***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective : Interferon ( IFN ) beta has repeatedly shown benefit in multiple sclerosis ( MS ) in reducing the rate of relapse , the disease activity as shown with magnetic resonance imaging and , to some degree , the progression of disability ; however , it is unknown how much the therapeutic response depends on the dose , the subgroup involved , and the disease stage . This multicentre , double blind , placebo controlled study explored the dose−response curve by examining the clinical benefit of low dose IFN beta-1a ( Rebif ® ) , 22 μg subcutaneously once weekly , in patients with secondary progressive MS . Methods : A total of 371 patients with clinical ly definite SPMS were r and omised to receive either placebo or subcutaneous IFN beta-1a , 22 μg once weekly , for 3 years . Clinical assessment s were performed every 6 months . The primary outcome was time to sustained disability , as defined by time to first confirmed 1.0 point increase on the Exp and ed Disability Status Scale ( EDSS ) . Secondary outcomes included a sensitive disability measure and relapse rate . Results : Treatment had no beneficial effect on time to confirmed progression on either the EDSS ( hazard ratio ( HR ) = 1.13 ; 95 % confidence interval ( CI ) 0.82 to 1.57 ; p = 0.45 for 22 μg v placebo ) or the Regional Functional Status Scale ( HR = 0.93 ; 95 % CI 0.68 to 1.28 ; p = 0.67 ) . Other disability measures were also not significantly affected by treatment . Annual relapse rate was 0.27 with placebo and 0.25 with IFN ( rate ratio = 0.90 ; 95 % CI 0.64 to 1.27 ; p = 0.55 ) . The drug was well tolerated with no new safety concerns identified . No significant gender differences were noted . Conclusions : This patient population was less clinical ly active than SPMS population s studied in other trials . Treatment with low dose , IFN beta-1a ( Rebif ® ) once weekly did not show any benefit in this study for either disability or relapse outcomes , including a subgroup with preceding relapses . These results add a point at one extreme of the dose−response spectrum of IFN beta therapy in MS , indicating that relapses in this phase may need treatment with higher doses than in the initial phases Background : The recently completed placebo-controlled multicenter r and omized trial of interferon beta-1b ( Betaferon ) in 718 patients with secondary progressive MS shows significant delay of disease progression and reduction of relapse rate . This study provides an opportunity to assess the level of relationship between clinical and MRI outcomes in this cohort of patients with secondary progressive MS . Methods : Brain T2-weighted lesion volume was measured annually in all available patients , with visual analysis to identify any new or enlarging ( active ) T2 lesions at each annual time point . A subgroup of 125 patients had monthly gadolinium-enhanced , T1-weighted imaging  at months 0 to 6 and 18 to 24 . Relapses were documented and exp and ed disability status scale ( EDSS ) was measured every 3 months . Results : For the annual MRI outcomes , a significant but modest correlation was identified between the change in T2 lesion volume from baseline to the final scan and the corresponding change from baseline in EDSS ( r = 0.17 , p < 0.0001 ) . There were significant correlations between the cumulative number of active T2 lesions and 1 ) change in EDSS ( r = 0.18 , p < 0.0001 ) and 2 ) relapse rate ( r = 0.24 , p < 0.0001 ) . In the subgroup of 125 patients undergoing monthly imaging , MRI lesion activity was correlated with relapse rate over months 0 to 24 ( r = 0.24 , p = 0.006 ) but not with change in EDSS . Conclusions : These results confirm that the clinical –MRI relationships previously identified in relapsing-remitting MS still are apparent in the secondary progressive phase of the disease and support the use of MRI as a relevant outcome measure . In view of the relatively modest nature of the correlations , it seems unwise to rely on such MRI measures alone as primary efficacy variables in secondary progressive MS trials Recently , the clinical efficacy of interferon beta-1b ( IFNbeta-1b ) was demonstrated for secondary progressive ( SP ) multiple sclerosis in a European multicentre study . We evaluated the effect of IFNbeta-1b treatment on the rate of development of hypointense T(1 ) MRI lesions , a putative marker of axonal damage . Unenhanced T(1)-weighted images were obtained in a subgroup of 95 multiple sclerosis patients from five centres at 6-month intervals ; this subgroup was similar to the total study population for all demographic , clinical