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INTRODUCTION
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system.
It is considered to be a T-cell-mediated autoimmune disorder that generates an inflam-
matory process in a cascade that compromises the oligodendrocytes and microglia, caus-
ing destruction of the myelin sheath and axonal injury. MS is characterized by demyelin-
ation, gliosis, axonal injury, and neuronal loss. Neurodegeneration that affects both white
matter and gray matter is observed from the onset of the disease.1-3 This complex physiopa-
thogeny, where inflammatory and degenerative processes are combined in different degrees
of predominance, results in a variable and unpredictable evolutionary course. In most pa-
tients, MS initially presents episodes of reversible neurological deficit, which with the pass-
ing of time can lead to progressive and nonreversible neurological impairment.4 Patients
can show increasing motor disability during the course of the disease, with half of cases show-
Received September 18, 2017 ing severe mobility compromise at 15 years from disease onset that strongly affects their
Revised April 1, 2018 quality of life.5
Accepted April 5, 2018 Corticosteroids were used in the 1960s to diminish the severity of MS relapses, but they
Correspondence failed to reduce the number of annual relapses or the progression rate of the disease. Dif-
Ricardo Alonso, MD, MSc ferent immunosuppressant drugs were studied in the 1970s and 1980s, such as cyclophos-
Multiple Sclerosis Clinic,
Ramos Mejia Hospital, Urquiza 609, phamide, cyclosporin, methotrexate, and azathioprine, and trials were carried out with glat-
C1221ADC Ciudad Autónoma de iramer acetate.6,7 The first study of interferon beta 1b (IFNβ-1b) was reported on in 1993,8
Buenos Aires, Buenos Aires, Argentina
Tel +54-11-45551335 cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Com-
and this was the first drug that was effective in reducing dis- and reasons for these changes (drug tolerance problems, lack
ability and the number of relapses. of adherence, or therapeutic failures such as loss of efficacy).
IFNβ-1b became available for clinical use in South America Therapeutic failure was defined according to the modified
in 1996, and this changed the paradigm of MS treatment in Rio score (MRS).10 The MRS is a rating system consisting of
our region. The number of disease-modifying drugs (DMDs) a combination of clinical and magnetic resonance imaging
available for treating relapsing-remitting multiple sclerosis (MRI) data that is used to predict those patients who may
(RRMS) has doubled worldwide in recent years. Numerous show a suboptimal response to treatment and be at a greater
drugs for treating RRMS have been approved since 2010 in risk of disease progression or relapse. Patients with an MRS
South America, and they vary in terms of administration of 1 or more were considered as therapeutic failure. We divid-
method, dosing, action mechanism, efficacy, safety, and toler- ed the presents into two groups according to the MRS: those
ability (Table 1). This increase in the available therapeutic with an MRS of 0 or 1 were considered low risk, and those
options has made treatment algorithms more complex. with an MRS of 2 or 3 were considered high risk.
The aim of this study was to determine the changes in MS The analysis was performed while considering when ap-
treatments relative to the underlying causes and the availabil- proval was granted for new therapies in Argentina, and hence
ity of new DMDs in Argentina. two time periods were selected: before and after 2010.
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JCN Changes in Multiple Sclerosis Treatment Paradigm
to predict which drug will be optimal in a specific patient.11 It servational study of 285 patients who had failed to respond to
also has to be considered that 30% of patients may show sub- IFN or glatiramer-acetate therapy, and evaluated if the switch
optimal responses during the first years of treatment,12,13 and to natalizumab (a scaling treatment) was more effective than
there are different studies claiming that the annual rate of out- switching between first-line drugs (a horizontal change in
breaks and residual disability are related.14 Although some treatment). They found no differences between the two groups
drugs exhibit greater efficacy, the available data are restrict- at 12 months, but after 24 months a greater proportion of the
ed by few prospective head-to-head trials having been per- patients in the scaling treatment group were free from relapse
formed. Moreover, there is a wide range of adverse effects (p<0.0001), disability progression (p=0.0045), and MRI ac-
with different levels of severity that may appear randomly in tivity (p=0.0003). However, as mentioned above, it has to be
only certain patients, making it difficult to predict tolerabili- considered that few head-to-head studies have compared the
ty. Lastly, adherence can be a significant cause of treatment efficacy of one drug against another, and that none of these
discontinuation.15 studies compared the so-called second-generation drugs.
