multiple sclerosis is a chronic inflammatory primary demyelinating disease of the central nervous system of unknown etiology ; as a result curative therapies have not yet been described [ 1 , 2 ] . however , in the last two decades , after the discovery and approval of immunomodulators which specifically modify the natural history of the disease , as such denominated disease - modifying drugs ( dmds ) , most ms patients have been worldwide subjected to this therapy .
interferon beta ( ifn ) formulations and glatiramer acetate ( ga ) are the first - line dmd for ms .
ifn is available in five distinct formulations : ifn-1b ( betaferon / extavia ) , ifn-1a intramuscular ( avonex ) , and ifn-1a subcutaneous ( rebif ) .
these dmds were firstly approved to the relapsing - remitting form of ms ( rrms ) , later for clinically isolated syndromes and ifn-1b for secondary progressive ms ( spms ) .
first - line dmds for ms were introduced in portugal in 1996 , after the licensing of betaferon for rrms .
the other formulations of ifn for rrms were introduced later : avonex in 1997 and rebif in 1998 . still , copaxone was introduced in 2001 .   in the last years the therapeutic armamentarium for ms was enlarged , with the approval of drugs with better efficacy yet potential limiting adverse effects , as mitoxantrone ( novantrone ) , natalizumab ( tysabri ) , and more recently the oral drug fingolimod ( gilenya ) .
together , these drugs constitute the second - line treatment for ms and they are usually indicated in more severe non - ifn-responder cases [ 1 , 2 ] .  
first - line dmds target multiple neuroimmunological mechanisms implied in the pathogenesis of ms , yet their therapeutic effects are rather modest , mainly traduced by a  30% reduction in the relapse rate and a decrease of magnetic resonance imaging ( mri ) t2 lesion burden and gadolinium - enhanced lesions [ 1 , 2 ] ; unfortunately , the benefit effects in disability at long - term remain to be settled . these drugs are usually safe and well tolerated ; however , they are not free from side effects .
failure of the first prescribed dmd was found to occur in 30% of patients usually within 3 years .
therefore , recommendations for escalating therapy were established and successively reviewed by international consensus . switch to another first- or second - line dmd is common and occurs in a median time of 2.9 years after the initially prescribed dmd ; overall , approximately half of ms patients discontinue the use of their dmd within 6 years .
even so , ms neurologists often recognize that , in the clinical setting , some patients maintain the initial treatment for a long period with clinical stability , low disability , and nonsignificant side effects .  
concerning this issue , which is poorly addressed in the literature , we aim to describe the demographic and clinical characteristics of mspatients followed in our ms clinic with long - term(>12 years ) maintenance of the first prescribed dmd .
from the database of our ms clinic regarding patients with the definite diagnosis of rrms ( revised mcdonald criteria 2005 ) , who started a first - line dmd between 1996 and 1999 ( n = 51 ) , we identified those who were still receiving the initial therapy in march 2012 ( cut - off date ) .
inclusion criteria were definite ms diagnosis ; rr course at the moment of dmd prescription ; age 18 years ; maintain treatment with first dmd .  
exclusion criteria were other ms course other than rr when starting dmd ; age < 18 years ; dmd discontinuation ; being treated with at least a second dms .
so , switch to another first- or second - line therapy , to a higher dose ( in the case of rebif ) , or to immunosuppressants , association therapy regimen , were exclusion criteria .  
we proceed to retrospectively review the demographic and clinical protocols of these patients , regarding age , gender , onset syndrome , dmd , annualized relapse rate ( arr ) before and after starting treatment , disease duration until march 2012 , pregnancy history , expanded disability status score ( edss ) at treatment start and currently , and the present multiple sclerosis severity score ( msss ) .
from the cohort of rrms patients who started ifn from 1996 to 1999 ( only ifn formulations were available in that time span ) , we identified 26 cases ( 51% ) treated with the same drug lasting for > 12 years ( mean = 14 years , range 1316 ) ( table 1 ) .
fourteen patients ( 54% ) were treated with betaferon , 8 ( 31% ) with avonex and 4 ( 15% ) with rebif ( figure 1 ) .
no serious adverse effects were reported . concerning gender distribution , 18 patients ( 69% ) were females and 8 males ( ratio 2.3  :  1 ) .
first symptoms began in the mean age of 31 years ( range 1648 ) , with a mean disease duration of 18.6 years ( range 1332 ) until march 2012 . regarding clinical presentation ,
motor symptoms were the most common , occurring in 11 patients ( 42% ) ; brainstem occurred in 8 ( 31% ) , sensory in 4 patients ( 15% ) , optic neuritis in 2 ( 8% ) , and cerebellar in 1 ( 4% ) ( figure 2 ) .
median edss when starting treatment and currently was 1.5 ( range 06 ) and 4 ( range 06 ) , respectively ; present mean msss is 2.56 ( range 0.105.15 ) .
regarding pregnancy , only two women get pregnant during dmd treatment , both under avonex .
the remaining women , except one , already had children at the time of starting dmd .
the management of patients with chronic diseases , as ms , is a major challenge to the physicians . in this sense ,
the growing appearance of dmd specifically developed for ms with different degrees of efficacy , represents a huge step forward in the management of these patients .
however , the success of healthcare relies not only on effective therapies , but also on adherence and persistence . in ms
, there is evidence that dmd must be given as early as possible , usually with a first - line drug .
switch to another first - line dmd or escalating therapy to a second - line drug is common , mainly because of lack of efficacy or intolerance .  
open - label studies found that approximately 30% of ms patients discontinue therapy within 3years due to disease activity ; within 6 years , approximately half of the patients discontinue their dmd .
in particular , some authors found that 15% and 25% of patients stopped taking the initial dmd after 6 months and 1 year of treatment , respectively ; overall , 66% were no longer taking the original dmd at some point of the disease course .
