Caroline Helwick

February 19, 2016

NEW ORLEANS — Disability accumulation for patients with moderately advanced multiple sclerosis (MS) appears to be independent of prior disease progression, but the disease trajectory is still highly variable, an analysis of the international database MSBase has shown.

Australian investigators determined that greater relapse rates during the course of moderately advanced MS increased the probability of progression, but stronger immunomodulatory therapies appeared to mitigate the accrual of disability, said Nathaniel Lizak, a fourth-year medical student at Monash University in Clayton, Australia.

"We dispute the practice of treatment cessation on the basis of disability milestone attainment," Lizak said. "Patients should continue being treated at greater EDSS [Expanded Disability Status Scale] scores."

The investigators presented their findings at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016, the first meeting by ACTRIMS focused on progressive forms of MS. The study's senior investigator was Tomas Kalincik, MD, from the University of Melbourne in Australia.

Disease Trajectory After EDSS 3 Not Clear

Three large cohort studies have previously examined factors influencing disability accumulation in moderately advanced MS but reached contradictory conclusions. Their general implication has been that disease trajectories after the attainment of EDSS 3 are not modifiable, he said.

Moderately advanced MS was defined as the period between EDSS 3 and EDSS 6.5.

Few factors have been found to affect reaching EDSS 6. Studies have concluded, therefore, that moderately advanced MS must be "amnesic" to prior disease progression and that the new phase is primarily driven by neurodegeneration, he said.

However, prior studies have not accounted for the variability observed after EDSS 3 is attained, and most were conducted before the emergence of stronger immunomodulatory treatments, he noted.

The current study aimed to determine whether the disability accrual in moderately advanced MS is modifiable with immunomodulatory therapy.

"We hypothesized that individual disability trajectories are not homogenous and can be predicted based on demographic and clinical characteristics," Lizak said.

Three "epochs" were analyzed: the periods between EDSS 3/3.5 and EDSS 6 (EDSS 3-6), between EDSS 4 and 6 (EDSS 4-6), and between EDSS 6 and 6.5 (EDSS 6-6.5). Patients were required to have relapse-onset MS and progression confirmed for at least 6 months (without intermediate regression) to the initial EDSS step (ie, baseline). The outcome was attainment of the higher EDSS step from the lower step for each of the three epochs.

Records were obtained from the MSBase, a large international observational MS cohort study. Multivariable survival models examined the effect of relapse rate and proportion of time treated (before and during each epoch), age and disease duration at baseline on progression to the outcome, which was EDSS 6/6.5.

Disease Trajectories Heterogeneous

The analysis included 3415 patients, almost evenly divided among the three epochs.

Median disability-free survival for each epoch and the proportion of patients reaching the outcome of EDSS 6/6.5 were as follows:

  • EDSS 3-6: 17.3 years; 17% reached outcome EDSS

  • EDSS 4-6: 11.4 years; 27% reached outcome EDSS

  • EDSS 6-6.5: 3.7 years; 55% reached outcome EDSS

"We found what other studies have found, that disease progression during moderately advanced MS is amnesic to prior disease activity," Lizak reported. "But we found that this occurs repeatedly in MS, after EDSS 3, 3.5, 4, and 6. It is a general phenomenon occurring in MS that disease is continuously amnesic to prior progression."

"We also confirmed that while the disease trajectories during moderately advanced MS are independent of previous trajectories, they are still highly variable," he said.

Analysis of the disease trajectory showed substantial variability before the baseline EDSS, but heterogeneity was also observed after patients reached the landmarks of EDSS 3, 4, and 6, he reported.

To quantify this variability, the investigators determined coefficients of variance for the progression slopes. Pre- and postbaseline disability trajectories showed large coefficients of variance (0.85 - 0.92 and 1.95 - 2.26, respectively) and did not correlate with each other.

