in the treatment of patients with relapsing - remitting multiple sclerosis ( rrms ) there is a strong emphasis on the need for optimization and personalization of the therapy . no evidence for disease activity ( neda ) , defined with respect to clinical criteria , and results of magnetic resonance imaging ( mri ) are proposed as therapeutic objectives . injectable medications , such as interferons and glatiramer acetate ( ga ) , have been used for more than twenty years , affected the course of the therapy , and have been characterized with moderate efficacy and a good safety profile . in recent years , new forms of previously used injectable medications have been introduced : ga 40 mg three times a week , peginterferon beta-1a ; and new substances : fingolimod , natalizumab , teriflunomide , and dimethyl fumarate . the new medications are characterized as having better efficacy but greater risk of side effects . therefore , it is important to adjust medications based on expected efficacy for each patient at each stage of the disease individually , based on a thorough clinical and radiological evaluation and considering the safety of the administered therapy . in poland , treatment of patients with rrms is reimbursed under the medication program of the national health fund ( narodowy fundusz zdrowia , or nfz ) , which specifies the first - line treatment . in poland , this is based on injectable medications ( interferons and ga ) . for patients in whom the first - line therapy proves ineffective for a minimum period of one year , a second - line program has been created . within the program , the objective of this study is to evaluate the effects of treatment with second - line medications by means of the analysis of the impact of the therapy on the frequency of relapses , the degree of disability , and the occurrence of side effects . the study involved 44 patients ( 31 women and 13 men ) aged on average 38.36 years ( sd : 9.81 ) with rrms treated under the nfz program for ms treatment after the failure of the first - line therapy . all patients were diagnosed for ms according to mcdonald s 2010 criteria . prior to the qualification for a second - line treatment , 15 patients had been treated with interferon beta-1b , 6 patients with interferon beta-1a sc ( subcutaneous ) , 8 patients with interferon beta 1a i m ( intramuscular ) , and 15 patients with ga . an annual relapse rate and the average expanded disability status scale ( edss ) score during first - line treatment was calculated for the whole group . all patients had met the criteria for ineffectiveness of the first - line treatment and had entered into the second - line program according to nfz criteria : no response to a complete , lasting minimum one - year cycle of treatment with interferon beta or ga , defined as the fulfillment of these two criteria : the number and severity of relapses : a ) two or more moderate relapses requiring administration of steroids ( an increase of one to two points in edss score or of two points in one or two edss functional - system scores , or of one point in a minimum of four edss functional - system scores ) , or a severe relapse after five months of treatment ( an increase in edss score higher than in the definition of a moderate relapse ) . lesions demonstrated in mri performed after 12 months of the therapy : minimum three new t2-weighted lesions or minimum two gd+ lesions . thirty patients had fingolimod administered in oral daily doses of 0.5 mg and 14 patients had natalizumab administered intravenously every 28 days in doses of 300 mg . fingolimod was started as soon as the following contraindications had been excluded : hypersensitivity to fingolimod or its ingredients ; known immunodeficiency syndrome ; patients with higher risk of opportunistic infections , including patients with immunosupression ( including patients currently taking immunosuppressive drugs or patients with compromised resistance to infections as a result of the previous treatment ) ; severe active infections ; active chronic infections ( hepatitis , tuberculosis ) ; known active cancer diseases excluding basal cell carcinoma ; severe hepatic impairment ( child - pugh score : class c ) ; patients with coronary heart disease ; sick sinus syndrome with a history of myocardial infarction and treated with ia or iii anti - arrhythmic medications ; patients with no history of varicella or who had not been vaccinated against varicella - zoster virus ( vzv ) and have no antibodies against it ; and patients with secondary progressive ms ( spms ) . the treatment with fingolimod was initiated on an inpatient basis with ecg and heart rate ( rr ) monitoring for a minimum of six hours following the start of the therapy . the therapy was monitored according to the following scheme : morphology ; liver values at one month , and then at three , six , nine , and 12 months following the initiation of the therapy ; ophthalmic examination after three to four months ; dermatological examination after 12 months , and periodic check - ups of rr . natalizumab was started as soon as the contraindications had been excluded : pregnancy , breast feeding , progressive form , the increased risk of opportunistic infections , and the presence of anti - jcv ( john cunningham virus ) antibodies . all