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 Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate , a st and ard treatment for this disease . There is evidence that antitumour necrosis factor alpha ( TNFalpha ) is efficacious in relief of signs and symptoms . We therefore investigated whether infliximab , a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate .  METHODS In an international double-blind placebo-controlled phase III clinical trial , 428 patients who had active rheumatoid arthritis , who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks , were r and omised to placebo ( n=88 ) or one of four regimens of  infliximab  at weeks 0 , 2 , and 6 . Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate ( median 15 mg/week for > or = 6 months , range 10 - 35 mg/wk ) . Patients were assessed every 4 weeks for 30 weeks . FINDINGS At 30 weeks , the American College of Rheumatology ( 20 ) response criteria , representing a 20 % improvement from baseline , were achieved in 53 , 50 , 58 , and 52 % of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks , respectively , compared with 20 % of patients receiving placebo plus methotrexate ( p<0.001 for each of the four infliximab regimens vs placebo ) . A 50 % improvement was achieved in 29 , 27 , 26 , and 31 % of infliximab plus methotrexate in the same treatment groups , compared with 5 % of patients on placebo plus methotrexate ( p<0.001 ) . Infliximab was well-tolerated ; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group . INTERPRETATION During 30 weeks , treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate Objectives This r and omised , double-blind , placebo-controlled phase IIIb study evaluated the impact of abatacept on MRI pathology as a primary outcome in  methotrexate (MTX)-refractory patients with rheumatoid arthritis . Methods Patients received intravenous abatacept ( ∼10 mg/kg ) or placebo , on background MTX , for 4 months , followed by an 8-month open-label extension ( OLE ; all patients received abatacept plus MTX ) . Patients had 1.5 T MRI with intravenous contrast at baseline , Months 4 and 12 ; wrist synovitis ( three locations assessed ) , and wrist and h and ( 15 and eight locations assessed , respectively ) osteitis and erosion were scored using OMERACT-RAMRIS . Results 26/27 abatacept- and 23/23 placebo-r and omised patients completed Month 4 and entered the OLE ; 26 and 21 completed Month 12 . The primary endpoint was not achieved ; mean change ( SD ) from baseline in synovitis was −0.44 ( 1.47 ) for abatacept versus 0.52 ( 1.38 ) for placebo ( p=0.103 ) at Month 4 . For mean change in synovitis adjusted for baseline score ( sensitivity analysis ) , the difference between groups was −0.69 , p=0.078 . Adjusted mean changes ( SE ) in osteitis and erosion were −1.94 ( 0.86 ) and 0.45 ( 0.43 ) for abatacept , and 1.54 ( 0.90 ) and 0.95 ( 0.45 ) for placebo . Further MRI improvements were observed up to Month 12 for abatacept and from Months 4 to 12 for placebo-treated patients switched to abatacept at Month 4 . Clinical efficacy was shown with abatacept and sustained to Month 12 . Conclusions Despite small patient numbers , MRI detected structural and synovial benefit , sustained to Month 12 in abatacept+MTX-treated patients , and improvements in structural and inflammatory outcomes for placebo+MTX-treated patients following addition of abatacept . Clinical trial registration Clinical trials.gov NCT00420199 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 Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response  versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function  versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : Objective : To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis ( RA ) despite sulfasalazine therapy . Methods : Patients were r and omly assigned to etanercept ( 25 mg twice weekly ; sulfasalazine was discontinued at baseline ) , etanercept plus sulfasalazine ( unchanged regimen of 2–3 g/day ) or sulfasalazine in a double-blind , r and omised , 2-year study in adult patients with active RA despite sulfasalazine therapy .  Efficacy was assessed using the American College of Rheumatology criteria , disease activity scores ( DAS ) and patient-reported outcomes ( PRO ) . Results : Demographic variables and baseline disease characteristics were comparable among treatment groups ; mean DAS 5.1 , 5.2 and 5.1 for etanercept ( n = 103 ) , etanercept plus sulfasalazine ( n = 101 ) and sulfasalazine ( n = 50 ) , respectively . Withdrawal due to lack of efficacy was highest with sulfasalazine ( 26 ( 52 % ) vs 6 ( 6 % ) for either etanercept group , p<0.001 ) . Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response , which was sustained at 2 years , than those receiving sulfasalazine : mean DAS 2.8 , 2.5 versus 4.5 , respectively ( p<0.05 ) ; ACR 20 response was achieved by 67 % , 77 % versus 34 % of patients , respectively ( p<0.01 ) Overall , PRO followed a similar pattern ; a clinical ly significant improvement in health assessment question naire was achieved by 76 % , 78 % versus 40 % of patients , respectively ( p<0.01 ) . Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis ( p<0.01 ) . Conclusion : Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA . The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine OBJECTIVES To describe the changes in functional ability ( FA ) taking place over 5 yr in patients with rheumatoid arthritis ( RA ) starting disease-modifying anti-rheumatic drug ( DMARD ) therapy  , to investigate the factors having most influence upon FA and to compare these factors at baseline and after 5 yr of treatment . METHODS Three hundred and sixty-six patients with active RA were studied as part of a 5-yr r and omized controlled study of DMARD therapy . FA was assessed by  Health Assessment Question naire  ( HAQ )  score every 6 months . Multiple linear regression was used to identify factors affecting FA at baseline and at 5 yr . The independent variables used were age , sex , visual analogue scale ( VAS ) pain , Ritchie articular index , C-reactive protein ( CRP ) , Larsen score and log-transformed morning stiffness ( EMS ) . RESULTS Mean HAQ score was 1.64 at baseline , improved by 21 % at 1 yr and gradually returned towards baseline levels by 5 yr . At baseline only 34 % of variance in HAQ score could be explained ; the most significant explanatory variables were the Ritchie articular index and CRP . At 5 yr the variance explained was 60 % . The Ritchie articular index remained the strongest factor followed by VAS pain , log(10 ) EMS and Larsen score . CONCLUSIONS Improvement in function did occur after commencement of the first DMARD therapy but was not maintained to 5 yr . The most consistent factor affecting function was joint tenderness . Global pain and duration of EMS were of lesser importance . Disease activity measures such as the CRP exerted an influence in the earlier , more active stages of disease : radiographic damage assumed greater importance as the arthritis progressed Objective : To evaluate the ability of tocilizumab ( 
    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 Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate , a st and ard treatment for this disease . There is evidence that antitumour necrosis factor alpha ( TNFalpha ) is efficacious in relief of signs and symptoms . We therefore investigated whether infliximab , a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate .  METHODS In an international double-blind placebo-controlled phase III clinical trial , 428 patients who had active rheumatoid arthritis , who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks , were r and omised to placebo ( n=88 ) or one of four regimens of  infliximab  at weeks 0 , 2 , and 6 . Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate ( median 15 mg/week for > or = 6 months , range 10 - 35 mg/wk ) . Patients were assessed every 4 weeks for 30 weeks . FINDINGS At 30 weeks , the American College of Rheumatology ( 20 ) response criteria , representing a 20 % improvement from baseline , were achieved in 53 , 50 , 58 , and 52 % of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks , respectively , compared with 20 % of patients receiving placebo plus methotrexate ( p<0.001 for each of the four infliximab regimens vs placebo ) . A 50 % improvement was achieved in 29 , 27 , 26 , and 31 % of infliximab plus methotrexate in the same treatment groups , compared with 5 % of patients on placebo plus methotrexate ( p<0.001 ) . Infliximab was well-tolerated ; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group . INTERPRETATION During 30 weeks , treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate Objectives This r and omised , double-blind , placebo-controlled phase IIIb study evaluated the impact of abatacept on MRI pathology as a primary outcome in  methotrexate (MTX)-refractory patients with rheumatoid arthritis . Methods Patients received intravenous abatacept ( ∼10 mg/kg ) or placebo , on background MTX , for 4 months , followed by an 8-month open-label extension ( OLE ; all patients received abatacept plus MTX ) . Patients had 1.5 T MRI with intravenous contrast at baseline , Months 4 and 12 ; wrist synovitis ( three locations assessed ) , and wrist and h and ( 15 and eight locations assessed , respectively ) osteitis and erosion were scored using OMERACT-RAMRIS . Results 26/27 abatacept- and 23/23 placebo-r and omised patients completed Month 4 