Abstract

Disability in multiple sclerosis accrues predominantly in the progressive forms of the disease. While disease-modifying treatment of relapsing MS has drastically evolved over the last quarter-century, the development of efficient drugs for preventing or at least delaying disability in progressive MS has proven more challenging. In that way, many drugs (especially disease-modifying treatments) have been researched in the aspect of delaying disability progression in patients with a progressive course of the disease. While there are some disease-modifying treatments approved for progressive multiple sclerosis, their effect is moderate and limited mostly to patients with clinical and/or radiological signs of disease activity. Several phase III trials have used different primary outcomes with different time frames to define disease progression and to evaluate the efficacy of a disease-modifying treatment. The lack of sufficiently sensitive outcome measures could be a possible explanation for the negative clinical trials in progressive multiple sclerosis. On the other hand, even with a potential outcome measure that would be sensitive enough to determine disease progression and, thus, the efficacy or failure of a disease-modifying treatment, the question of clinical relevance remains unanswered. In this systematic review, we analyzed outcome measures and definitions of disease progression in phase III clinical trials in primary and secondary progressive multiple sclerosis. We discuss advantages and disadvantages of clinical and paraclinical outcome measures aiming for practical ways of combining them to detect disability progression more sensitively both in future clinical trials and current clinical routine.

Highlights

  • Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, pathophysiologically characterized by inflammation, as well as neurodegeneration occurring in even early stages of the disease [1]

  • We identified 12 outcome measures from 11 trials dealing with the efficacy of DMT in both primary progressive MS (PPMS) and secondary progressive MS (SPMS)

  • We have identified several outcome measures dealing with different aspects of disease pathology, as well as with different definitions of and the sensibility to predict disease progression

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Summary

Introduction

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, pathophysiologically characterized by inflammation, as well as neurodegeneration occurring in even early stages of the disease [1]. While 10–15% of patients display a progressive disease course from onset, called primary progressive MS (PPMS), natural history studies have indicated that about two-thirds of untreated patients with an initially relapsing course develop a progressive disease course, called secondary progressive MS (SPMS), after a mean of 15–20 years with broad interindividual variance [2,3,4]. Efforts in recent years have yielded the first effective treatment options for PMS, albeit currently not as effective as in RMS [11,12]. Both the continuing quest for finding effective treatments for PMS and the growing challenge for navigating and sequencing treatment options require reliable methods for assessing response or failure of a given treatment.

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