Disability progression in multiple sclerosis is slower than previously reported

British Columbia has one of the highest rates of multiple sclerosis (MS) in Canada and in the world, affecting 93.3 per 10⁵.¹ The University of British Columbia’s MS clinic was established in 1980 and now includes four clinics serving the entire province of British Columbia. Demographic and clinical information, including Expanded Disability Status Scale (EDSS) evaluations, have been entered prospectively into the MS Clinics’ central database. Historical data are obtained at the first visit and included in the database; all subsequent visits are encoded.

An inherent difficulty in natural history studies is the absence of an unequivocal date to start the clock when measuring disease progression. The date of onset is traditionally used, generally defined as the appearance of the first symptoms, as recalled by the patient.² However, onset symptoms can be indistinct, occurring years before medical attention is sought, such that the date of onset, although useful, is dependent somewhat on a physicians’ history taking skills, and can be hampered by patient recall, cognitive impairment, and fatigue. The date of diagnosis provides an alternative, but is equally subject to variable influences such as new diagnostic imaging technologies, changing diagnostic criteria, patient motivation to seek medical attention, and the newly licensed immunomodulatory drugs potentially driving the desire for a prompt diagnosis. We proposed to assess the natural history of MS in British Columbia and possible predictors of progression using date of birth as well as the more traditional date of onset to start the progression clock.

Methods.

The study was a retrospective review of prospectively collected data. All patients registered with one of the four MS clinics in British Columbia were prospectively entered onto the clinics’ database. Inclusion criteria were laboratory-supported or clinically definite MS (Poser criteria³); first onset symptoms prior to July 1988 (to maximize the possibility of a substantial and meaningful follow-up time); at least one EDSS score; and registered with a British Columbian MS clinic before July 1998 (to enable establishment of the disease course). No minimum active follow-up time was required; therefore those who died or moved away could still be eligible. Data gathered until July 1, 2003, were included. Patients’ disease course was classified clinically into either a primary progressive or relapsing course from onset. The latter group included those who remained relapsing-remitting or who entered a secondary progressive phase. The main outcome measure was time to EDSS 6 (requires a cane), the secondary outcome being EDSS 8 (wheelchair bound). The date of disease onset and the date of birth were used to start the progression clock in two separate analysis. Progression had to be confirmed and sustained; every subsequent disability score had to be greater than or equal to the defined outcome (one of which had to be >150 days later). The majority (>95%) of disability scores were gathered prospectively, through a neurologic examination with the patient; a minority of patients (138/2,837, 4.9%) had one or more scores retrospectively assigned from clinic charts by an MS-specialist neurologist.

The influence of individual risk factors—sex, initial disease course (relapsing or primary progressive), age at onset, and onset symptoms (motor, sensory, optic neuropathy, and cerebellar/ataxia/brainstem)—on time to EDSS 6 were investigated as categorical factors using Kaplan-Meier curves and Cox proportional hazards model for survival analysis. The simultaneous effect of these risk factors was examined using a multivariate Cox model. Time from birth to onset was not used as a predictor variable for time from birth to EDSS 6 as the latter will always be greater than the former for every patient, making it an unreasonable predictor. Instead, the categorized age at onset was used as a controlling (strata) variable in the multivariate Cox model.

The effect of potential bias created by patients who could not be assigned a time to EDSS 6 because it had already been reached by the first clinic visit was explored through a best, worst, and middle case scenario Kaplan-Meier analysis. Missing times were imputed as follows: best case scenario assumed patients reached EDSS 6 on their first clinic assessment; worst case assumed patients did so at onset; middle case assumed the middle value from onset to first assessment. Immunomodulatory drugs (IMDs)—beta-interferon or glatiramer acetate—were used by a small number of patients, either through clinical trials or clinical practice; these were examined. A Kaplan-Meier and Cox-regression subgroup analyses assessed the effect of time to sustained moderate disability (EDSS 3) on time to EDSS 6 and on time from EDSS 3 to 6.

