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 Circadian rhythms are changed in patients with rheumatoid arthritis . A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit-risk ratio of glucocorticoid therapy in rheumatoid arthritis . We aim ed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease . METHODS In a 12-week , multicentre , r and omised , double-blind trial , 288 patients with active rheumatoid arthritis were r and omly assigned to either a modified-release prednisone tablet ( n=144 ) or to an immediate-release prednisone tablet ( n=144 ) . The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion . This treatment was compared with morning administration of immediate-release prednisone as an active comparator . The primary outcome measure was duration of morning stiffness of the joints . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00146640 . FINDINGS The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone ( -22.7%vs -0.4 % ; difference=22.4 % [ 95 % CI 0.49 - 44.30 ] ; p=0.045 ) . Patients in the prednisone modified-release group achieved a mean reduction of 44.0 ( SD 136.6 ) min compared with baseline . The absolute difference between the treatment groups was 29.2 min ( 95 % CI -2.59 to 61.9 ) in favour of modified-release prednisone ( p=0.072 ) . The safety profile did not differ between treatments . INTERPRETATION Modified-release prednisone is well tolerated , convenient to administer , and produces a clinical ly relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone Objective This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study ( CAPRA 1 ) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release ( MR ) prednisone for up to 12 months . Methods Of 288 patients with rheumatoid arthritis originally r and omised to MR or immediate-release ( IR ) prednisone , 249 continued with prednisone chronotherapy ( 2–10 mg/day ) in the 9-month open-label extension . Duration of morning stiffness of the joints ( MS ) , disease activity scores ( DAS28 ) , American College of Rheumatology ( ACR20 ) responses and plasma levels of interleukin 6 ( IL-6 ) were assessed . Safety was analysed from adverse event reports and laboratory investigations . Results During the 3-month double-blind phase , patients in the MR group achieved a reduction in MS of 33.1 % while no change was observed in the IR group . After 6 months of treatment , MS was reduced in the IR/MR group by 54 % and in the MR/MR group by 56 % . MS reduction after 12 months was 45 % ( IR/MR group ) and 55 % ( MR/MR group ) . Plasma levels of IL-6 declined on MR treatment . DAS28 was reduced from 5.8 to 4.8 ( MR/MR group ) and 4.9 ( IR/MR group ) , respectively . 37 % of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria . Adverse events did not differ from the known profile of low-dose prednisone . Conclusions Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which result ed in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months BACKGROUND The value of intensive combination therapy in early rheumatoid arthritis is unproven . In a multicentre , double-blind , r and omised trial ( COBRA ) , we compared the combination of sulphasalazine ( 2 g/day ) , methotrexate ( 7.5 mg/week ) , and prednisolone ( initially 60 mg/day , tapered in 6 weekly steps to 7.5 mg/day ) with sulphasalazine alone . METHODS 155 patients with early rheumatoid arthritis ( median duration 4 months ) were r and omly assigned combined treatment ( 76 ) or sulphasalazine alone ( 79 ) . Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks , respectively . The main outcomes were the pooled index ( a weighted change score of five disease activity measures ) and the Sharp/Van der Heijde radiographic damage score in h and s and feet . Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation . FINDINGS At week 28 , the mean pooled index was 1.4 ( 95 % CI 1.2 - 1.6 ) in the combined treatment group and 0.8 ( 0.6 - 1.0 ) in the sulphasalazine group ( p < 0.0001 ) . At this time , 55 ( 72 % ) and 39 ( 49 % ) patients , respectively , were improved according to American College of Rheumatology criteria . The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped , and there were no further changes after methotrexate was stopped . At 28 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 28 ) in the combined-therapy group and 4 ( 0 - 44 ) in the sulphasalazine group ( p < 0.0001 ) . The increases at week 56 ( 2 [ 0 - 43 ] vs 6 [ 0 - 54 ] , p = 0.004 ) , and at week 80 ( 4 [ 0 - 80 ] vs 12 [ 0 - 72 ] , p = 0.01 ) were also significant . Further analysis suggests that combined therapy immediately suppressed damage progression , whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months . There were fewer withdrawals in the combined therapy than the sulphasalazine group ( 6 [ 8 % ] vs 23 [ 29 % ] ) , and they occurred later . INTERPRETATION This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped . Although confirmatory studies and long-term follow-up are needed , this approach may prove useful in the treatment of early rheumatoid arthritis OBJECTIVE Assessment of the cost-effectiveness and cost-utility of early intervention in rheumatoid arthritis ( RA ) patients , with combined step-down prednisolone , methotrexate and sulphasalazine , compared to sulphasalazine alone . METHODS Multicentre 56 week r and omized double-blind trial with full economic analysis of direct costs and utility analysis with rating scale and st and ard gamble measurement techniques . RESULTS The combined-treatment group included 76 patients and the sulphasalazine group 78 patients . The mean total costs per patient in the first 56 weeks of follow-up were $ 5519 for combined treatment and $ 6511 for treatment with sulphasalazine alone ( P = 0.37 ) . Out-patient care , in-patient care and non-health care each contributed about one-third to the total costs . The combined-treatment group appeared to generate savings in the length of hospital stay for RA , non- protocol drugs and costs of home help , but comparisons were not statistically significant . Protocol drugs and monitoring were slightly more expensive in the combined-treatment group . Clinical , radiographic and functional outcomes significantly favoured combined treatment at week 28 ( radiography also at week 56 ) . Utility scores also favoured combined treatment . CONCLUSION Combined treatment is cost-effective due to enhanced efficacy at lower or equal direct costs Objective . To investigate the effects of longterm low-dose chronotherapy with modified-release ( MR ) prednisone for rheumatoid arthritis ( RA ) on the hypothalamus-pituitary-adrenal ( HPA ) axis as part of the Circadian Administration of Prednisone in Rheumatoid Arthritis ( CAPRA-1 ) study . This consisted of a 3-month active-controlled phase and a 9-month open-label extension with MR prednisone  including patients previously treated with prednisone  ( Clinical Trials.gov number NCT00146640 ) . Methods .  Corticotropin-releasing hormone ( CRH ) tests were performed on 28 patients at 3 timepoints : at baseline on pre study immediate-release ( IR ) prednisone , after the 3-month double-blind phase on either IR prednisone or MR prednisone , and after the 9-month open-label extension on MR prednisone . Changes of cortisol were assessed and compared to individual patients ’ efficacy and safety data . Results . The increase ( mean , SD ) of cortisol plasma concentrations after injection of corticorelin was 5.5 ( 4.37 ) μg/dl on IR prednisone at baseline ( n = 21 ) and 5.3 ( 4.07 ) μg/dl on MR prednisone at 12 months ( n = 22 ) . Numbers of normal/suppressed/no response reactions did not differ among treatments . Switching from IR to MR prednisone did not influence responses , nor did longterm treatment of up to 12 months with MR prednisone . No worsening of adrenal impairment was observed on treatment with nighttime-release prednisone in patients with low responsiveness to CRH testing before the treatment with MR prednisone . Conclusion . Treatment with nighttime-release prednisone did not change adrenocortical function over 12 months . We presume that chronotherapy with this nighttime-release prednisone may improve the efficacy of longterm low-dose glucocorticoid treatment in patients with RA OBJECTIVE The effects of a 12-week treatment with modified-release prednisone ( MR-pred ) on the costs of drug treatment of RA were modelled . METHODS With the results of a recent r and omized trial as source data , we expressed the effect of treatment ( MR-pred vs placebo ) on the decrease in the proportion of RA patients meeting disease activity thresholds for reimbursement of biologic treatment . RESULTS The results showed 11 - 13 % more patients on MR-pred than on placebo dropped below reimbursement thresholds for The Netherl and s , Belgium and the UK . Assuming 1 year of biologics cost € 15,000 and MR-pred costs € 1/day , € 396 are saved in each patient delaying biologic treatment by 12 weeks . CONCLUSION Despite a considerably higher cost than conventional prednisone , MR-pred is