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 investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis ( RA ) combined with monitoring both disease activity and cartilage degradation . METHODS In a pilot trial , 21 patients with active early RA ( mean DAS28 5.3 ; mean disease duration 3 months ) were treated with COBRA treatment comprising sulfasalazine , methotrexate and high-dose step-down prednisolone , intensified by adding hydroxychloroquine and continued low-dose prednisolone . In addition , based on measurements of disease activity or a marker of cartilage degradation ( CTX-II ) , treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks ; and with infliximab after 21 weeks . RESULTS Nineteen of 21 patients ( 90 % ) were in remission ( DAS28 < 2.6 ) after 40 weeks ( 8 weeks , 57 % ; 21 weeks , 76 % ) . American College of Rheumatology ( ACR ) criteria , ACR20 , 50 , 70 and 90 improvements rates were 100 % , 95 % , 71 % and 43 % respectively . CTX-II excretion decreased by mean ( SD ) 347(292 ) ng/mmol creatinine , but only 50 % of patients reduced their CTX-II excretion below the cut-off point . The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion , despite a trend towards more intensive treatment in the CTX-II group . Treatment intensification was feasible according to protocol . CONCLUSIONS This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA . TRIAL REGISTRATION NUMBER IS RCT N96372677 OBJECTIVE To determine the efficacy , toxicity , utilities , and costs of 4 treatment strategies for patients with recent-onset rheumatoid arthritis ( RA ) . METHODS 508 patients with recent-onset active RA [ mean Disease Activity Score ( DAS ) 4.4 , mean Health Assessment Question naire score 1.4 ] were r and omized into 4 strategy groups : ( 1 ) sequential monotherapy ; ( 2 ) step-up to combination therapy [ both starting with methotrexate ( MTX ) ] ; ( 3 ) initial combination therapy with MTX , sulfasalazine , and prednisone ; ( 4 ) initial combination therapy with MTX and infliximab . Treatment adjustments were based on 3-monthly calculations of the DAS ( target DAS ? 2.4 ) , by research nurses who were blinded to the strategy group . They also collected data on treatment toxicity , functional ability , costs , and utilities . Yearly anonymized radiographs of h and s and feet were scored in r and om order by 2 independent physicians , using the Sharp/van der Heijde score . RESULTS Functional ability improved significantly earlier in Groups 3 and 4 than in Groups 1 and 2 , but was comparable among the groups at the end of the first year of treatment . Radiographic joint damage progression was significantly lower in Groups 3 and 4 than in Groups 1 and 2 , but low in all groups compared to other RA population s , probably due to DAS-driven treatment adjustments in all groups . More patients in Groups 3 and 4 than in Groups 1 and 2 achieved clinical remission ( DAS 1.6 ) , and patients who achieved early continued remission in Groups 3 and 4 had significantly less joint damage progression than those who achieved the same in Groups 1 and 2 . More patients could taper and stop all antirheumatic drugs and still retained remission in Group 4 ( 17 % at t = 3 years ) than in the other groups ( 10 % , 5 % , 9 % , respectively ) . Toxicity was comparable between groups . Quality of life measures were significantly higher in Group 4 than in the other groups , but costs of treatment were also the highest in Group 4 . Depending on the method used , higher productivity in Group 4 compensated for the higher medical costs . CONCLUSION In patients with recent-onset RA , initial combination therapy including prednisone or infliximab results in earlier clinical improvement and less joint damage progression than initial monotherapy . Initial treatment with infliximab result ed in the highest quality of life , highest productivity , and highest medical costs . DAS-driven treatment adjustments were effective to suppress disease activity and damage progression in all groups OBJECTIVE To test the efficacy of st and ardised monitoring using the disease activity index DAS28 versus usual care on disease modifying antirheumatic drug ( DMARD ) prescription and disease activity in rheumatoid arthritis . METHODS A 24 week cluster r and omised trial . Rheumatology outpatient centres were r and omised to systematic monitoring of disease activity  using the  DAS28  ( 12 centres , 205 patients ) or usual care ( 12 centres , 179 patients ) . The aim for the DAS group was to reach a DAS28 score of < or = 3.2 by changes in DMARD treatment , at the discretion of the rheumatologist and the patient . RESULTS At baseline ,  disease activity  was the same in both groups , with an overall mean ( SD ) DAS28  of 4.5 ( 1.2 ) ; 13 % of the patients had a  DAS28 of < or = 3.2 . At 24 weeks , 31 % of patients in the DAS group had a DAS28 < or = 3.2 , while in the usual care centres this was 16 % ( p = 0.028 ) .  