***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: BACKGROUND Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis ( MS ) delays conversion to clinical ly definite MS ( CDMS ) . Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS . METHODS In the initial placebo-controlled phase of the double-blinded BENEFIT study , patients with a first event suggestive of MS and a minimum of two clinical ly silent lesions in MRI were r and omised to receive either interferon beta-1b 250 microg ( n=292 ) or placebo ( n=176 ) subcutaneously every other day for 2 years , or until diagnosis of CDMS . Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b . In the current prospect ively planned analysis 3 years after r and omisation , the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study . The primary outcomes of this ITT analysis were time to diagnosis of CDMS , time to confirmed exp and ed disability status scale ( EDSS ) progression , and score on a patient-reported functional assessment scale ( FAMS-TOI ) . This trial is registered with Clinical Trials.gov , number NCT00185211 . FINDINGS Of the 468 patients originally r and omised , 418 ( 89 % ) entered the follow-up phase ; 392 ( 84 % ) completed 3 years ' post-r and omisation follow-up . After 3 years , 99 ( 37 % ) patients in the early group developed CDMS compared with 85 ( 51 % ) patients in the delayed treatment group . Early treatment reduced the risk of CDMS by 41 % ( hazard ratio 0.59 , 95 % CI 0.44 - 0.80 ; p=0.0011 ; absolute risk reduction 14 % ) compared with delayed treatment . Over 3 years , 42 ( 16 % ) patients in the early group and 40 ( 24 % ) in the delayed group had confirmed EDSS progression ; early treatment reduced the risk for progression of disability by 40 % compared with delayed treatment ( 0.60 , 0.39 - 0.92 ; p=0.022 ; absolute risk reduction 8 % ) . The FAMS-TOI score was high and stable in both groups over the 3-year period ( p=0.31 ) . INTERPRETATION Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability , supporting its use after the first manifestation of relapsing-remitting MS Objective Early treatment following a first clinical demyelinating event ( FCDE ) delays further disease activity in patients with multiple sclerosis ( MS ) . This study determined the effects of early versus delayed treatment ( DT ) with subcutaneous interferon ( sc IFN ) β-1a 44 μg in patients with an FCDE up to 60 months postr and omisation . Methods Patients who completed the 24-month double-blind REFLEX ( REbif FLEXible dosing in early MS ) study entered an extension ( REFLEXION , REbif FLEXible dosing in early MS extensION ) : patients initially r and omised to sc IFN β-1a  and not reaching clinical ly definite MS ( clinical ly definite MS , CDMS ( second attack or sustained Exp and ed Disability Status Scale ( EDSS ) score increase ) ) continued original treatment ( three times weekly ( tiw ) or once weekly ( qw ) ) ; placebo patients switched to tiw ( DT ) ; patients with CDMS switched to tiw . Clinical , MRI and adverse event data up to month 60 are reported . Results 402/517 ( 77.8 % ) REFLEX patients  entered REFLEXION ( DT , n=133 ; tiw , n=127 ; qw , n=142 ) . At month 60 , cumulative probability of CDMS was : DT 44.6 % ; qw 40.7 % ( nominal p=0.084 vs DT ) ; tiw 39.2 % ( nominal p=0.032 vs DT ) . Cumulative probability of McDonald MS conversion ( CDMS or new MRI activity ) at month 60 was also reduced for tiw versus DT ( nominal p<0.001 ) . At month 60 , mean cumulative numbers of new T2 , gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN β-1a qw ( nominal p<0.05 ) and tiw versus DT ( nominal p<0.001 ) ; T2 and T1 hypointense lesion volume change was lower for sc IFN β-1a tiw versus DT ( nominal p<0.01 ) . Treatment was well tolerated ; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies . Conclusions Over 5 years in patients presenting with an FCDE , early sc IFN β-1a tiw administration versus DT prolonged time to CDMS and McDonald MS , and reduced overall MRI activity . Trial registration number NCT00813709 ; Results BACKGROUND Several studies have confirmed the predictive value of baseline and follow-up magnetic resonance ( MR ) imaging variables for conversion to clinical ly definite multiple sclerosis ( CDMS ) , depending on the population , follow-up duration , and treatment intervention . However , the timing of follow-up imaging and the effect of treatment intervention on the predictive value of baseline MR imaging variables require further elucidation . OBJECTIVES To assess the prognostic value of baseline MR imaging variables for conversion to CDMS over 3 years and whether this was affected by treatment intervention and ( 2 ) to assess the increased risk for conversion posed by dissemination in time on follow-up MR imaging . DESIGN Cohort study . SETTING Multicenter r and omized clinical trial . PATIENTS Four hundred sixty-eight patients with a clinical ly isolated syndrome who had an initial clinical demyelinating event within the past 60 days who received early treatment ( 3 years of interferon beta-1b ) or delayed treatment ( placebo first , followed by > or = 1 year of interferon beta-1b ) . Intervention Magnetic resonance imaging . Main Outcome Measure Time to CDMS . RESULTS The overall conversion rate to CDMS was 42 % . Barkhof criteria with the strongest prognostic value were the presence at baseline of at least 9 T2-weighted lesions ( hazard ratio [ HR ] , 1.64 ; 95 % confidence interval [ CI ] , 1.15 - 2.33 ; P = .006 ) and at least 3 periventricular lesions ( 1.66 ; 1.14 - 2.41 ; P = .009 ) . No specific advantage was noted in using a fixed cutoff of at least 3 Barkhof criteria ( HR , 1.31 ; 95 % CI , 0.95 - 1.79 ; P = .10 ) . The prognostic value of all MR imaging criteria was unaffected by treatment intervention ( P > or = .20 for all ) . Dissemination in time result ed in increased risk for CDMS only in patients without dissemination in space at baseline and was most informative at the 9-month MR imaging ( HR , 2.72 ; 95 % CI , 1.26 - 5.87 ; P = .01 ) . CONCLUSIONS The modified Barkhof criteria showed moderate predictive value for conversion to CDMS , although all patients had received interferon beta-1b therapy for at least 1 year . The predictive value was unaffected by treatment intervention . Follow-up MR imaging was most informative after 9 months in patients without dissemination in space at baseline Objective To examine the long-term impact of early treatment initiation of interferon beta-1b ( IFNB1b , Betaferon/Betaseron ) in patients with a first event suggestive of multiple sclerosis ( MS ) . Methods In the original placebo-controlled phase of BENEFIT , patients were r and omised to IFNB1b 250 μg or placebo subcutaneously every other day . After 2 years or diagnosis of clinical ly definite MS ( CDMS ) , all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years . Thereafter , patients were enrolled in an observational extension study for up to 8.7 years . Results Of the initial 468 patients , 284 ( 60.7 % ; IFNB1b : 178 ( 61.0 % of the original arm ) , placebo : 106 ( 60.2 % of original arm ) ) were enrolled in the extension study . 94.2 % of patients were receiving IFNB1b . Patients originally r and omised to IFNB1b had a reduced risk of developing CDMS by 32.2 % over the 8-year observation period ( HR 0.678 ; 95 % CI 0.525 to 0.875 ; p=0.0030 ) , a longer median time to CDMS by 1345 days ( 95 % CI 389 to 2301 ) , and a lower annualised relapse rate ( 0.196 ( 95 % CI 0.176 to 0.218 ) versus 0.255 ( 95 % CI 0.226 to 0.287 ) , p=0.0012 ) , with differences mainly emerging in the first year of the study . Cognitive outcomes remained higher in the early treated patients . EDSS remained low over time with a median of 1.5 in both arms . Conclusions These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS BACKGROUND Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes . We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis . METHODS We r and omly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets ( either 3.5 mg or 5.25 mg per kilogram of body weight ) or matching placebo , given in two or four short courses for the first 48 weeks , then in two short courses starting at week 48 and week 52 ( for a total of 8 to 20 days per year ) . The primary end point was the rate of relapse at 96 weeks . RESULTS Among patients who received cladribine tablets ( either 3.5 mg or 5.25 mg per kilogram ) , there was a significantly lower annualized rate of relapse than in the placebo group ( 0.14 and 0.15 , respectively , vs. 0.33 ; P<0.001 for both comparisons ) , a higher relapse-free rate ( 79.7 % and 78.9 % , respectively , vs. 60.9 % ; P<0.001 for both comparisons ) , a lower risk of 3-month sustained progression of disability ( hazard ratio for the 3.5-mg group , 0.67 ; 95 % confidence interval [ CI ] , 0.48 to 0.93 ; P=0.02 ; and hazard ratio for the 5.25-mg group , 0.69 ; 95 % CI , 0.49 to 0.96 ; P=0.03 ) , and significant reductions in the brain lesion count on magnetic resonance imaging ( MRI ) ( P<0.001 for all comparisons ) . Adverse events that were more frequent in the cladribine groups included lymphocytopenia ( 21.6 % in the 3.5-mg group and 31.5 % in the 5.25-mg group , vs. 1.8 % ) and herpes zoster ( 8 patients and 12 patients , respectively , vs. no patients ) . CONCLUSIONS Treatment with cladribine tablets significantly reduced relapse rates , the risk of disability progression , and MRI measures of disease activity at 96 weeks . The benefits need to be weighed against the risks . ( Clinical Trials.gov number , NCT00213135 . Natural history studies have identified factors that predict evolution to multiple sclerosis or risk of disability accumulation over time . Although these studies are based on large multicentre cohorts with long follow-ups , they have limitations such as lack of st and ardized protocol s , a retrospective data collection or lack of a systematic magnetic resonance imaging acquisition and analysis protocol , often result ing in failure to take magnetic resonance and oligoclonal b and s into account as joint covariates in the prediction models . To overcome some of these limitations , the aim of our study was to identify and stratify baseline demographic , clinical , radiological and biological characteristics that might predict multiple sclerosis development and disability accumulation using a multivariate approach based on a large prospect i ve cohort of patients with clinical ly isolated syndromes . From 1995 to 2013 , 1058 patients with clinical ly isolated syndromes were included . We evaluated the influence of baseline prognostic factors on the risk for developing clinical ly definite multiple sclerosis , McDonald multiple sclerosis , and disability accumulation ( Exp and ed Disability Status Scale score of 3.0 ) based on univariate ( hazard ratio with 95 % confidence intervals ) and multivariate ( adjusted hazard ratio with 95 % confidence intervals ) Cox regression models . We ultimately included 1015 patients followed for a mean of 81 ( st and ard deviation = 57 ) months . Female/male ratio was 2.1 . Females exhibited a similar risk of conversion to multiple sclerosis 
    Output:
    
We found no differences between the included drugs with respect to the hazard of conversion to CDMS .
Very low- quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses .
The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low- quality evidence .
Low- quality evidence suggests that the chances of relapse are less with early treatment compared with delayed .
Early treatment reduced the hazard of conversion to CDMS compared either with placebo , no treatment or delayed treatment , both in short- and long-term follow-up .
Low- quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo .
Very low- quality evidence suggests that , compared with placebo , early treatment leads to more withdrawals or treatment discontinuation due to AEs .