The Clinical Research Ethics board at the University of British Columbia approved the study.

Results.

On July 1, 2003, 2,837 patients fulfilled the study criteria (figure 1); demographics and clinical characteristics are presented in table 1. The study included 22,723 prospectively followed patient-years. Patients had a disability score measured on average every 1.1 year (SD 0.97). At the first disability assessment, 1,287 (45%) had already reached EDSS 3 (moderate disability), 518 (18%) EDSS 6 (required a cane), and 100 (3.5%) EDSS 8 (were wheelchair bound).

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Figure 1. Selection of patients from the British Columbian MS clinics’ database.

Patients took a median 27.9 years to reach sustained EDSS 6 from onset (95% CI: 26.5 to 29.3). At 15 years after onset 21% required a cane, increasing to 69% by 40 years after onset. One quarter of the population took 44.2 years (SE 2.67) to reach EDSS 8. At 30 years after onset, 14% reached EDSS 8 and 22% did so 40 years after onset. The median time to EDSS 8 could not be calculated because 50% of the population had not reached this defined outcome.

The analysis from birth showed that patients took a median 59 years to reach EDSS 6 (95% CI: 58.1 to 60.8). By 50 years of age, 28% required a cane, increasing to 52% by age 60. One quarter of the population took 44.2 years (SE 2.67) to reach sustained EDSS 8. By 50 years of age, 6% reached EDSS 8, which doubled to 12% by age 60.

Men progressed 38% more quickly (95% CI: 19% to 60%, p < 0.0005) than women from disease onset (table 2 and figure E-1 [available on the Neurology Web site at www.neurology.org); however, when controlling for other factors (onset symptoms, age at onset, and disease course), no sex differences were seen (table 3) and furthermore both sexes required a cane at a similar age, p = 0.082 (see table 2 and figure E-2).

Those younger at onset exhibited a slower progression from onset, yet they were still significantly younger when requiring a cane compared to their older (at onset) counterparts; there was little evidence of convergence between the age categories (table 2 and figure 2).

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Figure 2. Kaplan–Meier survival curve of time to use of a cane (sustained Expanded Disability Status Scale score 6) from birth by age at onset (n = 2,319)

Progression from onset was more rapid in those with a primary progressive course compared to a relapsing course (p < 0.0005) (see table 2 and figure E-3). The mean age at onset in the primary progressive population was 40.1 years (SD 11.5), older than the relapsing population’s 29.2 years (SD 9.0), p < 0.0005. Despite this older age at onset, the patients with primary progressive MS were actually younger when reaching EDSS 6 (p < 0.0005, see table 2 and figure E-4). Controlling for other factors did not change findings (see table 3).

Motor and cerebellar, ataxia or brainstem onset symptoms were associated with a more rapid progression from onset and conversely sensory symptoms and optic neuropathy a slower progression, compared to those without these onset symptoms (see table 2). However, when controlling for other factors, none of these onset symptoms was a significant risk factor (see table 3). Furthermore, the age at which patients required a cane was not affected by the presence or absence of any of the onset symptoms (see table 2).

A total of 439 (15.5%) patients with relapsing MS were prescribed an IMD. Assuming once prescribed an IMD, always prescribed an IMD thereafter, 7.5% of active follow-up (from first to last recorded EDSS) was during the use of an IMD. Those prescribed an IMD had a slightly more rapid progression from onset, with patients taking a median of 28.1 years (95% CI: 26.1 to 30.1) to reach EDSS 6 compared to 32.6 years (95% CI: 29.2 to 36.0) in those relapsing subjects not prescribed an IMD (p = 0.001) and patients were younger when they reached EDSS 6 (54.0 years [95% CI: 52.4 to 55.5] vs 63.8 years [95% CI: 61.8 to 65.8], p < 0.0005).

