Clinical outcomes and measures of progression in secondary progressive multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The mainphenotype is a relapsing-remitting form (RRMS), which often converts to secondary progressiveMS (SPMS) years/decades after the disease onset. The pathology behind this conversion is notclearly understood and clinical, imaging and pathological biomarkers for a timely detection of theconversion are absent. The gold standard neurological scale has been the Expanded DisabilityStatus Scale (EDSS) since 1983, although the low sensitivity for disability changes above score 4.0has been known since the 1990s. The limitations are apparent for the detection of SPMS in theeveryday practice, and also as an outcome in clinical SPMS trials. Clinical phase III trials do not reflect the real-world population, where prevalence of older MSpatients with co-morbidities is increasing. The efficacy and safety issues of new treatments amongolder patients is undetermined. The Multiple Sclerosis Impairment Scale (MSIS) was developed in 1997, as a measure ofaccumulated neurological deficits. The total score increases in a linear way with each additionalneurological deficit. MSIS has been shown to be superior in responsiveness to the correspondingEDSS range. Thus, MSIS might be a better candidate for clinical randomized SPMS trials. However,validation against MRI biomarkers has only been performed on spinal volume measures, andvalidation against functional tests and PROs has not been performed. 


Study I
This study reports the real-world efficacy and safety of alemtuzumab treatment in the nationalDanish population during 2014-2019. The cohort comprised 209 patients, which was the largestreal-world cohort at the time. We examined the efficacy based on EDSS changes and relapse-ratesin RRMS patients and in suspected SPMS patients. The study showed similar efficacy and safetycompared to the phase III trials CARE-MS I and II, even though the cohort was older and hadhigher EDSS at baseline. We found no novel adverse events, although adverse events were mostlikely underreported in this national cohort. 

Study II 
The aim of the study was to compare the correlation between MSIS and EDSS respectively, againststandard MRI biomarkers for disease burden and functional tests in a SPMS cohort. We found thatMSIS and EDSS and the respective subscores correlated strongly with each other. Motor subscoreof MSIS correlated stronger with T-25FW compared with pyramidal score of EDSS, and cerebellarand sensory subscores of MSIS correlated stronger with 9-HPT and 6-SST than functional scores ofEDSS. MSIS correlated stronger with thalamus volumes and the mean upper cervical spinal cordarea, and MSIS cerebellar subscore correlated also with thalamus and total lesion volumes.We concluded that MSIS is possibly better than EDSS for detection of cerebellar and sensorysymptoms and that MSIS can potentially be a sensitive scale for disability detection in SPMS.7 


Study III 
We investigated, how different MS-specific and non-MS-specific patient reported outcomemeasures (PROs) correlated with other objective measures in a SPMS cohort. We found thatphysical subscores, WPAI: MS activity impairment and EQ-5D-5L correlated strongly with MSIS,EDSS, T-25FW, 6-SST and 9-HPT. In contrast, the psychological subscores did not correlate withobjective physical measures or cognition. Furthermore, the only correlation with MRI measureswas the correlation of physical MSIS-29v2 and EQ-5D-5L with mean upper cervical spinal cordarea.In conclusion, we found that physical PROs and subscores correlated with physical objectivemeasures of disease burden in SPMS, but the psychological subscores measured a domain ofmental health not recognized by the other measures.


Conclusion 
In this PhD thesis, I show the benefit of a real-world cohort for evaluation of efficacy and safety ofa new treatment outside the stringent inclusion criteria of phase III trials. We found thatalemtuzumab had high efficacy and safety even with older patients and greater disability. In asubgroup of suspected SPMS patients, alemtuzumab had at least a 2-year stabilizing effect onprogression.Moreover, we examined MSIS against EDSS in a SPMS cohort, and found that MSIS was moresensitive to scale cerebellar and sensory symptoms and correlated better with MRI outcomes.MSIS is easy to administer and the training is fast even for younger residents. The sensitivity forprogression is thought to be superior to EDSS. Longitudinal studies of SPMS progression andcomparison of MSIS with EDSS is warranted.In a SPMS cohort, we also examined different PROs, and their correlation with conventionalobjective measures of disease burden. We found that PROs can be of high value for SPMSresearch, adding a new domain of mental health not correlated with cognition or any otherobjective measure.