and entered the OLE ; 26 and 21 completed Month 12 . The primary endpoint was not achieved ; mean change ( SD ) from baseline in synovitis was −0.44 ( 1.47 ) for abatacept versus 0.52 ( 1.38 ) for placebo ( p=0.103 ) at Month 4 . For mean change in synovitis adjusted for baseline score ( sensitivity analysis ) , the difference between groups was −0.69 , p=0.078 . Adjusted mean changes ( SE ) in osteitis and erosion were −1.94 ( 0.86 ) and 0.45 ( 0.43 ) for abatacept , and 1.54 ( 0.90 ) and 0.95 ( 0.45 ) for placebo . Further MRI improvements were observed up to Month 12 for abatacept and from Months 4 to 12 for placebo-treated patients switched to abatacept at Month 4 . Clinical efficacy was shown with abatacept and sustained to Month 12 . Conclusions Despite small patient numbers , MRI detected structural and synovial benefit , sustained to Month 12 in abatacept+MTX-treated patients , and improvements in structural and inflammatory outcomes for placebo+MTX-treated patients following addition of abatacept . Clinical trial registration Clinical trials.gov NCT00420199 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 Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response  versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function  versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : Objective : To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis ( RA ) despite sulfasalazine therapy . Methods : Patients were r and omly assigned to etanercept ( 25 mg twice weekly ; sulfasalazine was discontinued at baseline ) , etanercept plus sulfasalazine ( unchanged regimen of 2–3 g/day ) or sulfasalazine in a double-blind , r and omised , 2-year study in adult patients with active RA despite sulfasalazine therapy .  Efficacy was assessed using the American College of Rheumatology criteria , disease activity scores ( DAS ) and patient-reported outcomes ( PRO ) . Results : Demographic variables and baseline disease characteristics were comparable among treatment groups ; mean DAS 5.1 , 5.2 and 5.1 for etanercept ( n = 103 ) , etanercept plus sulfasalazine ( n = 101 ) and sulfasalazine ( n = 50 ) , respectively . Withdrawal due to lack of efficacy was highest with sulfasalazine ( 26 ( 52 % ) vs 6 ( 6 % ) for either etanercept group , p<0.001 ) . Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response , which was sustained at 2 years , than those receiving sulfasalazine : mean DAS 2.8 , 2.5 versus 4.5 , respectively ( p<0.05 ) ; ACR 20 response was achieved by 67 % , 77 % versus 34 % of patients , respectively ( p<0.01 ) Overall , PRO followed a similar pattern ; a clinical ly significant improvement in health assessment question naire was achieved by 76 % , 78 % versus 40 % of patients , respectively ( p<0.01 ) . Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis ( p<0.01 ) . Conclusion : Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA . The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine OBJECTIVES To describe the changes in functional ability ( FA ) taking place over 5 yr in patients with rheumatoid arthritis ( RA ) starting disease-modifying anti-rheumatic drug ( DMARD ) therapy  , to investigate the factors having most influence upon FA and to compare these factors at baseline and after 5 yr of treatment . METHODS Three hundred and sixty-six patients with active RA were studied as part of a 5-yr r and omized controlled study of DMARD therapy . FA was assessed by  Health Assessment Question naire  ( HAQ )  score every 6 months . Multiple linear regression was used to identify factors affecting FA at baseline and at 5 yr . The independent variables used were age , sex , visual analogue scale ( VAS ) pain , Ritchie articular index , C-reactive protein ( CRP ) , Larsen score and log-transformed morning stiffness ( EMS ) . RESULTS Mean HAQ score was 1.64 at baseline , improved by 21 % at 1 yr and gradually returned towards baseline levels by 5 yr . At baseline only 34 % of variance in HAQ score could be explained ; the most significant explanatory variables were the Ritchie articular index and CRP . At 5 yr the variance explained was 60 % . The Ritchie articular index remained the strongest factor followed by VAS pain , log(10 ) EMS and Larsen score . CONCLUSIONS Improvement in function did occur after commencement of the first DMARD therapy but was not maintained to 5 yr . The most consistent factor affecting function was joint tenderness . Global pain and duration of EMS were of lesser importance . Disease activity measures such as the CRP exerted an influence in the earlier , more active stages of disease : radiographic damage assumed greater importance as the arthritis progressed Objective : To evaluate the ability of tocilizumab ( 
    Output:
    