Progressive MSers; we haven’t forgotten you. #MSBlog #MSResearch
“The following is an excellent state of the art series on progressive MS. It indicates that the community is not ignoring the disease and if anything there is a push to find new treatments for the disease. You can also listen to the podcasts; i.e. a 3-part series by Alan Thompson and Steven Goodrick on progressive MS. We are currently in the process of writing a grant application to address some of the new insights when have in progressive MS; the deadline is for the progressive MS alliance at the end of the month. Nothing is quite on the progressive MS front; if anything it all seems to go!”
Progressive multiple sclerosis. Lancet Neurology, January 12, 2015
Although the past two decades have seen a profound change in the management of relapsing-remitting multiple sclerosis, almost no disease-modifying treatments exist for primary and secondary progressive multiple sclerosis. In the first of three Series papers in The Lancet Neurology, Hans Lassmann and colleagues provide an overview of the pathological mechanisms underlying progressive multiple sclerosis. Next, Anthony Feinstein and colleagues consider the promise of concurrent, potentially synergistic interventions to alleviate symptoms and improve function. And finally, Daniel Ontaneda and colleagues summarise lessons learned from clinical trials to date, and consider steps that could be taken to facilitate a new era of therapeutic discovery.
The past two decades have seen a profound change in the treatment of multiple sclerosis. With recent regulatory approvals, 12 disease-modifying treatments are available in many countries for relapsing-remitting multiple sclerosis (RRMS) and there is a robust pipeline of experimental treatments at various stages of clinical development. Such progress should be a cause for celebration; however, much still needs to be done to make available a similar range of treatments to people living with progressive forms of multiple sclerosis.
Few neurological disorders have seen so great a transformation in public perception as multiple sclerosis. Over the past 20 years, the disease has moved from being an untreatable disorder with few management options to one with active management underpinned by a wide range of oral and injectable treatments, at least for patients with the relapsing-remitting form of the disease (RRMS). The effect that this development has had on people affected by RRMS is difficult to overstate, but these improvements overshadow a less palatable fact: for a sizeable proportion of patients—those with progressive multiple sclerosis—almost no treatment options are available.
A better understanding of the pathological mechanisms that drive neurodegeneration in individuals with multiple sclerosis is needed to develop therapies that will effectively treat patients in the primary and secondary progressive stages of the disease. We propose that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death. The evidence suggests that treatment of progressive multiple sclerosis should be based on a combination of anti-inflammatory, regenerative, and neuroprotective strategies.
Disease-modifying drugs have mostly failed as treatments for progressive multiple sclerosis. Management of the disease therefore solely aims to minimise symptoms and, if possible, improve function. The degree to which this approach is based on empirical data derived from studies of progressive disease or whether treatment decisions are based on what is known about relapsing-remitting disease remains unclear. Symptoms rated as important by patients with multiple sclerosis include balance and mobility impairments, weakness, reduced cardiovascular fitness, ataxia, fatigue, bladder dysfunction, spasticity, pain, cognitive deficits, depression, and pseudobulbar affect; a comprehensive literature search shows a notable paucity of studies devoted solely to these symptoms in progressive multiple sclerosis, which translates to few proven therapeutic options in the clinic. A new strategy that can be used in future rehabilitation trials is therefore needed, with the adoption of approaches that look beyond single interventions to concurrent, potentially synergistic, treatments that maximise what remains of neural plasticity in patients with progressive multiple sclerosis.
Progressive multiple sclerosis is characterised clinically by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or can be preceded by a relapsing disease course (secondary progressive). An effective disease-modifying treatment for progressive multiple sclerosis has not yet been identified, and so far the results of clinical trials have generally been disappointing. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets for neuroprotection, and in improved outcome measures could lead to effective treatments for progressive multiple sclerosis. In this Series paper, we summarise the lessons learned from completed clinical trials and perspectives from trials in progress in progressive multiple sclerosis. We review promising clinical, imaging, and biological markers, along with novel designs, for clinical trials. The use of more refined outcomes and truly neuroprotective drugs, coupled with more efficient trial design, has the capacity to deliver a new era of therapeutic discovery in this challenging area.