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: For many years , the Stanford Health Assessment Question naire ( HAQ ) has provided an effective measure of disability . Recently , some debate has emerged about whether or not the HAQ is an " ordinal ' or " interval ' scale . The opportunity to test its level of measurement arose when the scale was applied in a community survey which undertook a two-stage r and om sample using postal question naires to ascertain the health care needs of those with arthritis . The HAQ data are fitted to the Rasch model which tests for the presence of certain desirable characteristics of measurement , e.g. unidimensionality . The fit of the data to the model for those self-reporting rheumatoid arthritis ( RA ) was adequate . The transformed  HAQ score , derived from the Rasch analysis , is compared with the ordinary HAQ ( raw ) score . This shows that , for those with RA , incremental units of the raw score at the margins of the scale reflect an increasing level of (dis)ability compared to similar units in the centre of the scale . Thus , the traditional  HAQ score ( range 0 - 3 ) is an ordinal score . The findings also indicate that scoring all 20 items may lead to greater sensitivity . Questions are also raised about the construct validity for those with other types of arthritis . For osteoarthrosis , the grip item does not appear to belong to the same underlying construct as the other items 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 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 Objective : To compare the efficacy and toxicity of cyclosporin A ( CsA ) monotherapy with CsA plus methotrexate ( MTX ) combination therapy in patients with early rheumatoid arthritis ( RA ) . Patients and methods : 120 patients with active RA , rheumatoid factor positive and /or erosive , were r and omly allocated to receive CsA with MTX ( n=60 ) or CsA with placebo ( n=60 ) . Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks . MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16 . Primary outcomes were clinical remission ( Pinals criteria ) and radiological damage ( Larsen score ) , at week 48 . Results : Treatment was discontinued prematurely in 27 patients in the monotherapy group ( 21 because of inefficacy , and six because of toxicity ) and in 26 patients in the combination therapy group ( 14 and 12 , respectively ) . At week 48 , clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group ( p=0.5 ) . The median Larsen score increased to 10 ( 25th , 75th centiles : 3.5 ; 13.3 ) points in the monotherapy group and to 4 ( 1.0 ; 10.5 ) points in the combination therapy group ( p=0.004 ) . 28/60 ( 47 % ) of patients in the monotherapy group v 34/60 ( 57 % ) of patients in the combination therapy group had reached an American college of Rheumatology 20 % ( ACR20 ) response ( p=0.36 ) at week 48 ; 15/60 ( 25 % ) v 29/60 ( 48 % ) of patients had reached an ACR50 response ( p=0.013 ) ; and 7 ( 12 % ) v 12 ( 20 % ) of patients had reached an ACR70 response (p=0.11).Their was a tendency towards more toxicity in the combination therapy group . Conclusions : In patients with early RA , neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission . Combination therapy is probably better at improving clinical disease activity , and definitely better at slowing radiological progression . Combination therapy should still be compared with methotrexate monotherapy Objective . To compare the effects of aggressive tight control therapy and conventional care on radiographic progression and disease activity in patients with early mild inflammatory arthritis . Methods . Patients with two to five swollen joints , Sharp – van der Heijde radiographic score ( SHS ) < 5 and symptom duration ≤2 years were r and omized between two strategies . Patients with a definite non-RA diagnosis were excluded . The protocol of the aggressive group aim ed for remission ( DAS < 1.6 ) , with consecutive treatment steps : MTX , addition of adalimumab and combination therapy . The conventional care group followed a strategy with traditional DMARDs ( no prednisone or biologics ) without DAS-based guideline . Outcome measures after 2 years were SHS ( primary ) , remission rate and HAQ score ( secondary ) . Results . Eighty-two patients participated ( 60 % ACPA positive ) . In the aggressive group ( n = 42 ) , 19 patients were treated with adalimumab . In the conventional care group ( n = 40 ) , 24 patients started with hydroxychloroquin ( HCQ ) , 2 with sulfasalazine ( SSZ ) and 14 with MTX . After 2 years , the median SHS increase was 0 [ interquartile range ( IQR ) 0–1.1 ] and 0.5 ( IQR 0–2.5 ) , remission rates were 66 and 49 % and HAQ decreased with a mean of −0.09 ( 0.50 ) and −0.25 ( 0.59 ) in the aggressive and conventional care group , respectively . All comparisons were non-significant . Conclusion . In patients with early arthritis of two to five joints , both aggressive tight-control therapy including adalimumab and conventional therapy result ed in remission rates around 50 % , low radiographic damage and excellent functional status after 2 years . However , full disease control including radiographic arrest in all patients remains an elusive target even in moderately active early arthritis . Trial registration . Dutch Trial Register , http://www.trialregister.nl/ , NTR 144 OBJECTIVES To