DMARDs  were changed on average in 18 % of visits in the DAS centres ; in the 12 usual care centres they were changed on 8 % of the visits ( p = 0.013 ) . The doses of methotrexate , sulfasalazine , and corticosteroids  appeared to be higher in the DAS centres than in the usual care centres , but the differences were not significant . CONCLUSIONS In daily practice , systematic monitoring of disease activity in rheumatoid arthritis may lead to more changes in DMARD treatment , result ing in a larger number of patients with low disease activity Objectives To compare the efficacy and safety of intensive combination strategies with glucocorticoids ( GCs ) in the first 16 weeks ( W ) of early rheumatoid arthritis ( eRA ) treatment , focusing on high-risk patients , in the Care in early RA trial . Methods 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers . High-risk patients ( n=290 ) were r and omised to 1/3 treatment strategies : combination therapy for early rheumatoid arthritis ( COBRA ) Classic ( methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7 ) , COBRA Slim ( MTX+30 mg prednisone tapered to 5 mg from W6 ) and COBRA Avant-Garde ( MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6 ) . Treatment modifications to target low-disease activity were m and atory from W8 , if desirable and feasible according to the rheumatologist . The primary outcome was remission ( 28 joint disease activity score calculated with C-reactive protein < 2.6 ) at W16 ( intention-to-treat analysis ) . Secondary endpoints were good European League Against Rheumatism response , clinical ly meaningful health assessment question naire ( HAQ ) response and HAQ equal to zero . Adverse events ( AEs ) were registered . Results Data from 98 Classic , 98 Slim and 94 Avant-Garde patients were analysed . At W16 , remission was reached in 70.4 % Classic , 73.6 % Slim and 68.1 % Avant-Garde patients ( p=0.713 ) . Likewise , no significant differences were shown in other secondary endpoints . However , therapy-related AEs were reported in 61.2 % of Classic , in 46.9 % of Slim and in 69.1 % of Avant-Garde patients ( p=0.006 ) . Conclusions For high-risk eRA , MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile . EudraCT number : 2008 - 007225 - 39 Objectives : To determine whether prolonged intensive disease-modifying antirheumatic drug ( DMARD ) treatment ( PRINT ) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis ( RA ) . Methods : In this multicenter , r and omized and parallel treatment trial , 346 patients with active RA ( disease activity score ( 28 joints ) [ DAS28 ] ( erythrocyte sedimentation rate [ ESR ] ) > 5.1 ) were enrolled from 9 centers . In phase 1 , patients received intensive treatment with methotrexate , leflunomide , and hydroxychloroquine , up to 36 weeks , until remission ( DAS28 ⩽ 2.6 ) or a low disease activity ( 2.6 < DAS28 ⩽ 3.2 ) was achieved . In phase 2 , patients achieving remission or low disease activity were followed up with r and omization to 1 of 2 step-down protocol s : leflunomide plus hydroxychloroquine combination or leflunomide monotherapy . The primary endpoints were good European League Against Rheumatism ( EULAR ) response ( DAS28 ( ESR ) < 3.2 and a decrease of DAS28 by at least 1.2 ) during the intensive treatment and the disease state retention rate during step-down maintenance treatment . Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought . Results : A good EULAR response was achieved in 18.7 % , 36.9 % , and 54.1 % of patients at 12 , 24 , and 36 weeks , respectively . By 36 weeks , 75.4 % of patients achieved good and moderate EULAR responses . Compared with those achieving low disease activity and a high health assessment question naire ( HAQ > 0.5 ) , patients achieving remission ( DAS28 ⩽ 2.6 ) and low HAQ ( ⩽ 0.5 ) had a significantly higher retention rate when tapering the DMARDs treatment ( P = 0.046 and P = 0.01 , respectively ) . There was no advantage on tapering to combination rather than monotherapy . Conclusions : Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy .  Low disease activity at the start of disease taper leads to less subsequent flares . Leflunomide is a good maintenance treatment as single treatment Objectives To compare 1-year clinical efficacy of ( 1 ) initial triple disease-modifying antirheumatic drug therapy ( iTDT ) with initial methotrexate ( MTX ) monotherapy ( iMM ) and ( 2 ) different glucocorticoid ( GC ) bridging therapies : oral versus a single intramuscular injection in early rheumatoid arthritis . Methods In a single-blinded 