a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic agents OBJECTIVE To describe the effect of indirect costs for patients with early rheumatoid arthritis ( RA ) within the COBRA trial ( Combinatietherapie Bij Reumatoide Artritis ) on the cost-effectiveness of both therapies . Analyses of the efficacy and direct costs of the treatments have already been reported . METHODS Patients with early RA selected for the 56-week trial were r and omly assigned to prednisolone , methotrexate , and sulfasalazine ( the COBRA combination ) ( n = 76 , tapered after 28 weeks ) or to sulfasalazine ( SSZ ; n = 79 , of which 78 patients were evaluable ) alone . The main efficacy outcomes were a pooled index and radiographic damage score in h and s and feet , and utilities . Direct and indirect costs were measured ( from a societal perspective ) by means of cost diaries and interviews completed by patients during the intervention phase and the followup phase , each lasting 28 weeks . Differences in mean costs between groups and cost-utility ratios were evaluated by applying nonparametric bootstrapping techniques . RESULTS In the first 28 weeks , indirect costs per patient totaled US $ 2,578 and US $ 3,638 for COBRA and SSZ therapy , respectively ( p = 0.09 ) . The total costs were $ 5,931 and $ 7,853 , respectively ( p < 0.05 ) . These differences were lost in the second 28 weeks . For the total period the mean total costs per patient were $ 10,262 and $ 12,788 , respectively ( p = 0.11 ) . Sensitivity analyses showed robustness of the data . The point estimate of the cost per quality -adjusted life-year based on the rating scale was negative at $ -385 , suggesting dominance of COBRA ( more effect at lower cost ) . CONCLUSION COBRA therapy adds additional disease control ( improvements in disease activity , physical function , and rate of damage progression ) at lower or equal cost compared to SSZ in early RA OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis ( COBRA ) trial demonstrated that step-down combination therapy with prednisolone , methotrexate , and sulfasalazine ( SSZ ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis ( RA ) . The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time , and to determine which baseline 
    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 Circadian rhythms are changed in patients with rheumatoid arthritis . A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit-risk ratio of glucocorticoid therapy in rheumatoid arthritis . We aim ed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease . METHODS In a 12-week , multicentre , r and omised , double-blind trial , 288 patients with active rheumatoid arthritis were r and omly assigned to either a modified-release prednisone tablet ( n=144 ) or to an immediate-release prednisone tablet ( n=144 ) . The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion . This treatment was compared with morning administration of immediate-release prednisone as an active comparator . The primary outcome measure was duration of morning stiffness of the joints . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00146640 . FINDINGS The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone ( -22.7%vs -0.4 % ; difference=22.4 % [ 95 % CI 0.49 - 44.30 ] ; p=0.045 ) . Patients in the prednisone modified-release group achieved a mean reduction of 44.0 ( SD 136.6 ) min compared with baseline . The absolute difference between the treatment groups was 29.2 min ( 95 % CI -2.59 to 61.9 ) in favour of modified-release prednisone ( p=0.072 ) . The safety profile did not differ between treatments . INTERPRETATION Modified-release prednisone is well tolerated , convenient to administer , and produces a clinical ly relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone Objective This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study ( CAPRA 1 ) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release ( MR ) prednisone for up to 12 months . Methods Of 288 patients with rheumatoid arthritis originally r and omised to MR or immediate-release ( IR ) prednisone , 249 continued with prednisone chronotherapy ( 2–10 mg/day ) in the 9-month open-label extension . Duration of morning stiffness of the joints ( MS ) , disease activity scores ( DAS28 ) , American College of Rheumatology ( ACR20 ) responses and plasma levels of interleukin 6 ( IL-6 ) were assessed . Safety was analysed from adverse event reports and laboratory investigations . Results During the 3-month double-blind phase , patients in the MR group achieved a reduction in MS of 33.1 % while no change was observed in the IR group . After 6 months of treatment , MS was reduced in the IR/MR group by 54 % and in the MR/MR group by 56 % . MS reduction after 12 months was 45 % ( IR/MR group ) and 55 % ( MR/MR group ) . Plasma levels of IL-6 declined on MR treatment . DAS28 was reduced from 5.8 to 4.8 ( MR/MR group ) and 4.9 ( IR/MR group ) , respectively . 