#ECTRIMS2019 – Longer DMT Use and Female Sex Seen to Protect Against SPMS Conversion

Women with multiple sclerosis (MS), and people who stay in a relapsing stage or use disease-modifying therapies (DMTs) for longer periods are less likely to transition to secondary progressive multiple sclerosis (SPMS) than others, according to a study based on the Italian MS registry.

But patients whose disease starts after age 40, have a multifocal onset (multiple lesions and symptoms), greater disability at MS onset, and repeat relapses are more likely to progress to SPMS.

DMT exposure was the only significant “protective factor” in this transition found in two models of SPMS conversion used in this study.

These findings were detailed by Pietro Iaffaldano, a neurologist and researcher at the University of Bari Aldo Moro, in Italy, at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) running through Friday in Stockholm.

His presentation was titled “Defining the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register.”

SPMS is a second MS stage, one that follows relapsing-remitting MS (RRMS). In people transitioning to SPMS, the disease gradually changes from the inflammatory process seen in RRMS to a more steadily worsening phase characterized by nerve damage or loss, and the accumulation of disability over time.

Before DMTs became available, studies indicated that nearly all (about 90%) of those with RRMS would transition to SPMS within 25 years.

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According to Iaffaldano, however, while these medicines have brought unprecedented benefits, it is too early to say how much they have altered or delayed disease course.

Establishing a SPMS diagnosis is also challenging. Clinicians need to determine if symptom worsening is due to leftover damage owing to a relapse — in this case, the patient remains in an RRMS stage — or if the worsening continues without any inflammatory relapses, in which case the person has progressed to SPMS.

Repeat brain MRI scans and neurologic examinations can help in determining disease progression, but to date “no clear metrics for sensitive and reliable identification of the transition from RRMS to SPMS are available to assist the neurologists in daily clinical practice,” Iaffaldano said.

To better understand the prevalence of, and risk factors for, conversion to SPMS, researchers retrospectively reviewed the medical records of a large group of RRMS patients (19,318 people) enrolled in the Italian MS Registry. All had at least five years of follow-up data.

They assessed the time to transition to SPMS, and the time to reach an irreversible EDSS score of 6 after SPMS onset. (EDSS measures disability on a scale of 0 to 10; a score of 6 refers to an inability to walk 100 meters without an aid, like a cane.)

Researchers used two different definitions of SPMS: the date of conversion based on the subjective judgment of the neurologist; and a data-driven algorithm based on increases in disability in the absence of relapses, quantified by EDSS, and whose results are confirmed at least three months later. (This algorithm and the approach it uses is described in a research article published in 2016.)

For the algorithm, a significant increment in disability is defined as a minimum EDSS score of 4 and a pyramidal score of 2 (related to muscle weakness, or difficulty moving the limbs).

Of the 19,318 patients in the registry, 3,868 (20.0%) were classified as having SPMS by their neurologists. Under the algorithm, fewer of these patients were considered as having transitioned to SPMS: 2,343 (12.1%).

Based on the neurologists’ definition, the median time to conversion was 11.96 years, patients’ age at the time of transition was a median of 44.0 years, and they had a median EDSS score of 4.5 (range, 3.5 to 6). The median time to reach EDSS 6 after SPMS onset was 4.08 years.

Based on the algorithm, these values changed. Under its definition of transition to SPMS, two key values lengthened: the median time to conversion (15.28 years), and the median age at conversion (46.7 years).  Two others shortened: the median EDSS score at the time of conversion was again 4.5, but the range was 4 to 5. And the time to reach EDSS 6 after SPMS onset was a median of 2.37 years — a point stressed by the researcher.

Analysis of potential risk factors found — in both models — that older patients (40 or older at disease onset), people with multiple symptoms or lesions at onset (multifocal disease), a higher initial EDSS score, or greater number of relapses during the RRMS phase were more likely to progress to SPMS.

Women, those living with relapsing disease for a lengthier time, and those on longer use of DMTs were at a lower risk of transition.

Again, these results were seen in both models — the neurologist SPMS definition, and the algorithm-based definition.

The “only significant protective factor [against SMPS transition] in both models was DMT exposure,” Iaffaldano said.

“The highest it was the DMT exposure during the RRMS phase of the disease, the lowest was the risk of conversion to SPMS,” he added.

Lesser time before the start of DMT use was also associated with a reduced risk of SPMS conversion, but only if the neurologist definition was used.

Throughout SPMS, Iaffaldano noted that “the major driver of disability accumulation during … [this disease phase] were relapses,” and DMT exposure during this phase “doesn’t have an impact on the risk of disability accrual.”

“Real-world data from the Italian MS Registry,” the researcher concluded, “suggests that a timely and continuous DMT exposure reduces the risk of conversion from RRMS to SPMS.”

And, he added, “an accurate and less ambiguous SPMS definition is warranted to assist neurologists and the scientific community in the efforts to find newer treatment strategies against progressive MS.”