There has been considerable uncertainty and confusion about the diagnosis of secondary-progressive multiple sclerosis (SPMS), which may stem in part from the MS Phenotype Group’s early efforts to define the clinical course of MS (Lublin et al. Neurology 2014; 83:278-286). In that paper, four sub-phenotypes of SPMS were described: those with active disease with disability progression (once considered to be transitional SPMS); active disease without disability progression (once considered RRMS); non-active disease with progression (once considered SPMS); and non-active disease without progression.
One area of confusion that arose was how to assess disease activity. The Phenotype Group recommended annual clinical assessments, but annual brain imaging was only advised for relapsing, not progressive patients. The result, as might be expected, was an inconsistent application of the recommendations. In Europe, regulators define disease activity as relapses or new MRI lesions, whereas U.S. regulators define disease activity as relapses without mentioning MRI, a problem that the Phenotype Group noted in a recent paper meant to clarify the situation (Lublin et al. Neurology 2020;94:1088-1092). A further complication, the authors stated, was that disease activity without mention of a time frame (e.g. relapses in the previous year) is meaningless since all SPMS patients have disease activity at some point in the clinical course.
Phenotypes, by definition, concern themselves with appearances without regard for immunopathological or other changes. So a rather larger concern arising from this emphasis on relapses is that SPMS is now viewed as active or non-active. This has had two consequences. The FDA now approves DMTs for relapsing forms of MS (i.e. CIS, RRMS and active SPMS) without any fussy regard for phenotypes or, apparently, the evidence base from clinical trials. And the active/non-active divide is now translated as treatable versus non-treatable SPMS. In this regard, while immunomodulatory therapies do appear to have more of an effect in active SPMS, it has not been established that non-active SPMS patients achieve no benefit from treatment, either immediately or after a lag time with cumulative drug exposure.
As currently stated, an SPMS diagnosis should be based on the patient history, or objective measures of change (Lublin 2014). The objective measures to be used are not specified; a change in EDSS score is implied but not stated as a requirement. Other measures could conceivably be used as long as they are not subjective (e.g. clinical impression or patient-reported). The rate or amount of cumulative disability (e.g. a cut-off value for EDSS) required for an SPMS diagnosis has also not been determined.
These inconsistencies were reflected in several reports at ACTRIMS/ECTRIMS 2020 on progressive MS. An international survey of healthcare professionals reported that a higher proportion of SPMS patients are considered as active in the U.S. compared to Europe (59% vs. 44%) (White et al. ECTRIMS 2020; abstract P0254). Most active SPMS patients were receiving a DMT in the U.S. and Europe (96% and 74%, respectively); whereas non-active SPMS patients were more likely to be on treatment in the U.S. (80% vs. 49%). Interestingly, the most common identifier of disease activity was not relapses – 75% of non-active patients had relapses in the previous year – but MRI changes: patients were likely to be considered active if there was an increase in T2 or Gd+ T1 lesion load. Progression was evaluated with a neurological exam; only 49% of HCPs in the U.S. used EDSS to monitor disability change.
A U.S. survey in 2019 found that EDSS changes were used by MS specialists to diagnose SPMS, whereas general neurologists looked at worsening MRI and decreases in walking speed (Naismith et al. ECTRIMS 2020; abstract P0252). MS specialists were more likely than general neurologists to characterize SPMS as active (73% vs. 59%).
A consensus panel agreed that disability progression was best determined by EDSS; the minimum time to confirm progression was 6 months (Oreja-Guevara et al. ECTRIMS 2020; abstract P0248). The group also found that progression should be suspected if there was a 2-point change in any functional system (except visual) even in the absence of EDSS change, or a finding of sustained brain volume change. A >20% change in timed 25-foot walk (T25FW) or 9-Hole Peg Test (9HPT) can be used to confirm progression. A separate study found that worsening SDMT scores generally preceded the onset of SPMS at the group level, but variations made SDMT change less useful for predicting SPMS in individual patients (Karrenbauer et al. ECTRIMS 2020; abstract P0420).
A simplified approach to SPMS diagnosis was proposed by the BeAMS Study Group, which recently prepublished an algorithm based on the patient’s age and EDSS score at last visit (Ramanujam et al. medRxiv 2020.07.09.20149674; free full text at www.medrxiv.org/content/10.1101/2020.07.09.20149674v1.full.pdf). For example, the probability of SPMS was 93% for any patient with EDSS >6; 76% if EDSS >4.5 in a patient aged >45 years (38% if younger than 45 years); and so on. Applying this algorithm to five MS registries in Europe increased the proportion of patients diagnosed as SPMS from 17% to 31% (Hillert et al. ECTRIMS 2020; abstract PS05.05). This method of classification reportedly has greater accuracy (84%) compared to other methods used in database analyses or clinical trials (Forsberg et al. ECTRIMS 2020; abstract PS05.03).
Siponimod received approval in Canada earlier this year for the treatment of active SPMS based on the results of the EXPAND trial (Kappos et al. Lancet 2018;391:1263-1273). Results for the active subgroup in the EXPAND extension study are now available (Giovannoni et al. ECTRIMS 2020; abstract P0238). A sustained benefit was seen with continuous siponimod for up to five years; ARR was 0.06 during the extension, and the median time to 6-month CDP or 6-month confirmed cognitive worsening was not reached. Time to 6M CDP was delayed by 72%, and 6M confirmed cognitive worsening was delayed 73% with continuous siponimod versus placebo/siponimod. A subgroup analysis from EXPAND also reported improvements from baseline in SDMT scores both in patients with active and non-active SPMS (Penner et al. ECTRIMS 2020; abstract P806). A total of 34.1% in the active group and 35.6% in the non-active group experienced a clinically meaningful sustained improvement (>4-point change) in SDMT scores.
In the interim analysis of the EXCHANGE study, patients on an injectable or oral DMT were switched to siponimod without a washout period; patients on teriflunomide completed an active elimination protocol (Bar-Or et al. ECTRIMS 2020; abstract P0233). Siponimod was started immediately using the standard titration schedule. Overall, 4.5% of switched patients experienced a serious adverse event and 5.4% had an adverse event leading to discontinuation. There were no significant changes from baseline in heart rate after switching to siponimod, suggesting that many patients can transition to siponimod without an interruption in treatment.