Those patients who had already reached sustained EDSS 6 at first assessment (n = 518/2,837, 18%) were older with longer disease duration than those who had not (p < 0.05, data not shown), but there were no differences in sex, disease course (primary progressive vs relapsing), or age at onset (p > 0.05, data not shown). The median times to EDSS 6 for the best, worst, and middle case scenarios were similar to the actual analysis and can be viewed online (table E-1).

In the subgroup of patients who reached sustained moderate disability (EDSS 3) during active follow-up (n = 684), those who rapidly reached this milestone also required a cane (EDSS 6) more rapidly and at a younger age (table E-2). Those who reached moderate disability at an older age were not only older when they required a cane, but also took longer to require a cane than those patients younger at moderate disability (see table E-2). Only very rapid progression to sustained EDSS 3 (<5 years) had a significant effect on the subsequent time from EDSS 3 to 6 (see table E-3). Time from EDSS 3 to 6 was remarkably similar for those who took 5 to <10 or 10 to <15 or 15+ years to reach EDSS 3 (see table E-3). The age at which sustained EDSS 3 was reached had no significant influence on the subsequent time from EDSS 3 to 6.

Discussion.

Our geographically based natural history study shows MS to be a slowly progressing disease. Our British Columbian (BC) MS population took a median 27.9 years to reach EDSS 6 (n = 2,319), which was substantially longer than the 15.0 years found in London, Ontario (n = 1,099).⁴ Demographics differed—our BC MS population was comprised of 70% women compared to 66% in London, Ontario, and 12% of our BC patients exhibited a primary progressive course compared to 20% in London, Ontario. This would predispose the London, Ontario, population to be more rapidly progressing (from onset). The mean disease duration at final assessment was also longer in our study, at 20.1 years, compared to 11.9 years in London, Ontario,⁴ allowing those patients with a more slowly progressive disease to reach the selected outcomes. We also purposely chose a conservative, but in our view, appropriate definition of sustained progression; fluctuations in disability and remissions after apparent confirmed progression at 6 months are not uncommon.⁵ Smaller contemporary studies report rates of progression closer to ours, with a median time to requiring a cane being 28.6 years in Olmsted County, MN (n = 166, disease duration = 19.3),⁶ and 20.1 years in Lyon, France (n = 1,844, disease duration = 11.0).⁷

This slow insidious progression will not only impact on the prognosis given to patients, but creates a major challenge when considering initiating (or continuing) an immunomodulatory drug. Patients can fare relatively well without these treatments and available medications have, at best, moderate short-term efficacy,^8,9 with a side effect profile necessitating regular monitoring. Interpretation of long-term post-marketing effectiveness studies must take into account the slow disease progression shown in this and contemporary studies. Equally, those designing clinical trials must be cognizant of these findings and endeavor to prevent a reoccurrence of the large, costly multicentered primary progressive MS trial being terminated early, the blame being partly attributed to the unexpectedly slow progression rates of the placebo group.¹⁰

By using date of birth as an inception point we were able to challenge two fundamental concepts in MS, demonstrating that male sex and older age at onset are not synonymous with a worse disease outcome. Male sex has been frequently associated with a more rapid progression.^7,11–14 While we confirm that men progressed more rapidly from onset than women, we also show that both men and women required a cane at around the same age. Thus female sex conveys little benefit; rather women are more likely to develop MS and present clinically at an earlier age, starting with a predominantly relapsing course synonymous with inflammation but developing irreversible disability associated with axonal damage at a similar age to men.

A younger age at onset is often reported as indicative of a better prognosis in MS^{11–13,15–19} and an older age at onset has been referred to as “gloomy.”²⁰ Our data support this concept when observing disease progression from onset, but not from birth. Not only did those older at onset have a longer disease free period,²⁰ we show that they required a cane at an older age than their younger (at onset) counterparts.

