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: OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis ( RA ) with an inadequate response to methotrexate ( MTX ) .  Data from a planned 12-month interim analysis are reported . METHODS In this double-blind , parallel-group , placebo-controlled study , patients receiving background MTX  were r and omized 4:4:1:1 to tofacitinib at 5 mg twice daily , tofacitinib at 10 mg twice daily , placebo to tofacitinib at 5 mg twice daily , and placebo to tofacitinib at 10 mg twice daily . At month 3 , nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above ; remaining placebo-treated patients were advanced at 6 months . Four primary efficacy end points were all analyzed in a step-down procedure . RESULTS At month 6 , response rates according to the American College of Rheumatology 20 % improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo ( 51.5 % and 61.8 % , respectively , versus 25.3 % ; both P < 0.0001 ) . At month 6 , least squares mean ( LSM ) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06 , respectively , versus 0.47 for placebo ( P = 0.0792 and P ≤ 0.05 , respectively ) . At month 3 , LSM changes in the Health Assessment Question naire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 ( significance not declared due to step-down procedure ) and -0.54 ( P < 0.0001 ) , respectively , versus -0.15 for placebo . At month 6 , rates of remission ( defined as a value < 2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ) for tofacitinib at 5 mg and 10 mg twice daily were 7.2 % ( significance not declared due to step-down procedure ) and 16.0 % ( P < 0.0001 ) , respectively , versus 1.6 % for placebo . The safety profile was consistent with findings in previous studies . CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX The approach to treatment of RA has evolved substantially in recent years with the introduction of highly effective novel therapies that have result ed in new treatment paradigms , such as treat-to-target and the treatment of patients earlier in their disease course [ 1 , 2 ] . Clinicians are very interested in studies that compare the effectiveness of medications that could help them achieve optimal treatment outcomes for their patients . Extrapolation of the results of such studies into clinical practice depends on accurate assessment of data from the clinical trials . This assessment has become increasingly challenging as study design s have become increasingly complex , with multiple arms and changes in treatments over the course of a trial . There are many methods to analyse a given set of data ; with the same data set , depending on the method of analysis , different conclusions can be reached . To help st and ardize this process , a European League Against Rheumatism (EULAR)/ACR committee created guidelines on reporting data from clinical trials [ 3 ] . The complexities of this analysis are illustrated by a recent example . The R and omized Comparative Effectiveness Study of Oral Triple Therapy versus Etanercept plus Methotrexate in the Early , Aggressive Rheumatoid Arthritis ( TEAR ) trial was design ed to address two important clinical questions : ( i ) is it better to intensively treat all early RA patients with multiple DMARDs  , or reserve this treatment only for those who do not appropriately respond to MTX monotherapy ? and ( ii ) is the combination therapy of MTX plus etanercept ( ETN ) superior to triple combination therapy of MTX , SSZ and HCQ ( TT ) , either initially or after insufficient efficacy of MTX at 6 months ? [ 4 ] . Patients with early RA were r and omly assigned to receive MTX monotherapy , MTX plus ETN or TT . At 6 months , patients treated with MTX monotherapy who did not achieve DAS28 < 3.2 were stepped up to add either ETN or move to TT and treated for 102 weeks . The primary outcome , by the protocol , was the area under the curve ( AUC ) of DAS28 from weeks 48 to 102 . Although many of the items suggested by a joint EULAR/ACR committee on reporting disease activity in clinical trials of patients [ 3 ] were reported , several facets of the methods of data analysis need to be fully understood in order to establish whether the reader concurs with the authors ’ conclusions that this study showed no difference in clinical outcomes at 2 years between patients initially treated with MTX plus ETN or TT . The data reported were an observed analysis only for patients who continued in the trial from week 48 to 102 patients had to have done well clinical ly and not had a significant adverse event to remain in the study through week 48 . A more traditional statistical analysis , such as a nonresponder imputation or last observation carried forward from day 0 to week 102 might have given different results . The first question posed , whether it is more effective to start either