Algorithm May Help Define SPMS; ‘Gold Standard’ Still Neurologist
While EDSS score increase shows worsening, no established criteria exist to determine change to SPMS.
A data-driven algorithm may be useful for defining the sometimes unclear transition from relapsing-remitting (RRMS) to secondary progressive (SPMS) forms of multiple sclerosis, a study found.
The study, “Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register,” was published in the Multiple Sclerosis Journal.
RRMS is marked by periods of disease exacerbations with active symptoms (relapses) that disappear during phases of remission, with no apparent disease progression. SPMS is a disease stage that follows RRMS for some patients. As RRMS progresses into SPMS, symptoms steadily worsen even in the absence of relapses and disability accumulates.
No single test is used to diagnose SPMS. Instead, neurologists will usually diagnose it by reviewing disease progression over time.
The expanded disability status scale (EDSS) is a clinical tool often used to track disability progression. The scale ranges from 0–10, with higher scores reflecting a greater degree of disability. The EDSS also encompasses subscores, from 0–6, for eight different functional systems, or groups of nerves, involved in specific tasks.
While generally an increase in EDSS scores over time indicates disability worsening, there are no established criteria for determining at what point a patient has officially “converted” to SPMS.
“The lack of a single universally accepted definition and the difficulty in distinguishing RRMS and SPMS as a separate entity complicate the management of an already complex pathology [disease],” the researchers wrote.
The ‘gold standard’ definition
Researchers in Italy compared two different algorithms developed to identify the RRMS-to-SPMS transition against the “gold standard” neurologist’s definition — the date at which a neurologist records an SPMS conversion in a patient’s medical records.
The first method was dubbed the “data driven algorithm,” or DDA. The second was developed from the diagnostic criteria applied in a previous clinical trial called EXPAND (NCT01665144), which enrolled SPMS patients.
The DDA stipulated that a patient must have had an increasing EDSS score over three months (and confirmed at follow-up) to be diagnosed with SPMS. How much disability needed to be accumulated depended on a person’s initial EDSS score; those with lower disability levels needed to show a larger increase in their EDSS score to meet the criteria.
At the time of conversion, a minimum EDSS score should be at least 4, indicating significant disability, and a score of at least 2 in the pyramidal functional domain, which assesses muscle weakness and difficulty moving limbs. EDSS measurements taken within 30 days of a relapse are excluded to avoid the impact of acute relapses on disability measures.
EXPAND criteria required EDSS worsening to occur over at least six months, with an EDSS score from 3–6.5 at the time of conversion. Patients must not have had a recorded relapse in the three months before or six months after SPMS conversion.
To compare the methods, the team extracted from the Italian MS Register clinical information of 10,240 RRMS patients with at least five years of follow-up data. These patients, 67.6% of whom were female, had a median age at disease onset of 30.
Overall, 880 patients had been diagnosed with SPMS by their neurologist. If the DDA algorithm were applied instead, 1,806 would reach the diagnosis, compared with 1,134 people using the EXPAND criteria.
At the time of conversion, 56.2% of the neurologist group were using at least one disease-modifying treatment, compared with 86.8% of the DDA group, and 53.2% of the EXPAND group.
Between the neurologist and DDA groups, 678 patients overlapped. In other words, the DDA algorithm agreed with about 77% of the neurologist diagnoses. The overlap between the neurologist and EXPAND was 334 patients, or about 38% of the neurologist group.
Diagnosing SPMS earlier
Overall, the DDA was deemed more sensitive at identifying SPMS cases than EXPAND, but both were equally specific, meaning they had a low risk of identifying a patient as having SPMS when they were actually still in the RRMS phase. Ultimately, the EXPAND criteria identifies the progressive phase later than the DDA approach, the researchers noted.
However, “both criteria are not able to reach levels of sensitivity and specificity that can lead to consider them a valid replacement to the judgement of the neurologist: we have not found a method that can be identified as a possible new gold standard,” they added.
Identifying the transition to SPMS as early as possible has significant implications, the researchers emphasized.
RRMS relapses are thought to be driven by periods of acute inflammation, whereas the main characteristic of SPMS is neurodegeneration, or progressive nerve cell damage.
“Consequently, MS therapeutic strategies should be stage-specific,” the researchers wrote, adding that “early identification of SPMS can be considered a window of opportunity to intervene for therapeutic purposes.”
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