Relapsing-remitting multiple sclerosis is characterised by the occurrence of acute but brief episodes of neurological dysfunction (referred to as relapses, exacerbations, or attacks), which can be followed by complete or partial recovery. The characteristics of clinical relapses may vary widely in both type and severity, ranging from subjective sensory disturbances to a complete loss of motor functioning. About 85% of people with MS initially have RRMS. In this type of MS neurological problems from relapses may persist but, by definition, they are stable; that is, they do not worsen between the episodes of acute neurological dysfunction.

It is well known, however, that a significant proportion of people with RRMS subsequently enter a secondary progressive disease course, a phase characterised by a continuous worsening of neurological impairment with or without occasional relapses, minor remissions and plateaux (see page 13). The results of studies conducted in placebo groups of people with MS indicate that the time from RRMS onset to secondary progression is, on average, about 20 years. A minority of people with RRMS are termed as “benign” when, a long time after the onset of the disease, neurological impairment is absent or minimal. See page 15 for a description of benign MS.

Prognosis

Most studies investigating the likely course of the disease for those with RRMS indicate that an older age at onset, male gender, higher relapse rate or faster clinical deterioration during the first five years are hallmarks of an unfavourable disease evolution. Initial visual or sensory symptoms have been found to be associated with a longer time to secondary progression, while spinal cord-related symptoms (for example, urinary symptoms or lower limb dysfunction) are associated with a shorter time to secondary progression. Incomplete recovery from the initial exacerbation has also consistently been associated with a shorter time to secondary progression.

Studies conducted on post mortem samples or brain biopsies from people with MS have highlighted that focal, potentially reversible inflammation is the hallmark of tissue damage in RRMS; when present, a loss of axons (ie, irreversible damage) and diffuse white and grey matter pathology are less pronounced than in the more advanced and disabling stages of MS. The use of MRI has greatly increased our ability to study the evolution of all these types of damage in RRMS. It is now established that monthly MRI scans of the brain can detect the occurrence of disease activity (the presence of new lesions) in RRMS five to ten times more frequently than clinical monitoring alone, such as assessing the presence of new symptoms and signs. But the actual cost of performing monthly MRIs is impractical in most cases.

The high sensitivity of MRI makes it possible to determine the presence of the disease soon after its first clinical signs, thereby enabling an earlier diagnosis and disease-modifying treatment (DMT). In addition, MRI-derived measures of RRMS activity have become reliable markers to assess the efficacy of experimental treatments in clinical trials. It is also worth noting that the application of more sophisticated, “non-conventional” MRI techniques to the study of RRMS has improved our knowledge about the mechanisms of this disease. We have learned from non-conventional MRI studies that irreversible loss of neurons and axons is present from the early stages of RRMS, and that grey matter is not spared. The severity of these pathological features is less pronounced in people with stable RRMS and tends to increase when RRMS shifts to the secondary progressive phase.

There is, however, an extreme variability from person to person with regard to the presence and extent of all these features, in spite of similar clinical profiles. As shown by functional MRI studies, this variability can be explained by the differing efficacy of innate compensatory mechanisms among individuals, namely the reorganisation of cortical activity, which the brain uses from the earliest stages of RRMS to try to limit the consequences of tissue damage.
Disappointingly, MRI features still have limited value in giving individual prognoses to people with RRMS. Nonetheless, the results of recent studies seem to suggest that integrating clinical and MRI data may represent a valuable strategy to overcome this limitation.

Treatments
During the last 15 years, the efficacy of numerous experimental treatments has been investigated in RRMS, with the dual aim of reducing the frequency and/or severity of relapses and, possibly, the risk of subsequent secondary progression of the disease. Thanks to the use of MRI, we have been able to reduce the duration and sample size needed to run RRMS trials and this has led to the approval of several DMTs, namely beta-interferons and glatiramer acetate. These injectable drugs for people with RRMS are now widely accepted in that they are able to reduce clinical and MRI disease activity with a reasonably good risk/benefit ratio – that is, the risk of side effects is acceptable when compared to expected benefits.

Whether these DMTs work in preventing the shift from relapsing-remitting to secondary progressive MS remains debatable, but some evidence supporting their efficacy has come out of “post marketing” surveys, which are clinical trials that pharmaceutical companies conduct after approval to gather additional information about a product’s safety, efficacy or optimal use. Even though the average efficacy of interferons and glatiramer acetate does not seem to be significantly different, it is well known that individuals with RRMS may be “non-responders” to one or all of these treatments.

The early identification of non-responders and the development of further therapies remain, therefore, issues of outstanding importance in the therapeutic management of RRMS. There are already approved drugs in some countries, such as mitoxantrone (an immunosuppressant drug and chemotherapy agent) and natalizumab (a monoclonal antibody), which are used in more severe cases of RRMS, thanks to their average increased efficacy compared with first-line DMT.
This efficacy is, however, accompanied by a greater risk/benefit ratio.

Future treatment options
Several trials are being or have been recently conducted to assess the efficacy of oral compounds (for example, cladribine, fingolimod, laquinimod, teriflunomide) and monoclonal antibodies (such as rituximab, alemtuzumab, daclizumab) as potential therapies for RRMS. It is likely that some of these treatments will show a significantly greater efficacy than “traditional” DMT for RRMS. If such findings are combined with an acceptable safety profile, the scenario of RRMS treatment might further and dramatically improve during the next few years.