37 % of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria . Adverse events did not differ from the known profile of low-dose prednisone . Conclusions Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which result ed in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months BACKGROUND The value of intensive combination therapy in early rheumatoid arthritis is unproven . In a multicentre , double-blind , r and omised trial ( COBRA ) , we compared the combination of sulphasalazine ( 2 g/day ) , methotrexate ( 7.5 mg/week ) , and prednisolone ( initially 60 mg/day , tapered in 6 weekly steps to 7.5 mg/day ) with sulphasalazine alone . METHODS 155 patients with early rheumatoid arthritis ( median duration 4 months ) were r and omly assigned combined treatment ( 76 ) or sulphasalazine alone ( 79 ) . Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks , respectively . The main outcomes were the pooled index ( a weighted change score of five disease activity measures ) and the Sharp/Van der Heijde radiographic damage score in h and s and feet . Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation . FINDINGS At week 28 , the mean pooled index was 1.4 ( 95 % CI 1.2 - 1.6 ) in the combined treatment group and 0.8 ( 0.6 - 1.0 ) in the sulphasalazine group ( p < 0.0001 ) . At this time , 55 ( 72 % ) and 39 ( 49 % ) patients , respectively , were improved according to American College of Rheumatology criteria . The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped , and there were no further changes after methotrexate was stopped . At 28 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 28 ) in the combined-therapy group and 4 ( 0 - 44 ) in the sulphasalazine group ( p < 0.0001 ) . The increases at week 56 ( 2 [ 0 - 43 ] vs 6 [ 0 - 54 ] , p = 0.004 ) , and at week 80 ( 4 [ 0 - 80 ] vs 12 [ 0 - 72 ] , p = 0.01 ) were also significant . Further analysis suggests that combined therapy immediately suppressed damage progression , whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months . There were fewer withdrawals in the combined therapy than the sulphasalazine group ( 6 [ 8 % ] vs 23 [ 29 % ] ) , and they occurred later . INTERPRETATION This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped . Although confirmatory studies and long-term follow-up are needed , this approach may prove useful in the treatment of early rheumatoid arthritis OBJECTIVE Assessment of the cost-effectiveness and cost-utility of early intervention in rheumatoid arthritis ( RA ) patients , with combined step-down prednisolone , methotrexate and sulphasalazine , compared to sulphasalazine alone . METHODS Multicentre 56 week r and omized double-blind trial with full economic analysis of direct costs and utility analysis with rating scale and st and ard gamble measurement techniques . RESULTS The combined-treatment group included 76 patients and the sulphasalazine group 78 patients . The mean total costs per patient in the first 56 weeks of follow-up were $ 5519 for combined treatment and $ 6511 for treatment with sulphasalazine alone ( P = 0.37 ) . Out-patient care , in-patient care and non-health care each contributed about one-third to the total costs . The combined-treatment group appeared to generate savings in the length of hospital stay for RA , non- protocol drugs and costs of home help , but comparisons were not statistically significant . Protocol drugs and monitoring were slightly more expensive in the combined-treatment group . Clinical , radiographic and functional outcomes significantly favoured combined treatment at week 28 ( radiography also at week 56 ) . Utility scores also favoured combined treatment . CONCLUSION Combined treatment is cost-effective due to enhanced efficacy at lower or equal direct costs Objective . To investigate the effects of longterm low-dose chronotherapy with modified-release ( MR ) prednisone for rheumatoid arthritis ( RA ) on the hypothalamus-pituitary-adrenal ( HPA ) axis as part of the Circadian Administration of Prednisone in Rheumatoid Arthritis ( CAPRA-1 ) study . This consisted of a 3-month active-controlled phase and a 9-month open-label extension with MR prednisone  including patients previously treated with prednisone  ( Clinical Trials.gov number NCT00146640 ) . Methods .  