Twenty-five year data show a positive shift towards earlier diagnosis and treatment of multiple sclerosis (MS) as well as improved prognosis over time.
Results of a retrospective study show that, since 1994, the time to MS diagnosis has decreased and treatment initiation increased in patients with clinically isolated syndrome (CIS).
In addition, those who received a diagnosis in more recent periods, when newer diagnostic criteria were used, were less likely to reach disability milestones than patients diagnosed earlier.
For example, results showed patients who received an MS diagnosis between 2017 and March 2020 had a 93% lower risk for reaching an Expanded Disability Status Scale (EDSS) score of 3.0 or greater, compared with those who received a diagnosis between 1994 and 2000.
“We are now able to shorten by almost 70% the time from the first attack to the diagnosis,” study investigator Mar Tintoré, MD, PhD, senior consultant at the MS Center of Catalonia in Barcelona, Spain, told Medscape Medical News. “There is an 85% reduction in the median time from CIS to treatment onset.”
The findings were published online September 14 in Neurology.
Five Diagnostic Periods
Recent studies suggest the course of MS has become less severe over time. The regular introduction of revised diagnostic criteria for MS has enabled earlier diagnosis and treatment.
Investigators wanted to determine whether revisions of MS diagnostic criteria and changes in treatment initiation were associated with reduced disability in patients with CIS.
They retrospectively analyzed data for patients with CIS who presented to the MS Center of Catalonia between January 1994 and March 2020. Eligible patients were younger than age 50.
The investigators collected demographic information and clinical data and analyzed patients’ CSF for oligoclonal bands. Patients were evaluated every 3, 6, or 12 months for relapses and changes in disability.
The investigators also recorded the date of initiation as well as type of disease-modifying therapy (DMT). Patients who initiated treatment before the second demyelinating episode were considered to have early treatment. Others were considered to have late treatment.
Patients underwent MRI within 5 months of CIS diagnosis. Repeat MRI was performed at 12 months and every 5 years thereafter. The number of T2, contrast-enhancing, and active lesions were recorded.
Investigators defined five time periods corresponding to the diagnostic criteria that were in effect at the time. The Poser period lasted from 1994 to 2000 and was followed by the McDonald 2001 period (2001-2004). Next were the McDonald 2005 (2005-2009), McDonald 2010 (2010-2016), and McDonald 2017 (2017 to March 2020) periods.
The analysis included 1174 patients who were a median age of 31.6 years, and 68% were female. Median follow-up was 9.1 years, and the population’s mean EDSS score was 1.05.
Approximately 63% of patients received a diagnosis of MS. The proportion of patients who received the diagnosis increased steadily from 25.2% during the Poser period to 55.1% during the McDonald 2017 period.
The median time to MS diagnosis was 11.1 months. This time decreased across the five periods. From the Poser to the McDonald 2017 periods, the median time from CIS to MS diagnosis decreased by 77%. In a sensitivity analysis that accounted for the shorter follow-up times in the more recent periods, the reduction in time to diagnosis was 62.6%.
Approximately 53% of patients did not receive treatment, 22.5% received early treatment, and 24.9% received late treatment. In the early treatment group, the median time from CIS diagnosis to treatment initiation was 5.9 months. The median time was 23.8 months in the late-treatment group.
In addition, the median time from CIS to treatment initiation decreased by 82% from the first to the last diagnostic period. The median times were 35.8 months in the Poser period, 18.2 months in the McDonald 2001 period, 7.1 months in the McDonald 2005 period, 7.6 months in the McDonald 2010 period, and 6.6 months in the McDonald 2017 period.
The population’s median age at MS diagnosis was 32.9 years. However, age at diagnosis increased across diagnostic periods, and was 29.3 years in the Poser period and 36.4 years in the McDonald 2017 period.
In addition, the age at which patients achieved an EDSS score of 3.0 or greater increased over time. Multivariate analysis showed that patients diagnosed in more recent periods were at lower risk for reaching an EDSS score of 3.0 or greater at different ages.
