LAUSR

The predominant clinical disease course of multiple sclerosis (MS) which can be treated today by a variety of different disease-modifying treatments (DMT) is characterized by reversible episodes of neurological disability (relapsing remitting form of MS (RRMS)), which frequently evolves into progressive neurological decline (secondary progressive multiple sclerosis (SPMS)) which cannot be treated by DMTs as well. Some MS patients (about 10%) may exhibit a disease course with progressive neurological decline since the onset and they are classified as primary progressive MS (PPMS). The clinical course of PPMS differ from SPMS; and postmortem studies showed that there is significantly more inflammation in SPMS (perivascular cuffing and cellularity in the brain tissue) than in PPMS disease [1]. Such data reinforce our approach to use the term MS as an umbrella term referring to a group of possible different disease entities. Pathological studies have shown differences between RRMS and SPMS in terms of inflammatory environment, cellular responses, and the location of brain and spinal lesions. However, the debate is still open whether SPMS and RRMS should be considered as two different nosological entities or just two phases of the same disease. Today, the most supported theory is that RRMS and SPMS represent a continuum [2]. In acute RRMS, extensive axonal loss occurs in acute lesions; but the clinical deficits of these inflammatory relapses are mostly reversible, as the human brain has a remarkable ability to compensate for neuronal loss. With time and ongoing inflammatory activity, axonal loss can drive the conversion of RRMS to SPMS when the brain exhausts its capacity to compensate for further neuronal loss. However, entering in secondary progressive phase represents an insidious change for persons suffering from RRMS. Indeed, in SPMS the disability accrual becomes irreversible, and the ability to recover from clinical relapses begins to be frequently ineffective [3]. As we said long is the debate about to consider or not SPMS as the natural evolution of RRMS but no consensus is reached (see elsewhere, 4). The reality is that a majority of RRMS shifts to SPMS, even if they are treated with DMTs [3-5]. The introduction of DMTs since 1990s dramatically changes the natural history of RRMS, and in the last 5 years we witnessed the release of new and stronger biological therapies which showed impressive ability to impact the inflammatory activity in RRMS. Very recently, an observational study of patients with MS treated with autologous hematopoietic stem cell transplantation showed that almost half of them remained free from neurological progression for 5 years after transplant [6]. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline Expanded Disability Status Scale (EDSS) score were factors associated with better outcomes [6]. Overall, the efficacy of MS treatments seems to be higher in the earlier stages of RRMS and decreases over time. Frustrating results were collected about the treatment of progressive forms. Very recently, the scientific community was excited by the approval of the first drug for the treatment of PPMS, that is, ocrelizumab. It is a humanized monoclonal antibody who showed the ability in reducing by 24% the risk of 12-week confirmed disability progression in PPMS relative to placebo [7]. We are waiting for long-term clinical data. In our clinical practice, we are faced with the phenomenon that our MS patients become chronically treated with DMT. The optimal duration of DMT use remains an open and controversial question. There are patients who stay on DMT as long as they tolerate the treatment and the DMT seems effective. Others switch between DMTs in order to find one that is more effective or more tolerable, and others who cannot tolerate any of the DMTs, or show any clinical effect by this treatment. Determining when DMT is no longer helpful is challenging, as we have no comparator intraindividually available. In addition, no studies have directly assessed the clinical challenge to continue versus discontinue DMT in different MS populations. Moreover, with the aging of persons with MS who lived in the industrialized countries, we are facing with a new query: are there any difference in terms of the treatment in old (more than 50 years old) and young persons with MS? We do not know; and there are no treatment recommendations for aging population with MS; which includes a great percentage of persons with SPMS [8]. The scarce literature data (mostly looking at RRMS population) have tried to divide the reasons for treatment withdrawal