Corticotropin-releasing hormone ( CRH ) tests were performed on 28 patients at 3 timepoints : at baseline on pre study immediate-release ( IR ) prednisone , after the 3-month double-blind phase on either IR prednisone or MR prednisone , and after the 9-month open-label extension on MR prednisone . Changes of cortisol were assessed and compared to individual patients ’ efficacy and safety data . Results . The increase ( mean , SD ) of cortisol plasma concentrations after injection of corticorelin was 5.5 ( 4.37 ) μg/dl on IR prednisone at baseline ( n = 21 ) and 5.3 ( 4.07 ) μg/dl on MR prednisone at 12 months ( n = 22 ) . Numbers of normal/suppressed/no response reactions did not differ among treatments . Switching from IR to MR prednisone did not influence responses , nor did longterm treatment of up to 12 months with MR prednisone . No worsening of adrenal impairment was observed on treatment with nighttime-release prednisone in patients with low responsiveness to CRH testing before the treatment with MR prednisone . Conclusion . Treatment with nighttime-release prednisone did not change adrenocortical function over 12 months . We presume that chronotherapy with this nighttime-release prednisone may improve the efficacy of longterm low-dose glucocorticoid treatment in patients with RA OBJECTIVE The effects of a 12-week treatment with modified-release prednisone ( MR-pred ) on the costs of drug treatment of RA were modelled . METHODS With the results of a recent r and omized trial as source data , we expressed the effect of treatment ( MR-pred vs placebo ) on the decrease in the proportion of RA patients meeting disease activity thresholds for reimbursement of biologic treatment . RESULTS The results showed 11 - 13 % more patients on MR-pred than on placebo dropped below reimbursement thresholds for The Netherl and s , Belgium and the UK . Assuming 1 year of biologics cost € 15,000 and MR-pred costs € 1/day , € 396 are saved in each patient delaying biologic treatment by 12 weeks . CONCLUSION Despite a considerably higher cost than conventional prednisone , MR-pred is a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic agents OBJECTIVE To describe the effect of indirect costs for patients with early rheumatoid arthritis ( RA ) within the COBRA trial ( Combinatietherapie Bij Reumatoide Artritis ) on the cost-effectiveness of both therapies . Analyses of the efficacy and direct costs of the treatments have already been reported . METHODS Patients with early RA selected for the 56-week trial were r and omly assigned to prednisolone , methotrexate , and sulfasalazine ( the COBRA combination ) ( n = 76 , tapered after 28 weeks ) or to sulfasalazine ( SSZ ; n = 79 , of which 78 patients were evaluable ) alone . The main efficacy outcomes were a pooled index and radiographic damage score in h and s and feet , and utilities . Direct and indirect costs were measured ( from a societal perspective ) by means of cost diaries and interviews completed by patients during the intervention phase and the followup phase , each lasting 28 weeks . Differences in mean costs between groups and cost-utility ratios were evaluated by applying nonparametric bootstrapping techniques . RESULTS In the first 28 weeks , indirect costs per patient totaled US $ 2,578 and US $ 3,638 for COBRA and SSZ therapy , respectively ( p = 0.09 ) . The total costs were $ 5,931 and $ 7,853 , respectively ( p < 0.05 ) . These differences were lost in the second 28 weeks . For the total period the mean total costs per patient were $ 10,262 and $ 12,788 , respectively ( p = 0.11 ) . Sensitivity analyses showed robustness of the data . The point estimate of the cost per quality -adjusted life-year based on the rating scale was negative at $ -385 , suggesting dominance of COBRA ( more effect at lower cost ) . CONCLUSION COBRA therapy adds additional disease control ( improvements in disease activity , physical function , and rate of damage progression ) at lower or equal cost compared to SSZ in early RA OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis ( COBRA ) trial demonstrated that step-down combination therapy with prednisolone , methotrexate , and sulfasalazine ( SSZ ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis ( RA ) . The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time , and to determine which baseline 
    Output:
    