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: Background Preliminary , mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with RA without loss of disease control . However , long term safety , cost effectiveness and feasibility in clinical practice remain uncertain . Methods / Design This study is a 18-months pragmatic , non-inferiority , cost minimalisation , r and omized controlled trial on dose reduction and discontinuation of the subcutaneous tumour necrosis factor ( TNF ) blockers adalimumab and etanercept in RA patients with low disease activity . 180 RA patients with low disease activity ( DAS28 < 3.2 or clinical judgment of the rheumatologist ) are r and omized 2:1 to either increased spacing and eventually discontinuation after 6 months of the TNF blocker , and usual care . Implementation is done in routine daily care , using treat to target and feedback implementation in both treatment arms . The primary outcome is non-inferiority ( NI margin 20 % ) in cumulative incidence of persistent ( > 3 months ) RA flare , according to a recently vali date d DAS28 based flare criterion ( DAS28 change > 1.2 , or DAS28 increase of 0.6 and current DAS28 ≥ 3.2 ) . Secondary outcomes include mean disease activity , function , radiographic progression , safety and cost effectiveness . Cost per quality adjusted life year ( QALY ) differences between groups are expressed as a decremental cost effectiveness ratio ( DCER ) , i.e. saved costs divided by ( possible ) loss in QALY . Discussion The design of this study targeted several clinical and method ological issues on TNF blocker dose de-escalation , including how to taper the TNF blockers , the satisfactory control condition , how to define flare , implementation in clinical practice , and the choice of the non-inferiority margin . Pragmatic cost minimalisation studies using non-inferiority design s and DCERs will become more mainstream as cost effectiveness in healthcare gains importance .Trial registration Dutch Trial Register NTR3216 , The study has received ethical review board approval ( number NL37704.091.11 Objective To compare the effectiveness , safety and costs of st and ard versus individually tailored reduced doses of anti-tumour necrosis factor ( TNF ) drugs in patients with ankylosing spondylitis ( AS ) after achieving low-disease activity . Methods This was a single-centre prospect i ve observational study performed within the ATTRA registry . The anti-TNF dose tapering strategy was chosen by treating physicians , without prespecified protocol . We used propensity score ( PS ) methodology to identify two cohorts of patients matched for relevant baseline characteristics who were treated with either reduced ( n=53 ) or st and ard ( n=83 ) doses of TNF inhibitors .  One-year outcomes and costs of anti-TNF drugs  were compared between both PS-matched cohorts . Results In the reduced dosing group , the median dose of TNF inhibitor corresponded to 0.67 and 0.5 of the st and ard dose initially and at 12 months respectively , and 21 % of patients required return to st and ard dosing regimen . The mean change per year in Bath Ankylosing Spondylitis Activity Index , C-reactive protein , Health Assessment Question naire Disability Index and Bath AS functional index , as well as quality -adjusted life-year area under the curve were no different between both groups . The HR ( 95 % CI ) of reduced versus st and ard dosing group for relapse and any adverse event was 1.46 ( 0.66 to 3.19 ) and 0.56 ( 0.22 to 1.44 ) , respectively . Mean difference ( 95 % CI ) in cost of anti-TNF drugs  was € −4214 ( −4707 to −3701 ) per year of treatment in favour of reduced dosing strategy . Conclusions In patients with AS after reaching low-disease activity , a tailored approach to reduce doses of anti-TNF drugs produced similar clinical outcomes at 1 year , but was substantially less costly 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 ) Objectives To assess the effect of a temporary interruption in subcutaneous ( SC ) abatacept on immunogenicity , safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial . Methods Following a 12-week open-label introduction ( period I ; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg ) , patients were r and omised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks ( period II ) . At the end of period II , patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept ( 12-week open-label period III ) . The co- primary end points were ELISA-detected immunogenicity rate and safety at the end of period II . Efficacy was also monitored . Results Of 167 patients entering period I , 72 % qualified for period II ; during periods II and III , three patients discontinued treatment . Mean ( SD ) disease duration was 6.6 ( 6.5 ) years and Disease Activity Score 28 was 4.8 ( 0.8 ) . The primary end point was met , with a non-significant increase in immunogenicity upon withdrawal ( 7/73 placebo vs 0/38 abatacept in period II ; p=0.119 ) which was reversed upon re introduction of SC abatacept ( 2/73 vs 1/38 , end period III ) . Safety was comparable regardless of withdrawal , with no unexpected events upon re introduction . Two patients experienced reactions at the SC injection site . On withdrawal , patients experienced slight worsening in efficacy which improved following re introduction . Conclusions Overall immunogenicity to SC abatacept is low , consistent with intravenous abatacept , and is not significantly affected by a 3-month interruption and re introduction . This stop – start schedule was well tolerated , with little impact on safety and efficacy . These are important considerations for the clinical use of SC abatacept . Clinical Trials gov Identifier Objective To assess the efficacy and safety of tocilizumab ( TCZ ) plus methotrexate/placebo ( MTX/PBO ) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission . Methods ACT-RAY was a double-blind 3-year trial . Patients with active rheumatoid arthritis despite MTX were r and omised to add  TCZ  to ongoing MTX  ( add-on strategy ) or switch to  TCZ plus PBO  ( switch strategy ) . Using a treat-to-target approach , open-label conventional synthetic disease-modifying antirheumatic drugs ( csDMARDs ) , other than MTX , were added 