report from the Early Rheumatoid Arthritis Network ( ERAN ) , time from symptom onset to start of therapy , treatment choices and disease outcome in early RA . METHODS Patients with newly diagnosed RA were prospect ively enrolled from 19 centres in the UK and Eire . St and ardized information was collected on case report forms at first presentation , 3 - 6 months , 1 yr and annually thereafter . The choice and intensity of drug treatment was left to the discretion of individual centres . RESULTS A total of 808 patients were recruited between 2002 and 2007 , with a mean follow-up of 16 ( 0 - 60 ) months . Of them , 62 % fulfilled four or more ACR criteria for RA at first visit . The median time from onset of symptoms to referral to secondary care was 4 months [ interquartile range ( IQR ) 2 - 9 , n = 655 ] and to start of first DMARD 8 months ( IQR 4 - 13 , n = 638 ) . DMARDs were prescribed in 97 % of the patients , initially as monotherapy in 91 % , and as combination therapy in 9 % . The second DMARD ( n = 220 ) was a switch to another as monotherapy in 52 % and step-up to combination therapy in 48 % . The proportions with a 28-joint disease activity score > 5.1 at baseline and 3 yrs were 46 and 19 % , > 3.2 were 84 and 54 % and < 2.6 were 6 and 33 % , respectively . CONCLUSIONS Patients presenting with RA in ERAN do not receive DMARDs promptly , largely due to delays in referral to secondary care . Contemporary treatment practice is to start with DMARD monotherapy , and to use combination DMARDs as second-line therapy in approximately half of them . Over 3 yrs the proportion of patients continuing to have active disease remains high As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy , research studies with broader aims will become increasingly important . R and omized trials may need to accommo date multiple treatment options . In completely r and omized design s , patients are assigned at r and om to one of the options , requiring that patients and clinicians find each of the options acceptable . In " clinician 's choice " design s , patients are r and omized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician . The clinician 's choice design permits some scope to patient and clinician preferences , but sacrifices the ability to make r and omization-based comparisons of specific options . We describe a new approach , which we call the " equipoise stratified " design , that merges the advantages and avoids the disadvantages of the other two design s for clinical trials . The three design s are contrasted , using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate .  METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose 
    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: For many years , the Stanford Health Assessment Question naire ( HAQ ) has provided an effective measure of disability . Recently , some debate has emerged about whether or not the HAQ is an " ordinal ' or " interval ' scale . The opportunity to test its level of measurement arose when the scale was applied in a community survey which undertook a two-stage r and om sample using postal question naires to ascertain the health care needs of those with arthritis . The HAQ data are fitted to the Rasch model which tests for the presence of certain desirable characteristics of measurement , e.g. unidimensionality . The fit of the data to the model for those self-reporting rheumatoid arthritis ( RA ) was adequate . The transformed  HAQ score , derived from the Rasch analysis , is compared with the ordinary HAQ ( raw ) score . This shows that , for those with RA , incremental units of the raw score at the margins of the scale reflect an increasing level of (dis)ability compared to similar units in the centre of the scale . Thus , the traditional  HAQ score ( range 0 - 3 ) is an ordinal score . The findings also indicate that scoring all 20 items may lead to greater sensitivity . Questions are also raised about the construct validity for those with other types of arthritis . For osteoarthrosis , the grip item does not appear to belong to the same underlying construct as the other items 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 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 Objective : To compare the efficacy and toxicity of cyclosporin A ( CsA ) monotherapy with CsA plus methotrexate ( MTX ) combination therapy in patients with early rheumatoid arthritis ( RA ) . Patients and methods : 120 patients with active RA , rheumatoid factor positive and /or erosive , were r and omly allocated to receive CsA with MTX ( n=60 ) or CsA with placebo ( n=60 ) . Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks . MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16 . Primary outcomes were clinical remission ( Pinals criteria ) and radiological damage ( Larsen score ) , at week 48 . Results : Treatment was discontinued prematurely in 27 patients in the monotherapy group ( 21 because of inefficacy , and six because of toxicity ) and in 26 patients in the combination therapy group ( 14 and 12 , respectively ) . At week 48 , clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group ( p=0.5 ) . The median Larsen score increased to 10 ( 25th , 75th centiles : 3.5 ; 13.3 ) points in the monotherapy group and to 4 ( 1.0 ; 10.5 ) points in the combination therapy group ( p=0.004 ) . 