The true onset of MS is unknown; evidence suggests that MS is present subclinically long before the manifestation of clinical symptoms,² perhaps being triggered during gestation or soon after birth.²¹ Subsequent exposure to various environmental factors perhaps coupled with genetic factors may then dictate when and how the disease presents clinically. Therefore both birth and onset dates are useful starting points in the natural history of MS given current knowledge. The date of birth creates a unique perspective, first by reducing reliance on the imprecise dates of onset/diagnosis and secondly by allowing the age at which patients attain disability milestones to be expressed.

We also looked at other prognostic factors—disease course and onset symptoms. The primary progressive course was clearly associated with a more rapid progression from onset compared to the relapsing course, as found by others.²⁰ Unlike the other risk factors investigated, disease course also exhibited a similar effect on disease progression from birth; those with a primary progressive course were younger when requiring a cane, despite their older age at onset.

No onset symptom independently predicted a worse or better outcome. While motor and cerebellar, ataxia and brainstem symptoms predicted a more rapid progression from onset, as found by others,^{11,14,16,18,20,22} and sensory and optic neuropathy at onset a more favorable outcome, as previously observed,^17,20,22 controlling for other factors negated any effect and patients were of similar age when requiring a cane regardless of onset symptoms. Onset symptoms are likely a function of age at onset, disease course, and sex rather than being independent risk factors.

IMDs are prescribed to specific and select populations, specifically those with a more aggressive disease course. This probably explains the observation that those on IMDs faired worse than those not on drug. We believe a clinical impact unlikely as the time spent on drug was small in comparison with the total time followed and currently no IMD has convincingly been shown to alter (for better or worse) long-term disability.

Patients who already required a cane by the first assessment were unlikely to bias the main analysis as their fundamental demographics (sex, disease course, onset age) were similar to those who did not require a cane at first assessment and the sensitivity analysis showed little variation; our actual results were closest to the middle and worst scenarios, indicating a conservative estimate of the time to requiring a cane. A high proportion of our population, however, had already reached moderate disability (EDSS 3), which coupled with unreliability in the scoring of EDSS 3²³ made it a less robust milestone. Nonetheless, our subgroup analysis was consistent with others: those progressing more rapidly to moderate disability also required the use of a cane sooner.²² We also found that an older age rather than a younger age at moderate disability was predictive of a better outcome (time to EDSS 6); all these factors indicate that the progression rate is set relatively early on in the disease course. Time to moderate disability (either from birth or onset) had minimal impact on the subsequent time from EDSS 3 to 6, as others have shown (from onset),^22,24 with the exception that those progressing very rapidly (from onset) also progressed more rapidly from EDSS 3 to 6.

Our longitudinal study has several strengths, including a geographic and population-based study, incorporating over 80% of the MS population in BC^1,25; a substantial follow-up time and population size; prospective assignment of all disability scores by a face-to-face consultation with the neurologist for >95% of patients; and consistent care with the same four core neurologists treating over 85% of patients for the study duration, which should minimize inter-rater variability, a recognized problem with the EDSS.²³ Relapses were not included in the analysis because they were invariably recorded historically (at the initial visit or at yearly follow-up), which has been shown to be unreliable.²⁶ Furthermore, although relapses can be traumatic and undesirable in the short term, they do not appear related to long-term disability once moderate disability has been reached.^7,22

Acknowledgment

This article is dedicated to the memory of Dr. Don Paty, who had the foresight to create the London, Ontario, and University of British Columbia MS Clinics and databases; he died on December 8, 2004. This article would not have been possible without the neurologists in British Columbia (*reviewed the manuscript): S. Hashimoto,* D. Paty, J. Oger,* J. Hooge, L. Katrukoff, T. Traboulsee, P. Smyth, D. Parton, W. Shtybel, O. Hiebiceck, L. Daly, B. Jones, S. Meckling, D. Adams, D. Craig; the MS Clinic nurses: R. Grigg, A. Springer, A. Moore, L. Plashe; K. Ho (data programmer); and staff. Thanks also to the University of British Columbia’s Clinical Trials Group for providing IMD information and Y. Zhao* and J. Petkau* for statistical advice.