.   concluded that patients with a longer disease duration and higher level of disability are at higher risk for discontinuing dmd ; age , sex , and the initial dmd were not associated to discontinuation .  
as far as ms is better understood and new drugs with higher efficacy are regularly licensed , the clinicians are concerned with defining better escalating regimens , aiming that patients become  free from disease activity  ( no relapses , no progression , and no imagiological activity ) ; consequently , the literature data are mainly focused on those patients who experience a worse treatment response or clinical progression . on the contrary ,
patients that have an optimal response to the initial prescribed dmd are , apparently , subject of less interest , although this is a crucial issue in order to establish patterns of  good responders .
 in fact , data from 260 patients showed that 30% are taking ifn-1b after a median length of exposure of almost 10 years .  
this heterogeneity of treatment response to dmd in ms has beenevaluated by several studies [ 810 ] . among dmds
, responders seem to be older and to have longer disease duration at the time ifn was initiated . among patients with a rr course ,
also , responders seem to have a higher edss at initiation of ifn . a probable role of molecular biologic mechanisms contributing to the variable therapeutic response in ms patients has been raised .
for example , cucci et al . demonstrated that proinflammatory cytokine and chemokine mrna blood level , in ms are related to treatment response .  
although dmd may reduce the clinical relapse rate , their potential benefits in terms of disability progression may be small .
nevertheless , a favorable treatment response leads the patient and clinician to an expectation of a better prognosis .
a multiplicity of variables have been associated with favorable disease course , such as female gender , younger age at onset , sensory symptoms or optic neuritis at onset , and monosymptomatic presentation .
in contrast , male gender ; onset with motor , sphincter , or cerebellar features ; poor recovery from initial or early attacks ; higher attack rate in the first 5 years ; a progressive course were prognostic variables associated with a poor outcome [ 1315 ] .   in this study , we found a high percentage of patients who never needed to switch or escalate therapy , some of them treated with the initial prescribed dmd as long as 16 years .
interestingly , our patients had a good outcome despite preponderance of motor and brainstem symptoms at presentation , usually associated with worse prognosis as already stated .
following the same reasoning , we expected a higher prevalence of sensory symptoms or optic neuritis presentation  which in fact occurred only in a minority of our patients . also , as elsewhere stated , patients who maintain a rr disease course tend to be extremely well and it is only on entering the secondary progressive course of the disease that more rapid disability progression occurs .
so , it is possible that our cohort had a good outcome in terms of disability , not only because of the treatment , but also because only patients with rr course ( a favorable clinical form ) entered the study .
we also observed a low edss score and a low number of relapses , in agreement with ramsaransing and de keyser   who found these clinical factors to be predictive of a good outcome at 10 years .  
another explanationfor ourresultscan berelatedwith a good treatment adherence , defined as  the duration of time from initiation to discontinuation of therapy  ; although we have not collected this data in the present cohort , prior results obtained in a larger series of our ms clinic showed a very low rate of patient 's dmd abandon ( 4.6% ) , which may be related to the organization model of our ms consultation , as stressed by castro et al . .
this model is based on an open and multidisciplinary care , involving several ms dedicated human resources , namely , neurologists , urologists , psychiatrists , neuropsychologists , social worker , and nurses .
there is a personalized training in initial drug injections , complemented with extensive verbal and written information at that time .
further , our ms clinic provides a permanent ( except during night ) full access to a ms specialized neurologist . in case of doubts or new symptoms ,
patients are instructed to access this consultation , instead of emergency room , where misinterpretation of the symptoms is more frequent , particularly when neurologist is not available .
our small cohort is an obvious limitation of the study ; however , it would be rather difficult to find a large number of rrms patients on a single dmd for such a long period of time .
we are also aware of methodological limitations inherent to observational , retrospectivestudies , such asthe absence of standardizedprotocol . yet
we found a high percentage of patients who never needed to switch or escalate therapy , who were mainly females , with low arr , edss , and msss after long disease duration . identifying characteristicsassociated with therapy persistencemay beuseful in developingstrategies to improve therapy effectiveness .
 although therapy switch is common among patients with multiple sclerosis ( ms ) , sometimes the initial prescribed treatment is maintained for a long period with clinical stability , low disability , and nonsignificant side effects . 
 we aim to describe demographic and clinical characteristics of patients treated in our ms clinic with the same disease - modifying drug ( dmd ) lasting for > 12 years . from the cohort of 51 patients 
 followed in our ms clinic with relapse - remitting ms who started an dmd between 1996 and 1999 , we found a high percentage ( 51% ) of patients who were efficiently treated with the first dmd . 
 these patients were mainly females , with low annualized relapse rate and multiple sclerosis severity score ( msss ) . 
 our results may be related to the open and multidisciplinary model of our ms clinic organization . 
 identifying characteristics associated with therapy persistence may be useful in developing strategies to improve therapy effectiveness . 
1. Introduction 
2. Patients and Methods
3. Results
4. Discussion 
5. Conclusion