Susan Jeffrey

October 03, 2013

COPENHAGEN, Denmark — "Early and persistent" use of disease-modifying therapies (DMTs) in patients with clinically isolated syndrome (CIS), a first episode suggestive of multiple sclerosis (MS), can delay progression of disability, a new study suggests.

Researchers found that patients with CIS exposed to DMT for 50% to 80% of the observation period had a 45% reduction in disability progression, and those treated more than 80% of the time had a 68% reduction in disability relative to those receiving treatment less than 50% of the time.

"The most important finding in our study was that exposure to disease-modifying drug significantly delays the accumulation of disability," said lead author Vilija G. Jokubaitis, PhD, from the University of Melbourne, Australia. "Having said that, though, this was based on a stepwise decrease in the hazard of progression based on increasing treatment exposure, and patients who were exposed for less than 50% of the period did not derive significant benefit."

In the study, patients started treatment within an average of 8 months of CIS onset, and 81% had a diagnosis of relapsing-remitting MS.

"So together, our data suggests that it's both the early and persistent use of DMT treatments that's key in delaying the accumulation of MS-related disability," Dr. Jokubaitis concluded.

The findings were presented here at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Factors That Predict Progression

The first 12-month confirmed disability progression event after CIS onset "likely reflects persistent MS-related disability," the authors write. Several studies have tried to determine factors that predict conversion to clinically definite MS from CIS onset or, conversely, to identify indicators of poor prognosis from relapsing-remitting onset onwards, Dr. Jokubaitis explained.

"However, the patient characteristics that are associated with accumulation of disability at or near the onset of CIS are poorly characterized," she said.

In this analysis, the researchers assessed the relationship between demographic, clinical, and MRI predictors of time to first confirmed disability progression event. "At the same time, we're also interested in determining the effect of treatment exposure within our real-world cohort," she said.

They used data from the MSBase Incident Study (MSBasis), on ongoing observational prospective cohort study of patients with CIS begun in 2004 that collects data from 59 centers in 17 countries worldwide using standardized methods.

Patients diagnosed with CIS within 12 months of onset and seen by an MSBasis-participating neurologist were enrolled into the study. At baseline, demographic information, Expanded Disability Status Scale (EDSS) scores, Kurtzke functional system (KFS) scores, and cerebral MRI data were collected. The investigators had MRI images for 89% of patients, and the median time from onset to imaging was 30 days.

At follow-up, they collected EDSS and KFS scores and information on any treatment starts, stops, or changes. Most patients were seen more often than the minimum annual follow-up, Dr. Jokubaitis.

The primary outcome of interest for these patients was a disability progression event, defined as a minimum 1-point EDSS score step increase above a minimum baseline EDSS score of 1, which was maintained at 3 or 12 months. The researchers then used a Weibull hazards regression approach to assess time to first disability progression event.

Of more than 3600 patients with CIS enrolled, 1989 had at least 3 EDSS scores recorded, spanning a minimum 9 months, with complete baseline KFS scores. Of these, 391 patients had a 3-month confirmed disability progression event and 307 maintained the progression at 12 months. The analysis focused on this latter group, Dr. Jokubaitis said.

Patients with CIS were typical, she noted; 71% were female, the average age at onset was 33 years, the median EDSS score at baseline was 1.5, and fewer than 9% had fewer than 3 T2 lesions on cerebral MRI.

Among the 1989 patients, more than 6700 patient-years of follow-up data were available, with a median of 3 years per patient. About two thirds of the patients (67%) were treated before the onset of disability, for about 3200 patient-years of follow-up. Of those receiving DMT, the average time to initiation of treatment was 8 months from CIS onset, and at that point, 81% had a diagnosis of clinically definite MS.

Factors found to be predictive on univariate analysis were entered in a multivariate model and adjusted for other factors, including sex and country.