"Prebaseline, we have coefficients of variance around 1, showing substantial variability," he said. "More impressively, postbaseline, we have coefficients of variance of 2 to 2.5, which means the standard deviation is 2 to 2.5 times as large as the means themselves. This is an astounding amount of variability. It seems that one trajectory does not fit all."

The probability of reaching EDSS 6/6.5 was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch, with hazard ratios of 3.07 for EDSS 3-6. 2.41 for EDSS 4-6, and 1.58 for EDSS 6-6.5 (all P .001).

"We have definitely found that more relapses repeatedly increase the likelihood of reaching EDSS 6 or 6.5," he said. "This seems obvious — more relapses increase progression — but it's not been found in previous studies…This suggests that inflammation remains a key driver of disability in this stage, which is consistent with pathological studies."

Higher-Efficacy Treatments

The proportion of time on higher-efficacy therapies also was significantly associated with outcomes, with more time on these treatments during the epoch correlating with lower risk for the outcome EDSS. Hazard ratios were 0.27 (P =.002), 0.39 (P < .001), and 0.68 (P = .02), respectively, for the three groups.

"This is our most important conclusion: that stronger immunomodulatory therapies mitigate disability accrual in moderately advanced MS," he commented.

The researchers classified higher-efficacy therapies as natalizumab, fingolimod, alemtuzumab, dimethyl fumarate, cladribine, rituximab, and mitoxantrone and lower-efficacy therapies as interferon β-1a and β-1b, glatiramer acetate, and teriflunomide.

For example, almost 40% of patients with EDSS 6 at baseline had not progressed to EDSS 6.5 by 8 years, compared with about 20% receiving low-efficacy therapy or no treatment, according to a graph he showed.

"Patients on high-efficacy treatment had much better-looking disability-free survival curves," he observed. "These observations justify treatment even after moderately advanced disability has been attained.… We should continue treating patients at greater EDSS scores because we can prevent further disability from accumulating."

Treatment Decisions: Consider Risks as Well

Bibiana Bielekova, MD, from the National Institutes of Health, Bethesda, Maryland, commented that the study is "very important," but noted that she found the efficacy of the treatment to be "stunningly low."

"I agree that high-efficacy therapies do affect disability, based on the data, but I think the level of efficacy is quite small, especially in more advanced patients," she commented. "The confidence intervals were very close to 1. The curves showed the benefit with even the greatest treatment was rather marginal. It seemed that maybe 10% of patients were benefiting. The study didn't quantify this benefit, but it should have."

In an interview with Medscape Medical News, Dr Bielekova emphasized the need to weigh the risks vs the small potential benefit, especially in patients with high disability, who already are physically compromised.

"His conclusion was that we should be giving these drugs to patients, but if I have a patient, and I think the benefit can be less than 10% and the risks substantial, am I doing something good for the patient?" she commented.

Jack P. Antel, MD, from the Montreal Neurological Institute and McGill University, Quebec, agreed. "I would continue to treat these [moderately advanced] patients if I thought they still had a risk of relapses. But is treatment making a patient weaker, from its side effect profile? If so, they are not gaining in terms of quality of life.

"We must take into account the safety issues, and we don't really understand the safety profile of the new agents in patients who are significantly disabled," he added.

Dr Antel said future research should attempt to identify the subgroups of patients who accumulate more, vs less, disability over time. "The study showed there is heterogeneity," he noted. "Researchers examining these large databases are going to have to start dissecting these patient groups. There are probably some who benefit from treatment and some who do not."

Fiona Costello, MD, associate professor of neurology at the University of Calgary, Alberta, Canada, commented that these findings confirming the benefit of therapy in advanced disease are very important. Some countries actually dictate that treatment stop at some point in the disease process, she noted. "You may be short-changing the very patients you can help most," she told Medscape Medical News.

Mr Lizak, Dr Bielekova, and Dr Antel have disclosed no relevant financial relationships.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016. Abstract S1.1, P022. Presented February 18, 2016.


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