    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 investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis ( RA ) combined with monitoring both disease activity and cartilage degradation . METHODS In a pilot trial , 21 patients with active early RA ( mean DAS28 5.3 ; mean disease duration 3 months ) were treated with COBRA treatment comprising sulfasalazine , methotrexate and high-dose step-down prednisolone , intensified by adding hydroxychloroquine and continued low-dose prednisolone . In addition , based on measurements of disease activity or a marker of cartilage degradation ( CTX-II ) , treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks ; and with infliximab after 21 weeks . RESULTS Nineteen of 21 patients ( 90 % ) were in remission ( DAS28 < 2.6 ) after 40 weeks ( 8 weeks , 57 % ; 21 weeks , 76 % ) . American College of Rheumatology ( ACR ) criteria , ACR20 , 50 , 70 and 90 improvements rates were 100 % , 95 % , 71 % and 43 % respectively . CTX-II excretion decreased by mean ( SD ) 347(292 ) ng/mmol creatinine , but only 50 % of patients reduced their CTX-II excretion below the cut-off point . The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion , despite a trend towards more intensive treatment in the CTX-II group . Treatment intensification was feasible according to protocol . CONCLUSIONS This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA . TRIAL REGISTRATION NUMBER IS RCT N96372677 OBJECTIVE To determine the efficacy , toxicity , utilities , and costs of 4 treatment strategies for patients with recent-onset rheumatoid arthritis ( RA ) . METHODS 508 patients with recent-onset active RA [ mean Disease Activity Score ( DAS ) 4.4 , mean Health Assessment Question naire score 1.4 ] were r and omized into 4 strategy groups : ( 1 ) sequential monotherapy ; ( 2 ) step-up to combination therapy [ both starting with methotrexate ( MTX ) ] ; ( 3 ) initial combination therapy with MTX , sulfasalazine , and prednisone ; ( 4 ) initial combination therapy with MTX and infliximab . Treatment adjustments were based on 3-monthly calculations of the DAS ( target DAS ? 2.4 ) , by research nurses who were blinded to the strategy group . They also collected data on treatment toxicity , functional ability , costs , and utilities . Yearly anonymized radiographs of h and s and feet were scored in r and om order by 2 independent physicians , using the Sharp/van der Heijde score . RESULTS Functional ability improved significantly earlier in Groups 3 and 4 than in Groups 1 and 2 , but was comparable among the groups at the end of the first year of treatment . Radiographic joint damage progression was significantly lower in Groups 3 and 4 than in Groups 1 and 2 , but low in all groups compared to other RA population s , probably due to DAS-driven treatment adjustments in all groups . More patients in Groups 3 and 4 than in Groups 1 and 2 achieved clinical remission ( DAS 1.6 ) , and patients who achieved early continued remission in Groups 3 and 4 had significantly less joint damage progression than those who achieved the same in Groups 1 and 2 . More patients could taper and stop all antirheumatic drugs and still retained remission in Group 4 ( 17 % at t = 3 years ) than in the other groups ( 10 % , 5 % , 9 % , respectively ) . Toxicity was comparable between groups . Quality of life measures were significantly higher in Group 4 than in the other groups , but costs of treatment were also the highest in Group 4 . Depending on the method used , higher productivity in Group 4 compensated for the higher medical costs . CONCLUSION In patients with recent-onset RA , initial combination therapy including prednisone or infliximab results in earlier clinical improvement and less joint damage progression than initial monotherapy . Initial treatment with infliximab result ed in the highest quality of life , highest productivity , and highest medical costs . DAS-driven treatment adjustments were effective to suppress disease activity and damage progression in all groups OBJECTIVE To test the efficacy of st and ardised monitoring using the disease activity index DAS28 versus usual care on disease modifying antirheumatic drug ( DMARD ) prescription and disease activity in rheumatoid arthritis . METHODS A 24 week cluster r and omised trial . Rheumatology outpatient centres were r and omised to systematic monitoring of disease activity  using the  DAS28  ( 12 centres , 205 patients ) or usual care ( 12 centres , 179 patients ) . The aim for the DAS group was to reach a DAS28 score of < or = 3.2 by changes in DMARD treatment , at the discretion of the rheumatologist and the patient . RESULTS At baseline ,  disease activity  was the same in both groups , with an overall mean ( SD ) DAS28  of 4.5 ( 1.2 ) ; 13 % of the patients had a  DAS28 of < or = 3.2 . At 24 weeks , 31 % of patients in the DAS group had a DAS28 < or = 3.2 , while in the usual care centres this was 16 % ( p = 0.028 ) .  