerebrospinal venous insufficiency proposed by Zamboni and colleagues. Catheter venography data were available for 149 participants and ultrasound data for 171 participants. FINDINGS Catheter venography criteria for chronic cerebrospinal venous insufficiency were positive for one of 65 (2%) people with multiple sclerosis, one of 46 (2%) siblings, and one of 32 (3%) unrelated controls (p=1·0 for all comparisons). Greater than 50% narrowing of any major vein was present in 48 of 65 (74%) people with multiple sclerosis, 31 of 47 (66%) siblings (p=0·41 for comparison with patients with multiple sclerosis), and 26 of 37 (70%) unrelated controls (p=0·82). The ultrasound criteria for chronic cerebrospinal venous insufficiency were fulfilled in 35 of 79 (44%) participants with multiple sclerosis, 17 of 54 (31%) siblings (p=0·15 for comparison with patients with multiple sclerosis) and 17 of 38 (45%) unrelated controls (p=0·98). The sensitivity of the ultrasound criteria for detection of greater than 50% narrowing on catheter venography was 0·406 (95% CI 0·311-0·508), and specificity was 0·643 (0·480-0·780). INTERPRETATION This study shows that chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people. Extracranial venous narrowing of greater than 50% is a frequent finding in patients with multiple sclerosis, unaffected siblings, and unrelated controls. The ultrasound criteria are neither sensitive nor specific for narrowing on catheter venography. The significance of venous narrowing to multiple sclerosis symptomatology remains unknown. FUNDING MS Society of Canada, Saskatoon City Hospital Foundation, Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation, and the Wolridge Foundation.

Clinical outcomes of 90 isolated unilateral facet fractures, subluxations, and dislocations treated surgically and nonoperatively.

Study Design. A retrospective outcomes study. Objective. The purposes of this study were 1) to identify plausible patient and interventional variables that influence the outcome of unilateral facet injuries and 2) to determine if patients return to normal general health status after unilateral facet injuries. Summary of Background Data. The management of unilateral subaxial cervical facet fractures and dislocations lacks agreement on treatment options and the variables that influence outcome. Methods. Injury data, radiographs, and outcomes (North American Spine Society Cervical Follow-up Questionnaire and Short Form-36) were collected from 9 centers and 13 surgeons, members of the Spine Trauma Study Group. Results. Causally motor vehicle accidents (49%) and sports (31%) predominated. The C6–C7 level accounted for 60% of injuries and C5–C6 represented 17%. The mean SF-36 PCS score of the operative patients with follow-up >18 months was 6.70 points higher than the mean of the nonoperative patients (P = 0.017). The SF-36 Bodily Pain mean of all patients was 67.2 (SD = 27.6), significantly lower (more pain) than the normative mean of 75.2 (SD = 23.7) (P = 0.014). Nonoperative patients also reported a mean Bodily Pain score of 63.0 (SD = 30.5) that was significantly worse than normative values (P = 0.031). Similarly, the NASS PD mean score for all patients was 84.8 (SD = 17.9), significantly lower than the normative mean of 89.1 (SD = 15.5) (P = 0.014). Conclusion. To our knowledge this is the largest reported series of facet injuries to date and the only one using health-related quality of life instruments. Unilateral facet injuries of the subaxial cervical spine led to reported levels of pain and disability that are significantly worse than those of the healthy population. Although further study is required, we suggest that nonoperatively treated patients report worse outcomes than operatively treated patients, particularly at longer follow-up despite having a more benign fracture pattern. The presence of comorbidities, associated injuries, and advanced age adversely impact clinical outcomes.

Natural history comparisons of primary and secondary progressive multiple sclerosis reveals differences and similarities.

BackgroundSimilarities in the onset age of progression in secondary-progressive (SP) and primary-progressive multiple sclerosis (PPMS) have been previously reported. However, with longer follow-up, more relapsing-remitting (RRMS) patients reach SPMS, such that the baseline characteristics, including age at progression may shift. We aimed to examine how this phenomenon impacts on demographic and clinical comparisons made between PP and SPMS.Methods and resultsPatients with definite MS, onset by July 1988 and ≥ 1 Expanded Disability Status Scale (EDSS) score were selected from the British Columbia-wide MS database (n = 2837). Of these, 353 (12.4 %) had PPMS and 1445/2484 (58.2 %) of the RRMS population reached SPMS at study close (July 2003). Females predominated in the SPMS population regardless of follow-up time (p ≤ 0.032). From Kaplan-Meier analysis (all RR, SP and PP patients considered), the estimated median onset age of progression was greater in SPMS (49.0 years; 95 % CI: 48.3–49.7) than PPMS (41.0 years; 95 % CI: 39.7–42.4), p < 0.0005. If the RR patients (who had not developed SPMS) were excluded, median age of onset of SPMS was still greater (43.1 years (95 % CI: 42.3–43.9, p < 0.0005).ConclusionsAlthough there were some similarities between SPMS and PPMS, the former had a later onset age in our British Columbian MS cohort.

Two-year study of cervical cord volume and myelin water in primary progressive multiple sclerosis.

Background: Spinal cord involvement in multiple sclerosis (MS) is common and an important element in disability. Previous studies demonstrated smaller cervical cord area at the C2 level in MS compared to controls, and a decrease in cord area over 12 months, most marked in primary progressive MS (PPMS). A subset of subjects participating in a multicentre, double-blind, placebo-controlled clinical trial evaluating the efficacy of glatiramer acetate in PPMS (PROMiSe trial) were followed for 2 years. Methods: 24 PPMS subjects, randomized to placebo (n = 9) and glatiramer acetate (n = 15), and 24 matched controls were studied. Cervical cord volume (CCV) at C2—3 was determined using a 3D inversion recovery (IR)-prepared spoiled-gradient echo sequence. Myelin water fraction (MWF) at C2—3 was obtained using a 32-echo IR-prepared relaxation sequence. Scans were repeated at baseline, years 1 and 2. Results: Baseline CCV was significantly smaller for PPMS than controls [median (interquartile range) 951 (829—1043) vs. 1072 (1040—1129) mm3, p = 0.0004] and MWF trended to be lower in PPMS cord [median (interquartile range) 0.225 (0.187—0.267) vs. 0.253 (0.235—0.266), p = 0.12]. Baseline CCV correlated with baseline Expanded Disability Status Scale, disease duration, brain white and grey matter volume. In PPMS, CCV was significantly decreased at year 1 (—0.83%, p = 0.04) and year 2 (—1.65%, p = 0.02). Baseline MWF correlated with baseline CCV and brain white and grey matter volume. MWF was significantly decreased from baseline for PPMS at year 2 (—10.5%, p = 0.01). Treatment effect was not detected on change in CCV nor MWF. Conclusions: Metrics at the level of the cord, including volume and MWF at C2—3, were lower in PPMS than controls and changed over 2 years only in PPMS.

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.