The therapeutic options were scarce prior to the appear- The next most common switches were those motivated
ance of the new drugs, and so only one-third of the subjects by tolerance problems and lack of adherence, which similar
evaluated in our study had switched treatment before 2010. to previous findings.15 Nearly one-third of the present pa-
This could have been due to the lack of therapeutic options tients switched medication due to tolerance problems, and a
and established criteria for switching, since the main drugs smaller percentage did so due to loss of adherence. Previous
used until that time were IFNβ and glatiramer acetate. The studies have found that the percentage of patients switching
main reasons for changing treatment were therapeutic failure differs if each drug is analyzed separately, and also when
or a suboptimal response to the medication. It was observed randomized clinical trials (RCTs) controlled against placebo
that the choice of a certain drug varied according to the rea- are compared with observational studies.15 It must be re-
son for changing treatment: when the reason was therapeutic membered that strict inclusion criteria are applied in RCTs,
failure, the most frequently selected drugs were IFNβ before with these studies usually comparing groups of patients who
2010 and fingolimod and natalizumab after 2010. This anal- have been selected and monitored very carefully. The pa-
ysis was performed using the MRS, and most of the patients tients encountered in daily clinical practices are more hetero-
were at a high risk at the time of switching DMDs, which fur- geneous, which makes it difficult to extrapolate data from
ther justified the changes. RCTs to the general population.
We observed a decrease in the ARR in patients who switched Our analyses revealed a change in the treatment paradigm
treatment due to therapeutic failure, with it being signifi- in patients with RRMS since 2010, which is probably due to
cantly higher in patients with a high MRS. Since the high- the increased availability of drugs with greater efficacy and
MRS patients benefited, careful monitoring for treatment the existence of established criteria.20,21 This complex sce-
failure and active treatment change should be considered in nario could be related to the appearance of new DMDs that
this population.16 There are scales other than MRS for defining vary greatly in efficacy, safety, and tolerability. New DMDs
“therapeutic failure” and serving as a guide to assess changes that are currently in different stages of clinical development
in treatment. Recommendations specific to Argentineans for will probably be introduced in the near future for treating
identifying treatment failure in RRMS patients were pub- RRMS, which will further add to the complexity of the thera-
lished recently.17 That guide does not use the MRS for defin- peutic options for these patients. Another remaining chal-
ing therapeutic failure and provides recommendations for lenge is to develop individualized treatments based on clini-
optimizing the management of patients with MS in Argenti- cal, radiological, and laboratory variables. Individual needs
na. In relation to other authors,18 our study showed greater should be considered when treating each patient and for
reduction in the ARR among those patients who received a controlling the disease.
scaling treatment compared to those who received a horizon-
Conflicts of Interest
tal change in treatment. In Carrá et al.18 reported on an Ar-
Ricardo Alonso has received honorary-speaker payments from Biogen
gentinean study of changes in treatment among patients who and Gemzyme. María Bárbara Eizaguirre has received an honorary-
had experienced immunomodulatory therapy failure. Those speaker payment from Novartis. Lucía Zavala declares that he has no
authors analyzed switches from low-dose to high-dose IFN, conflict of interest. Cecilia Pita declares that he has no conflict of interest.
Berenice Silva has received honorary-speaker payments from Novartis,
from IFNβ to glatiramer acetate, and from glatiramer acetate
Biogen, and Gemzyme. Orlando Garcea has received honorary-speaker
to IFN. They found that patients who did not respond to payments from Teva, Novartis Biogen, and Gemzyme, and has received
first-line therapies benefited from switching to another im- research grants from Teva and Novartis.
munomodulatory agent. Prosperini et al.19 carried out an ob-
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