DMARDs  were changed on average in 18 % of visits in the DAS centres ; in the 12 usual care centres they were changed on 8 % of the visits ( p = 0.013 ) . The doses of methotrexate , sulfasalazine , and corticosteroids  appeared to be higher in the DAS centres than in the usual care centres , but the differences were not significant . CONCLUSIONS In daily practice , systematic monitoring of disease activity in rheumatoid arthritis may lead to more changes in DMARD treatment , result ing in a larger number of patients with low disease activity Objectives To compare the efficacy and safety of intensive combination strategies with glucocorticoids ( GCs ) in the first 16 weeks ( W ) of early rheumatoid arthritis ( eRA ) treatment , focusing on high-risk patients , in the Care in early RA trial . Methods 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers . High-risk patients ( n=290 ) were r and omised to 1/3 treatment strategies : combination therapy for early rheumatoid arthritis ( COBRA ) Classic ( methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7 ) , COBRA Slim ( MTX+30 mg prednisone tapered to 5 mg from W6 ) and COBRA Avant-Garde ( MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6 ) . Treatment modifications to target low-disease activity were m and atory from W8 , if desirable and feasible according to the rheumatologist . The primary outcome was remission ( 28 joint disease activity score calculated with C-reactive protein < 2.6 ) at W16 ( intention-to-treat analysis ) . Secondary endpoints were good European League Against Rheumatism response , clinical ly meaningful health assessment question naire ( HAQ ) response and HAQ equal to zero . Adverse events ( AEs ) were registered . Results Data from 98 Classic , 98 Slim and 94 Avant-Garde patients were analysed . At W16 , remission was reached in 70.4 % Classic , 73.6 % Slim and 68.1 % Avant-Garde patients ( p=0.713 ) . Likewise , no significant differences were shown in other secondary endpoints . However , therapy-related AEs were reported in 61.2 % of Classic , in 46.9 % of Slim and in 69.1 % of Avant-Garde patients ( p=0.006 ) . Conclusions For high-risk eRA , MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile . EudraCT number : 2008 - 007225 - 39 Objectives : To determine whether prolonged intensive disease-modifying antirheumatic drug ( DMARD ) treatment ( PRINT ) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis ( RA ) . Methods : In this multicenter , r and omized and parallel treatment trial , 346 patients with active RA ( disease activity score ( 28 joints ) [ DAS28 ] ( erythrocyte sedimentation rate [ ESR ] ) > 5.1 ) were enrolled from 9 centers . In phase 1 , patients received intensive treatment with methotrexate , leflunomide , and hydroxychloroquine , up to 36 weeks , until remission ( DAS28 ⩽ 2.6 ) or a low disease activity ( 2.6 < DAS28 ⩽ 3.2 ) was achieved . In phase 2 , patients achieving remission or low disease activity were followed up with r and omization to 1 of 2 step-down protocol s : leflunomide plus hydroxychloroquine combination or leflunomide monotherapy . The primary endpoints were good European League Against Rheumatism ( EULAR ) response ( DAS28 ( ESR ) < 3.2 and a decrease of DAS28 by at least 1.2 ) during the intensive treatment and the disease state retention rate during step-down maintenance treatment . Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought . Results : A good EULAR response was achieved in 18.7 % , 36.9 % , and 54.1 % of patients at 12 , 24 , and 36 weeks , respectively . By 36 weeks , 75.4 % of patients achieved good and moderate EULAR responses . Compared with those achieving low disease activity and a high health assessment question naire ( HAQ > 0.5 ) , patients achieving remission ( DAS28 ⩽ 2.6 ) and low HAQ ( ⩽ 0.5 ) had a significantly higher retention rate when tapering the DMARDs treatment ( P = 0.046 and P = 0.01 , respectively ) . There was no advantage on tapering to combination rather than monotherapy . Conclusions : Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy .  Low disease activity at the start of disease taper leads to less subsequent flares . Leflunomide is a good maintenance treatment as single treatment Objectives To compare 1-year clinical efficacy of ( 1 ) initial triple disease-modifying antirheumatic drug therapy ( iTDT ) with initial methotrexate ( MTX ) monotherapy ( iMM ) and ( 2 ) different glucocorticoid ( GC ) bridging therapies : oral versus a single intramuscular injection in early rheumatoid arthritis . Methods In a single-blinded 
    Output:
    