patients were declared to have read the information about the program and pml risk stratification , gave their informed consent to treatment , and received a medical warning card . for the purpose of qualification for the treatment with natalizumab , necessary laboratory tests were carried out ( morphology , liver and kidney parameters , general urinalysis , pregnancy test ) . monitoring of patients treated with natalizumab at each administration of the dose ( every 28 days ) included : neurological status , mental condition , cognitive functions , morphology , kidney values , liver values , general urinalysis , and jvc every six months . all patients who qualified for the study had mri of the head performed after 12 months from the start of the therapy . lack of efficacy was defined as the transition into sp or meeting two criteria of these three : the number and severity of relapses : a ) two or more moderate relapses requiring administration of steroids ( an increase of one to two points in edss score or of two points in one or two edss functional - system scores , or of one point in minimum four edss functional - system scores ) , or a severe relapse after five months of treatment ( an increase in edss score higher than in the definition of a moderate relapse ) . the progression of the disease despite the treatment , i.e. , decline in neurological status continued for a minimum of three months , expressed by at least : an increase of two points in edss score with edss up to 3.5 , or an increase of one point with edss score up to four . lesions demonstrated in mri performed after 12 months of the therapy with a minimum of three new t2-weighted lesions or a minimum of two gd+ lesions . the annual relapse rate during 12-month second - line therapy was calculated . the safety of the therapy was evaluated by means of analysis of the following : the development of severe infections during therapy ; the development of cancer ; a significant increase in transaminases ( 3 x uln ) ; an increased concentration of bilirubin ; kidney abnormalities ; and in case of fingolimod also cardiac events ( cardiac failure , rhythm and conduction disturbances ) ; severe sleep apnea ; macular edema ; or prolonged decrease of lymphocytes < 0.210/l . clinical data ( mean annual relapse rate and median edss growth ) during first - line therapy and second - line therapy as well as mri results were compared . the evaluation of mri results took into account the presence of new or larger t2-weighted lesions and the number of gd+ lesions in examinations performed after each 12-month period of the therapy ( the number of new t2-weighted and gd+ lesions in the examination performed at the end of the first - line treatment / initiation of second - line treatment was compared with the examination that took place a year earlier , and the number of new t2-weighted and gd+ lesions in second - line examination was compared with the examination at the end of first - line treatment / initiation of the second - line treatment ) . mri after 12 months of the second - line treatment was performed in 31 patients . the number of relapses , progression in edss score , and lesions in mri were also compared between patients treated with fingolimod and natalizumab . wilcoxon test was used to compare the measurements , student s t - test or umv was used to compare the groups and chi - square test was used to compare quality variables . wilcoxon test was used to compare the measurements , student s t - test or umv was used to compare the groups and chi - square test was used to compare quality variables . the mean duration of the first - line therapy was 36.3 months ( range 12108 ; sd 27.5 , 2575q : 1251 ) , and of the second - line therapy 16.3 months ( range 831 ; sd 6.36 , 2575q : 1218 ) ; p=0.00005 . there were no significant differences in terms of the average age of the patients , the mean therapy time , and the clinical condition assessed according to edss between the group qualified for the treatment with fingolimod and the group qualified for the treatment with natalizumab . the annual relapse rate in the first - line therapy group was significantly higher than in the second - line therapy group ( mean 2.13 ; sd : 0.87 ; median 2 , 2575q : 1.52.8 95% ci 13.8 vs. mean 0.35 ; sd : 0.74 , median 0 , 2575q : 00.67 , 95% ci : 01.41 ) ; p=0.00005 ( figure 1 ) . during first - line therapy , edss change was observed in 36 patients ; the median increase was 1.5 points ( range 04.5 ) . when entering patients into first - line treatment , median edss was 2.5 ( range 1.04.5 ) ; at the end of the first - line therapy it was 4.0 ( range 1.06.0 ) . during second - line therapy changes in edss were observed in 8 patients ( range 01.5 ; median 0 points ) . the difference in the increase of points during second - line treatment was significantly higher than during first - line therapy ( p=0.00002 ) ( figure 1 ) . the number of new or enlarged t2-weighted lesions in mri after one year of the second - line treatment was significantly lower in comparison to the number of new or enlarged t2-weighted lesions in mri performed at the end of the first - line therapy ( mean 0.61 ; median 0 ; range 03 , 2575q : 02 vs. mean 4.56 ; median 4 ; range 012 , 2575q : 2.56 ) ; p=0.0004 ( figure 1 ) . the number of gd+ lesions in mri after one year of the second - line treatment was significantly lower in comparison to the number of gd+ lesions in mri performed at the end of the first - line therapy ( mean 0.13 ; median 0 ; range 02 , 2575q : 00 vs. mean 1.98 ; median 2 ; range 010 , 2575q : 03 ) ; p=0.0009 ( figure 1 ) . during second - line therapy , four patients developed zoster infections and three patients developed herpes infections , all successfully treated with standard medications . apart from the above , no significant side effects listed in the methodology section were observed . three patients treated with natalizumab suffered from jcv seroconversion after 12 months of treatment . due to the inefficiency of the treatment ( relapses , progression of disability evaluated according to edss , the development of new lesions in mri ) , the therapy was stopped in four patients ( two treated with natalizumab , two treated with fingolimod ) after 12 months . no statistically significant differences in the annual relapse rate , change of edss points , the presence of new or enlarged t2-weighted lesions , or new gd+ lesions between the group treated with fingolimod and the group treated with natalizumab were observed . the decision about the right moment to introduce escalation therapy in patients with ms undergoing injectable first - line therapy of proven but limited efficacy is an important and difficult one . the suggested therapeutic objective of neda leaves no tolerance for relapses , disability progression evaluated according to edss , or the development of new lesions in mri . in recent years , new chemical substances the availability of therapies is regulated by nfz regulations , according to which second - line therapy is currently restricted to two medications ( natalizumab , fingolimod ) and only in patients who suffered relapses and developed new lesions observed in mri during first - line treatment in a minimum 12-month period . the efficacy of escalating treatment with these two medications has been confirmed by numerous studies [ 1317 ] . our study patients showed significant improvement during second - line treatment in all studied parameters ( relapse occurrence , edss progression , the development of new t2-weighted and gd+ lesions ) in comparison to the results achieved in patients during first - line therapy . the criteria for therapy escalation applied for our patients differed from neda , which ( together with the improvement observed in patients during second - line therapy ) would seem to challenge the neda s high stringency , and raise the question of whether second - line therapy should not be started earlier . on the other hand second - line medications may cause a greater number of side effects than first - line medications . fingolimod may cause cardiac events , ocular complications , and increase the risk of infections . therefore , strict initiation and monitoring rules should be applied . in our study , no significant side effects , apart from the infections successfully treated with standard medications , were observed . in the literature there are publications about risk - predicting algorithms for individual response to therapy and the potential need for escalation . researchers keep looking for biomarkers to estimate the risk of disease progression and the response to the applied therapy . canadian recommendations concerning therapy optimization are based on the evaluation of the relapses , new lesions in mri , and edss progression . the canadian authors propose the evaluation of first - line therapy every six or 12 months , and changing the therapy if a minimum of one severe relapse , significant edss progression , or new lesions in mri occurs ( minimum three t2-weighted or gd+ lesions ) . they also point to the necessity of therapy escalation in patients who suffer from less severe relapses with a slight radiologic progression ( two new t2-weighted or gd+ lesions ) or slight edss progression . according to canadian criteria , the escalation should take place when the activity occurs in one of the domains : relapse occurrence , edss progression , or new lesions in mri . in poland , to enter patients into second - line treatment , there must be a combination of relapses and new lesions in mri . freedman et al . indicated the possibility of a temporary escalation  for a period of one or two years , to minimize the risk of long - term exposure to the second - line treatment medications . however , they stressed that the escalation should be permanent in patients with aggressive forms of the disease and suboptimal responses to treatment . in poland , there is no possibility for de - escalation , and the criteria for introducing second - line therapy are much stricter that those proposed by freedman et al . patients with more aggressive forms of the disease are qualified . de - escalation of the therapy might be considered in patients who respond to the treatment but develop intolerance to the treatment , or patients treated with natalizumab who develop jcv seroconversion . there are no clear guidelines for patients for whom second - line therapy proved ineffective . in our study , it proved ineffective for three patients . as a  third - line  therapy , immunosuppressive medications ( such as mitoxantrone and