The researchers found that age at onset was a poor prognostic indicator, with every 10 years of advancing age associated with a 1.17 increase in the hazard of progression. Moreover, the strongest independent predictor of disability progression was dysfunction in the pyramidal system, with a KFS score of 2 or greater being associated with a 1.5-fold increase in the risk for disability progression relative to a KFS score of 0 or 1.

Confounded by Treatment

The researchers hoped to look at whether T2 lesion load was associated with disability progression, Dr. Jokubaitis said. "However, what we found was that this was confounded by the effect of treatment, where patients who had a higher T2 lesion load were now actually treated earlier and longer than we would have otherwise thought in natural history studies," she noted.

To assess the effect of treatment in the cohort, investigators used 2 different approaches, she said. They compared the 67% of patients treated before the accumulation of disability to the 33% of patients who weren't, although she noted that patients with a stable course tend to remain untreated. So to control for the effect of treatment within individuals, they looked at the cumulative time that patients received treatment over the observation period.

Patients receiving DMT for less than 50%, 50% to 80%, and more than 80% of the observation period were compared with those receiving no treatment. "What we were able to show was there was an innate, stepwise decrease in the hazard of disability progression with increasing patient exposure," Dr. Jokubaitis said.

Patients treated for 50% to 80% of the time had a 45% decrease in the rate of disability progression relative to those treated for 50% of the time or less. Those treated more than 80% of the time had a 68% decrease in disability progression, again relative to those treated for 50% of the time or less.

"But I think the really interesting thing here is that patients who were treated for up to 50% of the observation period did not derive any significant benefit of treatment relative to those patients who remained untreated," she noted.

The researchers found that all first-line injectable drugs had equivalent efficacy in delaying disability progression events, with an approximately 50% decrease in the hazard of progression.

"Just for a bit of fun, we decided to do a post hoc analysis to see if there were any subtle differences between the first-line injectable drugs," Dr. Jokubaitis added, comparing results against intramuscular interferon β-1a.

"What we found is although there were no statistical differences between the different drugs, we found that glatiramer acetate (Copaxone) trended to being the more effective drug," she said. "This is a bit of a controversial statement," she added. "This study was post hoc and wasn't actually designed to tease out these subtle differences so these results should be treated with caution."

Table. Post Hoc Comparison of DMTs

Treatment Adjusted Hazard Ratio (95% Confidence Interval) P Value
No DMT 1.83 (1.32 - 2.52) .000
Interferon β-1a intramuscular injection 1.00 (Reference)  
Interferon β-1b 0.84 (0.54 - 1.31) .440
Interferon β-1a subcutaneous injection 0.77 (0.53 - 1.12) .167
Glatiramer acetate 0.60 (0.36 - 1.00) .052

 

However, that finding is supported by a paper being presented here on Friday from Dr. Jokubaitis' colleague at the University of Melbourne, Tomas Kalincik, MUDr, PhD. This quasi-randomized propensity-matched analysis provided a head-to-head comparison of the drugs.

In that analysis, which also used MSBase data, glatiramer acetate and subcutaneous interferon β-1a showed better efficacy in decreasing relapse activity and preventing accumulation of disability than intramuscular interferon β-1a or interferon β-1b.

"The observed effects are of a small size," Dr. Kalincik and colleagues conclude. "The analyses should be interpreted with caution, as quasi-randomized, propensity-matched analysis is vulnerable to unknown confounders."

"This study adds some important contribution to the debate whether immunomodulatory treatments do slow down the accumulation of disability or not," one attendee told Dr. Jokubaitis during the discussion period after her presentation. "I think your study, in a large cohort of patients, shows clearly that when you start early, it does affect disease disability."

The study was supported by the Australian National Health and Medical Research Council, Merck Serono, Biogen Idec, Novartis, Genzyme, and CSL Biotherapies. The MSBasis Study Group is supported by Merck Serono. Dr. Jokubaitis has received conference travel support from Novartis. Disclosures for coauthors are available in the abstract.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstract #59, Poster #1202. Presented October 2 and 3, 2013.

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