and MRI parameters . An experienced observer blinded to the clinical data and treatment allocation measured volumes . The median baseline lesion load for hypointense T(1 ) lesions was 5.1 cm(3 ) for placebo-treated and 4.9 cm(3 ) for IFNbeta-1b-treated patients ( P = 0.56 ) . Placebo-treated patients showed an increase in T(1 ) lesion load by a median of 14 % per year ( P = 0.0002 compared with baseline ) ; this was reduced to 7.7 % per year in the IFNbeta-1b-treated patients ( P = 0.003 versus placebo ) . In the IFNbeta-1b arm there was a statistically significant correlation between absolute change in Exp and ed Disability Status Scale scores and T(1 ) lesion load by month 36 ( r = 0.38 , P = 0.0015 ) . In patients with SP multiple sclerosis , IFNbeta-1b treatment reduces the development of hypointense T(1 ) lesions , suggesting that reduced axonal damage in lesions may play a part in the beneficial effect that is observed clinical ly Several phase III studies have proven that the beta-interferons have positive effects on the number and severity of acute exacerbations of relapsing remitting multiple sclerosis . Recently the first study on the effectiveness of interferon beta-1b in secondary progressive multiple sclerosis was published . In a multicenter , double-blind , r and omized , Placebo-controlled study 718 patients with secondary progressive multiple sclerosis and an exp and ed disability status scale ( EDSS ) value between 3.0 and 6.5 were treated with either 8 Mio.interferon beta-1b or Placebo subcutaneously every second day for two to three years . The primary study end-point was the time until confirmed progression of the disease as signified by a one point increase of the EDSS value ( for initial EDSS values between 3.0 and 5.5 ) or 0.5 point increase when the initial EDSS value was between 6.0 and 6.5 . After two years an interim analysis showed a highly significant difference in delay of disease progression by nine to twelve months for the treatment group ( p = 0.0008 ) . This means that interferon beta-1b is the first recombinant beta-interferon to be shown effective in the treatment of secondary progressive multiple sclerosis Abstract Combination therapy may benefit the subgroup of patients with secondary progressive multiple sclerosis ( SPMS ) who do not respond to interferon beta ( IFNB ) . We performed a two-year study of azathioprine ( AZA ) combined with IFNB-1b in SPMS patients who had not responded well to IFNB-1b alone . Patients with SPMS were eligible for this non-controlled prospect i ve study if they had two or more relapses requiring corticosteroid treatment or deteriorated by at least 0.5 points on the Exp and ed Disability Status Scale ( EDSS ) while on IFNB-1b in the year preceeding the study . Patients were to continue treatment with IFNB-1b ( 8 MIU qod , subcutaneous ) and received AZA ( 50 mg tid , oral ) . Safety was assessed in terms of adverse reactions and laboratory measures grade d according to the WHO toxicity scale . Efficacy was explored by changes in relapse rate , EDSS , 9-hole peg test ( 9-HPT ) , neuropsychological scores , and magnetic resonance imaging ( MRI ) results . Neutralizing antibodies ( NAB ) were measured . Ten SPMS patients ( 6 females ) with a median EDSS score of 4.5 were enrolled . One patient withdrew because of gastrointestinal complaints , one was withdrawn owing to poor compliance , and 8 patients completed therapy . The only frequent side effect was lymphopenia , reported at least once in all patients . Annual relapse rate was reduced by approximately 50 % in the second year . There was a significant trend for EDSS increase . Total lesion load measured by MRI decreased at 12 and 24 months ; only one patient had active lesions . No changes were seen in the 9-HPT . There was a significant improvement in neuropsychological tests after 24 months ( p = 0.045 ) . One patient tested positive for NAB throughout the study , and transient NAB were detected in 4 patients . In conclusion , combination therapy with IFNB-1b and AZA was safe and generally well tolerated in patients with SPMS . Strict clinical and laboratory monitoring is recommended during this combination therapy Background Evidence for efficacy of disease-modifying drugs in multiple sclerosis ( MS ) comes from trials of short duration . We report results from a 16 y , retrospective follow-up of the pivotal interferon β-1b ( IFNB-1b ) study . Methods The 372 trial patients were r and omly assigned to placebo ( n=123 ) , IFNB-1b 50 μg ( n=125 ) or IFNB-1b 250 μg ( n=124 ) subcutaneously every other day for at least 2 y. Some remained r and omised for up