    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: Background Preliminary , mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with RA without loss of disease control . However , long term safety , cost effectiveness and feasibility in clinical practice remain uncertain . Methods / Design This study is a 18-months pragmatic , non-inferiority , cost minimalisation , r and omized controlled trial on dose reduction and discontinuation of the subcutaneous tumour necrosis factor ( TNF ) blockers adalimumab and etanercept in RA patients with low disease activity . 180 RA patients with low disease activity ( DAS28 < 3.2 or clinical judgment of the rheumatologist ) are r and omized 2:1 to either increased spacing and eventually discontinuation after 6 months of the TNF blocker , and usual care . Implementation is done in routine daily care , using treat to target and feedback implementation in both treatment arms . The primary outcome is non-inferiority ( NI margin 20 % ) in cumulative incidence of persistent ( > 3 months ) RA flare , according to a recently vali date d DAS28 based flare criterion ( DAS28 change > 1.2 , or DAS28 increase of 0.6 and current DAS28 ≥ 3.2 ) . Secondary outcomes include mean disease activity , function , radiographic progression , safety and cost effectiveness . Cost per quality adjusted life year ( QALY ) differences between groups are expressed as a decremental cost effectiveness ratio ( DCER ) , i.e. saved costs divided by ( possible ) loss in QALY . Discussion The design of this study targeted several clinical and method ological issues on TNF blocker dose de-escalation , including how to taper the TNF blockers , the satisfactory control condition , how to define flare , implementation in clinical practice , and the choice of the non-inferiority margin . Pragmatic cost minimalisation studies using non-inferiority design s and DCERs will become more mainstream as cost effectiveness in healthcare gains importance .Trial registration Dutch Trial Register NTR3216 , The study has received ethical review board approval ( number NL37704.091.11 Objective To compare the effectiveness , safety and costs of st and ard versus individually tailored reduced doses of anti-tumour necrosis factor ( TNF ) drugs in patients with ankylosing spondylitis ( AS ) after achieving low-disease activity . Methods This was a single-centre prospect i ve observational study performed within the ATTRA registry . The anti-TNF dose tapering strategy was chosen by treating physicians , without prespecified protocol . We used propensity score ( PS ) methodology to identify two cohorts of patients matched for relevant baseline characteristics who were treated with either reduced ( n=53 ) or st and ard ( n=83 ) doses of TNF inhibitors .  One-year outcomes and costs of anti-TNF drugs  were compared between both PS-matched cohorts . Results In the reduced dosing group , the median dose of TNF inhibitor corresponded to 0.67 and 0.5 of the st and ard dose initially and at 12 months respectively , and 21 % of patients required return to st and ard dosing regimen . The mean change per year in Bath Ankylosing Spondylitis Activity Index , C-reactive protein , Health Assessment Question naire Disability Index and Bath AS functional index , as well as quality -adjusted life-year area under the curve were no different between both groups . The HR ( 95 % CI ) of reduced versus st and ard dosing group for relapse and any adverse event was 1.46 ( 0.66 to 3.19 ) and 0.56 ( 0.22 to 1.44 ) , respectively . Mean difference ( 95 % CI ) in cost of anti-TNF drugs  was € −4214 ( −4707 to −3701 ) per year of treatment in favour of reduced dosing strategy . Conclusions In patients with AS after reaching low-disease activity , a tailored approach to reduce doses of anti-TNF drugs produced similar clinical outcomes at 1 year , but was substantially less costly 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 ) Objectives To assess the effect of a temporary interruption in subcutaneous ( SC ) abatacept on immunogenicity , safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial . Methods Following a 12-week open-label introduction ( period I ; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg ) , patients were r and omised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks ( period II ) . At the end of period II , patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept ( 12-week open-label period III ) . The co- primary end points were ELISA-detected immunogenicity rate and safety at the end of period II . Efficacy was also monitored . Results Of 167 patients entering period I , 72 % qualified for period II ; during periods II and III , three patients discontinued treatment . Mean ( SD ) disease duration was 6.6 ( 6.5 ) years and Disease Activity Score 28 was 4.8 ( 0.8 ) . The primary end point was met , with a non-significant increase in immunogenicity upon withdrawal ( 7/73 placebo vs 0/38 abatacept in period II ; p=0.119 ) which was reversed upon re introduction of SC abatacept ( 2/73 vs 1/38 , end period III ) . Safety was comparable regardless of withdrawal , with no unexpected events upon re introduction . Two patients experienced reactions at the SC injection site . On withdrawal , patients experienced slight worsening in efficacy which improved following re introduction . Conclusions Overall immunogenicity to SC abatacept is low , consistent with intravenous abatacept , and is not significantly affected by a 3-month interruption and re introduction . This stop – start schedule was well tolerated , with little impact on safety and efficacy . These are important considerations for the clinical use of SC abatacept . Clinical Trials gov Identifier Objective To assess the efficacy and safety of tocilizumab ( TCZ ) plus methotrexate/placebo ( MTX/PBO ) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission . Methods ACT-RAY was a double-blind 3-year trial . Patients with active rheumatoid arthritis despite MTX were r and omised to add  TCZ  to ongoing MTX  ( add-on strategy ) or switch to  TCZ plus PBO  ( switch strategy ) . Using a treat-to-target approach , open-label conventional synthetic disease-modifying antirheumatic drugs ( csDMARDs ) , other than MTX , were added 
    Output:
    