28/60 ( 47 % ) of patients in the monotherapy group v 34/60 ( 57 % ) of patients in the combination therapy group had reached an American college of Rheumatology 20 % ( ACR20 ) response ( p=0.36 ) at week 48 ; 15/60 ( 25 % ) v 29/60 ( 48 % ) of patients had reached an ACR50 response ( p=0.013 ) ; and 7 ( 12 % ) v 12 ( 20 % ) of patients had reached an ACR70 response (p=0.11).Their was a tendency towards more toxicity in the combination therapy group . Conclusions : In patients with early RA , neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission . Combination therapy is probably better at improving clinical disease activity , and definitely better at slowing radiological progression . Combination therapy should still be compared with methotrexate monotherapy Objective . To compare the effects of aggressive tight control therapy and conventional care on radiographic progression and disease activity in patients with early mild inflammatory arthritis . Methods . Patients with two to five swollen joints , Sharp – van der Heijde radiographic score ( SHS ) < 5 and symptom duration ≤2 years were r and omized between two strategies . Patients with a definite non-RA diagnosis were excluded . The protocol of the aggressive group aim ed for remission ( DAS < 1.6 ) , with consecutive treatment steps : MTX , addition of adalimumab and combination therapy . The conventional care group followed a strategy with traditional DMARDs ( no prednisone or biologics ) without DAS-based guideline . Outcome measures after 2 years were SHS ( primary ) , remission rate and HAQ score ( secondary ) . Results . Eighty-two patients participated ( 60 % ACPA positive ) . In the aggressive group ( n = 42 ) , 19 patients were treated with adalimumab . In the conventional care group ( n = 40 ) , 24 patients started with hydroxychloroquin ( HCQ ) , 2 with sulfasalazine ( SSZ ) and 14 with MTX . After 2 years , the median SHS increase was 0 [ interquartile range ( IQR ) 0–1.1 ] and 0.5 ( IQR 0–2.5 ) , remission rates were 66 and 49 % and HAQ decreased with a mean of −0.09 ( 0.50 ) and −0.25 ( 0.59 ) in the aggressive and conventional care group , respectively . All comparisons were non-significant . Conclusion . In patients with early arthritis of two to five joints , both aggressive tight-control therapy including adalimumab and conventional therapy result ed in remission rates around 50 % , low radiographic damage and excellent functional status after 2 years . However , full disease control including radiographic arrest in all patients remains an elusive target even in moderately active early arthritis . Trial registration . Dutch Trial Register , http://www.trialregister.nl/ , NTR 144 OBJECTIVES To report from the Early Rheumatoid Arthritis Network ( ERAN ) , time from symptom onset to start of therapy , treatment choices and disease outcome in early RA . METHODS Patients with newly diagnosed RA were prospect ively enrolled from 19 centres in the UK and Eire . St and ardized information was collected on case report forms at first presentation , 3 - 6 months , 1 yr and annually thereafter . The choice and intensity of drug treatment was left to the discretion of individual centres . RESULTS A total of 808 patients were recruited between 2002 and 2007 , with a mean follow-up of 16 ( 0 - 60 ) months . Of them , 62 % fulfilled four or more ACR criteria for RA at first visit . The median time from onset of symptoms to referral to secondary care was 4 months [ interquartile range ( IQR ) 2 - 9 , n = 655 ] and to start of first DMARD 8 months ( IQR 4 - 13 , n = 638 ) . DMARDs were prescribed in 97 % of the patients , initially as monotherapy in 91 % , and as combination therapy in 9 % . The second DMARD ( n = 220 ) was a switch to another as monotherapy in 52 % and step-up to combination therapy in 48 % . The proportions with a 28-joint disease activity score > 5.1 at baseline and 3 yrs were 46 and 19 % , > 3.2 were 84 and 54 % and < 2.6 were 6 and 33 % , respectively . CONCLUSIONS Patients presenting with RA in ERAN do not receive DMARDs promptly , largely due to delays in referral to secondary care . Contemporary treatment practice is to start with DMARD monotherapy , and to use combination DMARDs as second-line therapy in approximately half of them . Over 3 yrs the proportion of patients continuing to have active disease remains high As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy , research studies with broader aims will become increasingly important . R and omized trials may need to accommo date multiple treatment options . In completely r and omized design s , patients are assigned at r and om to one of the options , requiring that patients and clinicians find each of the options acceptable . In " clinician 's choice " design s , patients are r and omized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician . The clinician 's choice design permits some scope to patient and clinician preferences , but sacrifices the ability to make r and omization-based comparisons of specific options . We describe a new approach , which we call the " equipoise stratified " design , that merges the advantages and avoids the disadvantages of the other two design s for clinical trials . The three design s are contrasted , using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate .  METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose 
    Output:
    