to 5 y but , subsequently , patients received treatment according to physicians ' discretion . Patients were re-contacted and asked to participate . Efficacy related measures included MRI parameters , relapse rate , the Exp and ed Disability Status Scale , the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS . Results Of the 88.2 % ( 328/372 ) of patients who were identified , 69.9 % ( 260/372 ) had available case report forms . No differences in outcome between original r and omisation groups could be discerned using st and ard disability and MRI measures . However , mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group ( 18.3 % ( 20/109 ) for placebo versus 8.3 % ( 9/108 ) for IFNB-1b 50 μg and 5.4 % ( 6/111 ) for IFNB-1b 250 μg ) . Conclusions The original treatment assignment could not be shown to influence st and ard assessment s of long-term efficacy . On- study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of r and omisation and blinding . Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 μg or 250 μg . The data set provides important re sources to explore early predictors of long-term outcome This manuscript describes the outline of a double-blind , placebo-controlled , ( European ) , multicentre phase III study to evaluate the safety and efficacy of 8 MIU of interferon beta-Ib given subcutaneously every other day for 3 years in patients with secondary progressive multiple sclerosis . The primary efficacy variable of this trial is the time to confirmed neurological deterioration as documented by the Exp and ed Disability Status Scale . The essentials of the study design are presented , including the rationale for the performance of the study and the selection of both clinical and magnetic resonance imaging outcome parameters Objective : To investigate the relationship between neutralizing antibodies ( NAB ) and disease progression , relapses , and MR measures of MS . Methods : Sequential serum sample s from all 718 patients of the European Study Group in Interferon β-1b in Secondary Progressive MS were analyzed to investigate relations between NAB and disease progression , relapses , and MR measures . Results : This study showed no attenuating effect of NAB development on progression in disability . The effects of NAB on relapse rate showed substantial variation , depending on the statistical approach and definition of positivity , though analyses comparing low- and high-NAB+ periods with NAB− periods suggested a titer-related effect . MR T2 lesion volume changes from baseline were significantly higher for NAB+ patients but remained lower than for placebo patients . A substantial proportion of NAB+ patients became NAB−. No untoward effect of NAB development on safety was observed . Conclusion : These results support the conclusion that even though high NAB titers appear to have impact on treatment efficacy with respect to relapses , treatment decisions should be based primarily on clinical grounds Objective : To determine the percentage of patients with residual deficits following multiple sclerosis ( MS ) exacerbations and the magnitude of those deficits using a data base of pooled placebo patients from clinical trials . Methods : A data base of patients assigned to the placebo group in several r and omized clinical trials was queried to determine those patients with Exp and ed Disability Status Scale ( EDSS ) and Scripps Neurologic Rating Scale assessment s prior to , at the time of , and after an acute exacerbation of MS . The extent of deficit present at these time points was compared to determine the acute effect of exacerbations and the degree of persistent disability . Results : Forty-two percent of patients had residual deficit of at least 0.5 and 28 % had residual of ≥1.0 EDSS units , at an average of 64 days after an exacerbation . The results were reproduced across subsequent exacerbations and were sustained over 
    Output:
    
The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging ( MRI ) , performed in subgroups of patients ; in spite of no effect on progression , the radiological data supported an effect on MRI parameters .
The safety profile reflects what is commonly reported in MS IFN-treated patients .
Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS .
We were unable to verify the effect on cognitive function for the lack of comparable data .
This treatment significantly reduces the risk of relapse and of short -term relapse-related disability .
Overall , these results show that IFNs ' anti-inflammatory effect is unable to retard progression , when established .
We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS