human
***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 Anti-tumour necrosis factor alpha ( TNF-alpha ) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis ( RA ) , and on theoretical grounds large differences in the effective dose between patients can be expected . Together with the high costs , these differences warrant new approaches to the way patients are dosed . METHODS We used the Disease Activity Score ( DAS28 ) , a composite disease activity index , to titrate the dose of anti-TNF-alpha ( adalimumab , D2E7 ; Knoll ) in 21 patients with low disease activity in an open extension study lasting 40 weeks . The dose of anti-TNF-alpha was reduced stepwise and dosing intervals were kept stable . Disease activity and flares were assessed using the DAS28 . Patients who flared received the previous effective dose . RESULTS Dose reduction was accomplished in 15 patients . The total amount of anti-TNF-alpha  given to the patients was reduced by 67 % . At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA . CONCLUSION Dose titration of anti-TNF-alpha treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy . This approach will save costs and possibly prevent long-term side-effects Background The aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept ( ETN ) dose maintenance , reduction or withdrawal on patients with rheumatoid arthritis ( RA ) who had already achieved stable low disease activity ( LDA ) on ETN 50 mg+methotrexate ( MTX ) .  Methods Patients with RA ( n=91 ) and stable LDA with ETN 50 mg once weekly (QW)+MTX were included . After 8 weeks with unchanged treatment , 73 patients were r and omised in a double-blind design to ETN 50 mg QW+MTX ( ETN50 ) , ETN 25 mg QW+MTX ( ETN25 ) or placebo QW+MTX ( PBO ) for 48 weeks . Patients who flared were declared failures and treated with open-label ETN50 until week 48 . The primary outcome was the proportion of patients on ETN50 versus PBO who were non-failures after 48 weeks . Results The proportion of non-failure patients was significantly lower with ETN50 ( 52 % ; p=0.007 ) and ETN25 ( 44 % ; p=0.044 ) versus PBO ( 13 % ) . Median time to failure was significantly shorter with PBO ( 6 weeks ) compared with ETN50 ( 48 weeks ; p=0.001 ) and ETN25 ( 36 weeks ; p<0.001 ) . The majority of patients who flared regained LDA with open-label ETN50 quickly . Adverse events were consistent with the known side effect profiles of these medications . Conclusions In patients with established RA who have achieved stable LDA on ETN50+MTX , continuing both is superior to PBO+MTX . Reduced dose ETN was also more effective than PBO in maintaining a favourable response , suggesting that a maintenance strategy with reduced dose ETN may be possible in a number of patients with established RA . Trial registration number NCT00858780 Objectives To investigate the possibility of discontinuing adalimumab ( ADA ) for 1 year without flaring ( DAS28-erythrocyte sedimentation rate ( ESR ) ≥3.2 ) , and to identify factors enabling established patients with rheumatoid arthritis ( RA ) to remain ADA-free . Methods Of 197 RA patients treated with ADA+methotrexate ( MTX ) , 75 patients who met the ADA-free criteria ( steroid-free and sustained DAS28-ESR remission for 6 months with stable MTX doses ) were studied for 1 year . Results The mean disease duration and DAS28-ESR score in 75 patients was 7.5 years and 5.1 at baseline , respectively . The proportion of patients who sustained DAS28-ESR < 2.6 ( 48 % ) and DAS28-ESR < 3.2 ( 62 % ) for 1 year were significantly lower in the ADA discontinuation group than in the ADA continuation group ; however , in patients with deep remission ( DAS28-ESR ≤1.98 ) identified by receiver operating characteristics analysis following logistic analysis , these rates increased to 68 % and 79 % , respectively , with no significant difference between both groups . Remarkably , ADA readministration to patients with flare was effective in returning DAS28-ESR to < 3.2 within 6 months in 90 % and 9 months in 100 % patients ; among the patients who sustained DAS28-ESR < 3.2 during ADA discontinuation , 100 % remained in structural remission and 94 % in functional remission . Conclusions The possibility of remaining ADA-free for 1 year was demonstrated in established patients with RA with outcomes that ADA can be discontinued without flaring in 79 % patients with deep remission , with similar rates in the ADA continuation group , and showed no functional or structural damage in patients with DAS28-ESR < 3.2 . ADA readministration to patients with flare during ADA discontinuation was effective Objective To prospect ively analyse the risk for disease relapses in patients with rheumatoid arthritis ( RA ) in sustained remission , either continuing , tapering or stopping disease-modifying antirheumatic drugs ( DMARDs ) in a prospect i ve r and omised controlled trial . Methods Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre , r and omised controlled , parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and /or biological DMARDs in patients with RA in stable remission . Patients ( disease activity score 28 (DAS28)<2.6 for least 6 months ) were r and omised into three arms , either continuing DMARDs ( arm 1 ) , tapering DMARDs by 50 % ( arm 2 ) or stopping DMARDs after 6 months tapering ( arm 3 ) . The primary endpoint was sustained remission during 12 months . Results In this interim analysis , the first 101 patients who completed the study were analysed . At baseline , all patients fulfilled DAS28 remission  and 70 % also American College of Rheumatology- European League Against Rheumatism Boolean remission . 82.2 % of the patients received methotrexate , 40.6 % biological DMARDs and 9.9 % other DMARDs . Overall , 67 patients ( 66.3 % ) remained in remission for 12 months , whereas 34 patients ( 33.7 % ) relapsed . The incidence of relapses was related to study arms ( p=0.007 ; arm 1 : 15.8 % ; arm 2 : 38.9 % ; arm 3 : 51.9 % ) . Multivariate logistic regression identified anticitrullinated protein antibodies ( ACPA ) positivity ( p=0.038 ) and treatment reduction ( in comparison to continuation ) as predictors for relapse ( arm 2 : p=0.012 ; arm 3 : p=0.003 ) . Conclusions This r and omised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment . Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA . Trial registration number 2009 - 015740 - 42 Objective To investigate the long-term effects of induction therapy with adalimumab ( ADA ) plus methotrexate ( MTX ) in comparison with placebo ( PBO ) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis ( RA ) . Methods Patients with active early RA ( disease duration of ≤12 months ) were r and omly assigned to receive 40 mg ADA subcutaneously every other week ( eow ) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks . Thereafter , all patients received MTX monotherapy up to week 48 . The primary outcome was the Disease Activity Score 28 ( DAS28 ) at week 48 . Secondary outcomes included proportions of patients in remission ( DAS28<2.6 ) , ACR responses , Health Assessment Question naire ( HAQ ) score and radiographic progression . Results 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX . At baseline , DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups . At week 24 , treatment with ADA/MTX compared with PBO/MTX result ed in a greater reduction in DAS28 ( 3.0±1.2 vs 3.6±1.4 ; p=0.009 ) and other secondary outcomes such as DAS28 remission rate ( 47.9 % vs 29.5 % ; p=0.021 ) and HAQ ( 0.49±0.6 vs 0.72±0.6 ; p=0.0014 ) . At week 48 , the difference in clinical outcomes between groups was not statistically significant ( DAS28 : 3.2±1.4 vs 3.4±1.6 ; p=0.41 ) . Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX ( Sharp/van der Heijde score : ADA/MTX 2.6 vs PBO/MTX 6.4 ; p=0.03 , Ratingen score : 1.7 vs 4.2 ; p=0.01 ) . Conclusions A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48 , even after discontinuation of ADA treatment at week 24 . This sustained effect was not found at the primary endpoint ( DAS28 reduction ) OBJECTIVE To ascertain whether a 1-year remission induction therapy with an infliximab-MTX ( INF-MTX ) combination in patients with early RA provided sustained benefit after INF cessation compared with conventional treatment . METHODS Twenty patients with poor prognosis RA of < 1 year of disease duration were r and omized to receive either INF and MTX or placebo infusions and MTX for 1 year . They then stepped down to MTX monotherapy and were treated according to st and ard clinical care . After 8 years , disease activity , function and quality of life ( QoL ) data were collected . RESULTS At follow-up , data were available for 18 patients ( 1 in each group had died ) . Median 28-joint DAS was significantly lower in the INF-MTX group compared with placebo-MTX group ( 2.7 vs 4.3 , P = 0.02 ) . Four patients in the INF-MTX group were in remission vs none in the placebo-MTX group . One patient in the INF-MTX group achieved drug-free remission . Both RAQoL and HAQ median scores were lower in the INF-MTX group ; however , this did not reach statistical significance ( median RAQoL 3 vs 8 , P = 0.18 ; median HAQ 1.0 vs 1.5 , P = 0.12 ) . CONCLUSION A remission induction regime with an INF-MTX combination for 1 year in early RA can improve long-term clinical outcomes . Larger studies will be required to confirm the implication s of these findings OBJECTIVE To evaluate the efficacy , pharmacokinetics , immunogenicity , and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody ( cA2 ) ( infliximab ; Remicade , Centocor , Malvern , PA ) given alone or in combination with low-dose methotrexate ( MTX ) in rheumatoid arthritis ( RA ) patients . METHODS In a 26-week , double-blind , placebo-controlled , multicenter trial , 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were r and omized to 1 of 7 groups of 14 - 15 patients each . The patients received either intravenous cA2 at 1 , 3 , or 10 mg/kg , with or without MTX 7.5 mg/week , or intravenous placebo plus MTX 7.5 mg/week at weeks 0 , 2 , 6 , 10 , and 14 and were followed up through week 26 . RESULTS Approximately 60 % of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20 % Paulus criteria for response to treatment , for a median duration of 10.4 to > 18.1 weeks ( P < 0.001 versus placebo ) . Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 ( median duration 2.6 weeks ; P=0.126 versus placebo ) . However , coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic , prolonging 
    Output:
    
agent
***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 Anti-tumour necrosis factor alpha ( TNF-alpha ) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis ( RA ) , and on theoretical grounds large differences in the effective dose between patients can be expected . Together with the high costs , these differences warrant new approaches to the way patients are dosed . METHODS We used the Disease Activity Score ( DAS28 ) , a composite disease activity index , to titrate the dose of anti-TNF-alpha ( adalimumab , D2E7 ; Knoll ) in 21 patients with low disease activity in an open extension study lasting 40 weeks . The dose of anti-TNF-alpha was reduced stepwise and dosing intervals were kept stable . Disease activity and flares were assessed using the DAS28 . Patients who flared received the previous effective dose . RESULTS Dose reduction was accomplished in 15 patients . The total amount of anti-TNF-alpha  given to the patients was reduced by 67 % . At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA . CONCLUSION Dose titration of anti-TNF-alpha treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy . This approach will save costs and possibly prevent long-term side-effects Background The aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept ( ETN ) dose maintenance , reduction or withdrawal on patients with rheumatoid arthritis ( RA ) who had already achieved stable low disease activity ( LDA ) on ETN 50 mg+methotrexate ( MTX ) .  Methods Patients with RA ( n=91 ) and stable LDA with ETN 50 mg once weekly (QW)+MTX were included . After 8 weeks with unchanged treatment , 73 patients were r and omised in a double-blind design to ETN 50 mg QW+MTX ( ETN50 ) , ETN 25 mg QW+MTX ( ETN25 ) or placebo QW+MTX ( PBO ) for 48 weeks . Patients who flared were declared failures and treated with open-label ETN50 until week 48 . The primary outcome was the proportion of patients on ETN50 versus PBO who were non-failures after 48 weeks . Results The proportion of non-failure patients was significantly lower with ETN50 ( 52 % ; p=0.007 ) and ETN25 ( 44 % ; p=0.044 ) versus PBO ( 13 % ) . Median time to failure was significantly shorter with PBO ( 6 weeks ) compared with ETN50 ( 48 weeks ; p=0.001 ) and ETN25 ( 36 weeks ; p<0.001 ) . The majority of patients who flared regained LDA with open-label ETN50 quickly . Adverse events were consistent with the known side effect profiles of these medications . Conclusions In patients with established RA who have achieved stable LDA on ETN50+MTX , continuing both is superior to PBO+MTX . Reduced dose ETN was also more effective than PBO in maintaining a favourable response , suggesting that a maintenance strategy with reduced dose ETN may be possible in a number of patients with established RA . Trial registration number NCT00858780 Objectives To investigate the possibility of discontinuing adalimumab ( ADA ) for 1 year without flaring ( DAS28-erythrocyte sedimentation rate ( ESR ) ≥3.2 ) , and to identify factors enabling established patients with rheumatoid arthritis ( RA ) to remain ADA-free . Methods Of 197 RA patients treated with ADA+methotrexate ( MTX ) , 75 patients who met the ADA-free criteria ( steroid-free and sustained DAS28-ESR remission for 6 months with stable MTX doses ) were studied for 1 year . Results The mean disease duration and DAS28-ESR score in 75 patients was 7.5 years and 5.1 at baseline , respectively . The proportion of patients who sustained DAS28-ESR < 2.6 ( 48 % ) and DAS28-ESR < 3.2 ( 62 % ) for 1 year were significantly lower in the ADA discontinuation group than in the ADA continuation group ; however , in patients with deep remission ( DAS28-ESR ≤1.98 ) identified by receiver operating characteristics analysis following logistic analysis , these rates increased to 68 % and 79 % , respectively , with no significant difference between both groups . Remarkably , ADA readministration to patients with flare was effective in returning DAS28-ESR to < 3.2 within 6 months in 90 % and 9 months in 100 % patients ; among the patients who sustained DAS28-ESR < 3.2 during ADA discontinuation , 100 % remained in structural remission and 94 % in functional remission . Conclusions The possibility of remaining ADA-free for 1 year was demonstrated in established patients with RA with outcomes that ADA can be discontinued without flaring in 79 % patients with deep remission , with similar rates in the ADA continuation group , and showed no functional or structural damage in patients with DAS28-ESR < 3.2 . ADA readministration to patients with flare during ADA discontinuation was effective Objective To prospect ively analyse the risk for disease relapses in patients with rheumatoid arthritis ( RA ) in sustained remission , either continuing , tapering or stopping disease-modifying antirheumatic drugs ( DMARDs ) in a prospect i ve r and omised controlled trial . Methods Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre , r and omised controlled , parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and /or biological DMARDs in patients with RA in stable remission . Patients ( disease activity score 28 (DAS28)<2.6 for least 6 months ) were r and omised into three arms , either continuing DMARDs ( arm 1 ) , tapering DMARDs by 50 % ( arm 2 ) or stopping DMARDs after 6 months tapering ( arm 3 ) . The primary endpoint was sustained remission during 12 months . Results In this interim analysis , the first 101 patients who completed the study were analysed . At baseline , all patients fulfilled DAS28 remission  and 70 % also American College of Rheumatology- European League Against Rheumatism Boolean remission . 82.2 % of the patients received methotrexate , 40.6 % biological DMARDs and 9.9 % other DMARDs . Overall , 67 patients ( 66.3 % ) remained in remission for 12 months , whereas 34 patients ( 33.7 % ) relapsed . The incidence of relapses was related to study arms ( p=0.007 ; arm 1 : 15.8 % ; arm 2 : 38.9 % ; arm 3 : 51.9 % ) . Multivariate logistic regression identified anticitrullinated protein antibodies ( ACPA ) positivity ( p=0.038 ) and treatment reduction ( in comparison to continuation ) as predictors for relapse ( arm 2 : p=0.012 ; arm 3 : p=0.003 ) . Conclusions This r and omised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment . Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA . Trial registration number 2009 - 015740 - 42 Objective To investigate the long-term effects of induction therapy with adalimumab ( ADA ) plus methotrexate ( MTX ) in comparison with placebo ( PBO ) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis ( RA ) . Methods Patients with active early RA ( disease duration of ≤12 months ) were r and omly assigned to receive 40 mg ADA subcutaneously every other week ( eow ) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks . Thereafter , all patients received MTX monotherapy up to week 48 . The primary outcome was the Disease Activity Score 28 ( DAS28 ) at week 48 . Secondary outcomes included proportions of patients in remission ( DAS28<2.6 ) , ACR responses , Health Assessment Question naire ( HAQ ) score and radiographic progression . Results 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX . At baseline , DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups . At week 24 , treatment with ADA/MTX compared with PBO/MTX result ed in a greater reduction in DAS28 ( 3.0±1.2 vs 3.6±1.4 ; p=0.009 ) and other secondary outcomes such as DAS28 remission rate ( 47.9 % vs 29.5 % ; p=0.021 ) and HAQ ( 0.49±0.6 vs 0.72±0.6 ; p=0.0014 ) . At week 48 , the difference in clinical outcomes between groups was not statistically significant ( DAS28 : 3.2±1.4 vs 3.4±1.6 ; p=0.41 ) . Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX ( Sharp/van der Heijde score : ADA/MTX 2.6 vs PBO/MTX 6.4 ; p=0.03 , Ratingen score : 1.7 vs 4.2 ; p=0.01 ) . Conclusions A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48 , even after discontinuation of ADA treatment at week 24 . This sustained effect was not found at the primary endpoint ( DAS28 reduction ) OBJECTIVE To ascertain whether a 1-year remission induction therapy with an infliximab-MTX ( INF-MTX ) combination in patients with early RA provided sustained benefit after INF cessation compared with conventional treatment . METHODS Twenty patients with poor prognosis RA of < 1 year of disease duration were r and omized to receive either INF and MTX or placebo infusions and MTX for 1 year . They then stepped down to MTX monotherapy and were treated according to st and ard clinical care . After 8 years , disease activity , function and quality of life ( QoL ) data were collected . RESULTS At follow-up , data were available for 18 patients ( 1 in each group had died ) . Median 28-joint DAS was significantly lower in the INF-MTX group compared with placebo-MTX group ( 2.7 vs 4.3 , P = 0.02 ) . Four patients in the INF-MTX group were in remission vs none in the placebo-MTX group . One patient in the INF-MTX group achieved drug-free remission . Both RAQoL and HAQ median scores were lower in the INF-MTX group ; however , this did not reach statistical significance ( median RAQoL 3 vs 8 , P = 0.18 ; median HAQ 1.0 vs 1.5 , P = 0.12 ) . CONCLUSION A remission induction regime with an INF-MTX combination for 1 year in early RA can improve long-term clinical outcomes . Larger studies will be required to confirm the implication s of these findings OBJECTIVE To evaluate the efficacy , pharmacokinetics , immunogenicity , and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody ( cA2 ) ( infliximab ; Remicade , Centocor , Malvern , PA ) given alone or in combination with low-dose methotrexate ( MTX ) in rheumatoid arthritis ( RA ) patients . METHODS In a 26-week , double-blind , placebo-controlled , multicenter trial , 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were r and omized to 1 of 7 groups of 14 - 15 patients each . The patients received either intravenous cA2 at 1 , 3 , or 10 mg/kg , with or without MTX 7.5 mg/week , or intravenous placebo plus MTX 7.5 mg/week at weeks 0 , 2 , 6 , 10 , and 14 and were followed up through week 26 . RESULTS Approximately 60 % of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20 % Paulus criteria for response to treatment , for a median duration of 10.4 to > 18.1 weeks ( P < 0.001 versus placebo ) . Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 ( median duration 2.6 weeks ; P=0.126 versus placebo ) . However , coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic , prolonging 
    Output:
    