cyclophosphamide ) or newly introduced medications of proven high effectiveness ( alemtuzumab ) can be used . , it has been proposed to use these medications as an induction therapy , prior to interferons . rio et al . have created a points - based model of response to treatment based on the one - year evaluation of relapse occurrence , edss disability progression , and new lesions in mri in patients treated with interferons . points were granted if during a 12-month period a minimum of one relapse occurred , a minimum of two new lesions in mri developed ( t2-weighted or gd+ ) , or edss progression by one point took place . in a modified - rio scale , points are granted for relapses ( one point if one relapse occurred during 12 months , two points if a minimum of two relapses occurred ) and the development of new lesions in mri ( minimum of four t2-weighted or gd+ lesions ) . patients with two or three points in these scales were considered non - responsive to therapy and declared candidates for escalation . in both scales , one isolated relapse without activity in mri does not indicate a lack of response to the administered therapy . the same situation applies to our patients  to acknowledge the failure of the first - line therapy , clinical activity ( relapses ) must be accompanied by radiological symptoms ( new lesions in mri ) . rio scale ( similarly to modified - rio scale ) provides for a long - term response to treatment on the basis of the first year of treatment . high specificity ( 72% ) and accuracy ( 65% ) of the modified - rio scale in predicting edss disability progression during a four - year period of observation we reviewed the therapy of our patients every 12 months . in our investigated group , the ineffectiveness of the therapy ( according to the study criteria ) after one year of a first - line therapy was observed in 10 patients ( 22.78% ) ; in others , the ineffectiveness was declared in the following years of injectable medications ( on average after 42 months ) . it is worth emphasizing that nfz does not reimburse for treatment with new oral medications ( dmf , teriflunomide ) or new forms of injectable medications ( peginterferon ) . we are waiting for the possibility of using them in patients who do not tolerate injectable medications , who do not respond to the therapy , or who have a mild disease activity  who do not meet the criteria for inclusion into second - line treatment . patients who do respond to treatment with interferons , but developed antibodies against interferons , could also be potential candidates for new oral medications or ga . however , one must note that the results of treatment with new medications come mostly from clinical trials where the medications are compared against placebo . our research was limited by the small number of patients and relatively short observation period for patients treated with a second - line therapy ; hence our results should be treated as provisional observations . on the other hand , we are waiting for modification of criteria for introducing second - line treatment , and reimbursement of new medications , which will give us the ability to administer modern therapies to patients in poland who have multiple sclerosis . therapy with natalizumab and fingolimod achieved comparable results in terms of efficacy and safety during a one - year observation period in patients with rrsm after failure of treatment with interferon and ga . the possibility of more flexible and personalized therapy , including new therapeutic options , should be examined further .
backgroundin poland , natalizumab or fingolimod treatment can be delivered as a second - line therapy to those patients with relapsing - remitting multiple sclerosis ( rrms ) who demonstrated no response to interferon or glatiramer acetate treatment for a minimum of one year.the objective of this study was to evaluate the impact of second - line therapy on the frequency of relapses , the disability progression , and the occurrence of side effects.material/methodsanalysis covered 44 rrms patients switched from first- to second - line therapy . the annualized relapse rate , disability progression ( assessed with expanded disability status scale , edss ) and mri results ( new or enlarged t2 lesions and new gd - positive lesions ) before and after switching were compared . 
 the occurrence of adverse events was also assessed.resultsthe annualized relapse rate for second - line therapy was significantly lower than for first - line therapy ( 0.350.74 vs. 2.130.87 , p=0.00005 ) . 
 median of edss progression with first - line therapy was significantly higher than that with natalizumab or fingolimod treatment ( p=0.00002).the mean number of new or enlarged t2 and gd+ lesions in mri after one - year second - line treatment was significantly lower in comparison to lesions in mri performed at the end of the first - line therapy ( for t2 : 0.61 vs. 4.56 , p=0.0004 ; for gd+ : 0.13 vs. 1.98 , p=0.0009 ) . 
 no significant differences in the clinical data , mri results , and side effects between fingolimod and natalizumab patients have been observed.conclusionstreatment with natalizumab or fingolimod as a second - line therapy in rrms patients is safe and effective . 
 less restrictive criteria for switching should be considered .