Multiple sclerosis (MS) is the most common demyelinating disease of the CNS and may be a major cause of disability in young adults. However, disease-modifying drugs (DMDs) have improved its natural history in the last two decades. This effect is more apparent if medication is administered at the early stages of the disease Citation[1]. Therefore, age at MS diagnosis is relevant for therapeutic decisions. There appears to be an association of this age with the presence of the HLA DR15 phenotype Citation[2]. This suggests that immunogenetic background not only confers MS susceptibility but also influences disease onset.
In areas with easy access to neurological departments, age at MS diagnosis reflects age of onset. Over the last few years that age has been reduced in every day clinical settings. Increasing awareness of MS in the general population has resulted in earlier requests for medical advice, even for mild or transitory symptoms that otherwise may have been considered unimportant by patients. This improves the sensitivity of MS diagnosis. This fact and the constant re-evaluation of diagnostic criteria Citation[3,4] lead to an earlier diagnosis and treatment of the disorder.
The identification of potential targets of therapy and the development of current DMDs are due to our progress in the understanding of disease mechanisms. Despite intense research, MS etiology remains unknown. However, a large body of evidence supports the argument that autoimmunity plays a crucial role in its pathogenesis. The disease usually begins with a relapsing–remitting phase. It reflects a CNS inflammatory cascade leading to myelin damage and conduction blocks. This inflammation, clinically reflected by relapses and new gadolinium-enhanced and T2 MRI lesions, is characteristic of young age and earlier stages of MS Citation[5]. Accordingly, children with MS suffer more relapses Citation[6] and greater T2-lesion load than adults Citation[7]. Initially, symptoms completely recover. Axonal ionic channel rearrangement and remyelination are involved in this improvement. After a variable number of years, cumulative deficits following individual attacks supervene, and eventually many patients suffer secondary progression (SP).
It is now widely accepted that axonal loss is responsible for irreversible neurological disability and progression of MS patients, but the exact mechanisms of axonal damage remain unknown. Axonal fragmentation can occur due to inflammation at the very early stages of the disease Citation[8]. Nevertheless, progressive axonal loss occurring at later stages seems to be caused by a degenerative process. Disability progression and brain atrophy secondary to neurodegeneration are characteristic features of long-term evolution and older age. An incompletely resolved question is to what extent late axonal loss relates to the initial inflammatory process. Natural history studies showed that this may be the case, at least explaining part of long-term disability development. A high frequency of relapses during the first years of disease evolution correlates with more disability on follow-up Citation[9]. A similar predictive value was found for the initial MRI lesion burden Citation[10]. Nevertheless, once a certain degree of disability or the SP phase have been reached, neither new relapses nor new MRI lesions seem to affect further disability progression Citation[11]. Noninflammatory causes of axonal damage that may play a role in this phase of the disease are vulnerability of chronically demyelinated axons to an inflammatory milieu, lack of myelin-derived trophic factors, calcium accumulation within neurons and energy failure.
Disease-modifying drugs decrease the relapse rate in relapsing–remitting MS, although their benefit in the reduction of disability progression is more controversial. Moreover, immunotherapy is ineffective in SP MS. A demonstrative example was the effect of treatment of SP MS with Campath-1H. This is a humanized monoclonal antibody that leads to systemic lymphocyte depletion targeting the CD52 antigen present on all T and B lymphocytes, monocytes and eosinophils. It induced a very significant reduction of new gadolinium-enhanced MRI. This correlated with a clear reduction in relapse rate. Nevertheless, during and after treatment, progression advanced despite the suppression of inflammatory activity Citation[12]. A similar effect was observed in the pivotal SP MS clinical trial of IFN-β, which reported a significant decrease in relapses, but no impact on short-term disease progression Citation[13]. These studies showed dissociation between the response of inflammation and disease progression to DMDs, once a certain level of clinical disability has been reached. This suggests there is a window early in the evolution of MS, specifically, the inflammatory phase, in which immunomodulation has a beneficial and lasting effect on long-term disability. Once this phase is over, relapses can still be reduced by medication. Nevertheless, the progressive deterioration of neurological function is unaffected by current DMDs.
Several studies seem to confirm that treatment after early diagnosis of MS patients improves their long-term outcome. After a follow-up of 8 years, it was observed that patients with relapsing–remitting MS with early IFN-β1a treatment experienced sustained benefit showing lower expanded disability status scale progression, relapse rate and T2 burden of disease compared with those whose treatment was delayed by 2 years Citation[14]. There are also data showing that IFN-β and glatiramer acetate delay the onset of MS in patients with clinically isolated syndrome, the first demyelinating event. IFN-β1b showed this effect in the BENEFIT trial. Patients who completed the randomized phase of the study were eligible to enter an open-label follow-up study in which they were all offered IFN-β1b. A 3-year integrated data analysis compared patients who were originally treated with IFN-β1b (early treatment) with those who were originally given placebo (delayed treatment). This study found that early treatment reduced disability progression by 40% compared with delayed treatment Citation[15]. Moreover, a recent study performed in the every day clinical setting showed that the best results for treatment initiation, in terms of halting disability progression, were obtained when relapsing–remitting MS patients were treated within the first year of diagnosis Citation[1].
Therefore, these data show that early diagnosis of MS allows early initiation of treatment, thus maximizing DMDs efficacy.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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