The adjusted hazard ratio (aHR) of EDSS score of 3.0 or greater was 0.47 for the McDonald 2001 period (P = .023), 0.25 for the McDonald 2005 period (P < .001), 0.30 for the McDonald 2010 period (P = .010), and 0.07 for the McDonald 2017 period (P = .005) compared with the Poser period.
Early treatment was associated with a lower risk of reaching an EDSS score of 3.0 or greater compared with late treatment (HR, 0.53; P = .008). To adjust for the possibility that the revision of diagnostic criteria over time might change MS prognosis, the investigators analyzed the data using only the McDonald 2017 criteria. This analysis confirmed that the risk for reaching an EDSS score of 3.0 or greater was lower among early treated patients than among late-treated patients.
“Part of this change in prognosis can be due to other hidden factors, but early diagnosis and early treatment can probably be two of the main factors that have contributed to this change in prognosis,” said Tintoré.
The investigators plan to examine whether early high-efficacy treatment is better than the traditional escalation strategy. For many patients, the latter approach “means that you are going to lose a lot of your brain and spinal cord until you are put on a high-efficacy treatment,” said Tintoré.
In an accompanying editorial, Oliver Tobin, MBBCh, PhD, a neurologist at the Mayo Clinic in Rochester, Minnesota, noted that it is difficult to determine the effect of highly effective DMTs on the outcome of this study. However, he noted, “the analyses all point in the same direction — early diagnosis and treatment of MS results in lower MS-associated disability.”
One limitation of the study is that more than half of the population did not receive any treatment, Tobin noted. Furthermore, patients who received treatment tended to have markers of more aggressive disease.
“Therefore, although we can conclude that, as a group, patients with relapsing-onset MS are likely best served by early treatment, this does not discount the existence of patients for whom DMTs may confer no benefit or possibly even pose harm (so-called benign MS),” Tobin writes.
Commenting on the findings for Medscape Medical News, Jeffrey Cohen, MD, director of experimental therapeutics at the Cleveland Clinic Mellen Center in Ohio, noted the finding that time to MS diagnosis has become shorter is not surprising.
“In part, that was the purpose of the diagnostic criteria and the revisions that were made over time,” he said.
The more difficult finding to interpret is that the time to achieve an EDSS score of 3 or greater has become longer, Cohen added. One possible explanation is that, as the diagnostic criteria have become more sensitive and enabled earlier diagnosis, patients with milder disease may receive the diagnosis, and they would have a better prognosis. “In fact,” he said, “their data suggest that that’s not the full explanation for things.”
Although the article emphasizes the changes in diagnostic criteria over time, the data make a stronger case that the real improvements have been the earlier use of DMTs, the availability of better DMTs, and factors such as increased emphasis on improving general health, said Cohen.
These factors “may be equally or more important in the seemingly improved prognosis,” he added. “They emphasized the criteria, but in fact, probably the criteria were not the main reason for better outcomes.”
The study’s explicit and prospective design is an advantage, said Cohen. “This was a cohort that’s been prospectively followed at a center where they utilized the criteria consistently across the various practitioners there.”
Outcome data were collected systematically over time. “Those things have a lot of advantages over other similar studies, many of which were retrospective,” said Cohen.
However, the study did not evaluate how important other factors are, such as addressing health behaviors and comorbidities, for the prognosis of people in the early stages of MS. Another open question is the importance of the choice of initial DMT. “These investigators could go back and look at those data in this cohort,” said Cohen.
In addition, the study did not address the issue of misdiagnosis. “These patients almost certainly had MS, but one of the issues with the diagnostic criteria is how well they protect us against misdiagnosis,” said Cohen.
The study was funded by the European Regional Development Fund and Instituto Carlos III. Tintoré has received compensation for consulting services and speaking honoraria from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela-Bio, and Teva Pharmaceuticals. Cohen has reported no relevant financial relationships.
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