combination or MTX monotherapy , was not answered ; the results are not presented for those patients initially treated with MTX  who achieved DAS28 < 3.2 at week 26 and then continued to week 102 . The primary outcome reported in the manuscript was an observed group analysis of change in the mean DAS28-ESR from week 48 to 102 and not the AUC of the DAS28 during this time period . The authors stated that their statistical analysis plan was confirmed by their secondary analyses , which did include non-responder imputation and last observation carried forward . However , these analyses were also performed only on patients in the study from week 48 to 102 . In addition to design and statistical considerations , some of the data can be interpreted differently from the authors , and this might be worth some further examination . For instance , the authors reported that there was no difference in the change in DAS28 , or other clinical measures , between the patient groups studied . However , there was a treatment difference at week 102 between the ETN and TT groups for ACR70 ( 18.2 vs 11.3 % , P = 0.02 ) . This would suggest that ETN plus MTX was more effective in achieving a profound response . This difference in profound response may have led to the significant difference in radiographic progression reported with ETN and MTX treatment vs TT at week 102 . The radiographic difference was noted despite the fact that X-rays were not done in patients who withdrew early ; in other studies , results at the time of exit have been extrapolated to the final endpoint to allow comparison . In this case , radiological data are only in those observed or study completers ; by definition , such patients usually fare quite well and patients who do well have less progression of joint damage . Initial TT and initial MTX monotherapy with step-up had similar ACR20/50/70 response rates at 2 years , OBJECTIVE To determine the efficacy , safety , and tolerability of 3 different dosages of CP-690,550 , a potent , orally active JAK inhibitor , in patients with active rheumatoid arthritis ( RA ) in whom methotrexate , etanercept , infliximab , or adalimumab caused an inadequate or toxic response . METHODS Patients ( n = 264 ) were r and omized equally to receive placebo , 5 mg of CP-690,550 , 15 mg of CP-690,550 , or 30 mg of CP-690,550 twice daily for 6 weeks , and were followed up for an additional 6 weeks after treatment . The primary efficacy end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at 6 weeks . RESULTS By week 6 , the ACR20 response rates were 70.5 % , 81.2 % , and 76.8 % in the 5 mg , 15 mg , and 30 mg twice daily groups , respectively , compared with 29.2 % in the placebo group ( P < 0.001 ) . Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1 . ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4 . The most common adverse events reported were headache and nausea . The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4 % ( versus 26.2 % in the placebo group ) . No opportunistic infections or deaths occurred . Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels , and increases in mean serum creatinine level ( 0.04 - 0.06 mg/dl ) were seen in all CP-690,550 treatment arms . CONCLUSION Our findings indicate that CP-690,550 is efficacious in the treatment of RA , result ing in rapid , statistically significant , and clinical ly meaningful reductions in the signs and symptoms of RA . Further studies of CP-690,550 in RA are warranted OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA 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 pred 
    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: OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis ( RA ) with an inadequate response to methotrexate ( MTX ) .  Data from a planned 12-month interim analysis are reported . METHODS In this double-blind , parallel-group , placebo-controlled study , patients receiving background MTX  were r and omized 4:4:1:1 to tofacitinib at 5 mg twice daily , tofacitinib at 10 mg twice daily , placebo to tofacitinib at 5 mg twice daily , and placebo to tofacitinib at 10 mg twice daily . At month 3 , nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above ; remaining placebo-treated patients were advanced at 6 months . Four primary efficacy end points were all analyzed in a step-down procedure . RESULTS At month 6 , response rates according to the American College of Rheumatology 20 % improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo ( 51.5 % and 61.8 % , respectively , versus 25.3 % ; both P < 0.0001 ) . At month 6 , least squares mean ( LSM ) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06 , respectively , versus 0.47 for placebo ( P = 0.0792 and P ≤ 0.05 , respectively ) . At month 3 , LSM changes in the Health Assessment Question naire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 ( significance not declared due to step-down procedure ) and -0.54 ( P < 0.0001 ) , respectively , versus -0.15 for placebo . At month 6 , rates of remission ( defined as a value < 2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ) for tofacitinib at 5 mg and 10 mg twice daily were 7.2 % ( significance not declared due to step-down procedure ) and 16.0 % ( P < 0.0001 ) , respectively , versus 1.6 % for placebo . The safety profile was consistent with findings in previous studies . CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX The approach to treatment of RA has evolved substantially in recent years with the introduction of highly effective novel therapies that have result ed in new treatment paradigms , such as treat-to-target and the treatment of patients earlier in their disease course [ 1 , 2 ] . Clinicians are very interested in studies that compare the effectiveness of medications that could help them achieve optimal treatment outcomes for their patients . Extrapolation of the results of such studies into clinical practice depends on accurate assessment of data from the clinical trials . This assessment has become increasingly challenging as study design s have become increasingly complex , with multiple arms and changes in treatments over the course of a trial . There are many methods to analyse a given set of data ; with the same data set , depending on the method of analysis , different conclusions can be reached . To help st and ardize this process , a European League Against Rheumatism (EULAR)/ACR committee created guidelines on reporting data from clinical trials [ 3 ] . The complexities of this analysis are illustrated by a recent example . The R and omized Comparative Effectiveness Study of Oral Triple Therapy versus Etanercept plus Methotrexate in the Early , Aggressive Rheumatoid Arthritis ( TEAR ) trial was design ed to address two important clinical questions : ( i ) is it better to intensively treat all early RA patients with multiple DMARDs  , or reserve this treatment only for those who do not appropriately respond to MTX monotherapy ? and ( ii ) is the combination therapy of MTX plus etanercept ( ETN ) superior to triple combination therapy of MTX , SSZ and HCQ ( TT ) , either initially or after insufficient efficacy of MTX at 6 months ? [ 4 ] . Patients with early RA were r and omly assigned to receive MTX monotherapy , MTX plus ETN or TT . At 6 months , patients treated with MTX monotherapy who did not achieve DAS28 < 3.2 were stepped up to add either ETN or move to TT and treated for 102 weeks . The primary outcome , by the protocol , was the area under the curve ( AUC ) of DAS28 from weeks 48 to 102 . Although many of the items suggested by a joint EULAR/ACR committee on reporting disease activity in clinical trials of patients [ 3 ] were reported , several facets of the methods of data analysis need to be fully understood in order to establish whether the reader concurs with the authors ’ conclusions that this study showed no difference in clinical outcomes at 2 years between patients initially treated with MTX plus ETN or TT . The data reported were an observed analysis only for patients who continued in the trial from week 48 to 102 patients had to have done well clinical ly and not had a significant adverse event to remain in the study through week 48 . A more traditional statistical analysis , such as a nonresponder imputation or last observation carried forward from day 0 to week 102 might have given different results . The first question posed , whether it is more effective to start either combination or MTX monotherapy , was not answered ; the results are not presented for those patients initially treated with MTX  who achieved DAS28 < 3.2 at week 26 and then continued to week 102 . The primary outcome reported in the manuscript was an observed group analysis of change in the mean DAS28-ESR from week 48 to 102 and not the AUC of the DAS28 during this time period . The authors stated that their statistical analysis plan was confirmed by their secondary analyses , which did include non-responder imputation and last observation carried forward . However , these analyses were also performed only on patients in the study from week 48 to 102 . In addition to design and statistical considerations , some of the data can be interpreted differently from the authors , and this might be worth some further examination . For instance , the authors reported that there was no difference in the change in DAS28 , or other clinical measures , between the patient groups studied . However , there was a treatment difference at week 102 between the ETN and TT groups for ACR70 ( 18.2 vs 11.3 % , P = 0.02 ) . This would suggest that ETN plus MTX was more effective in achieving a profound response . This difference in profound response may have led to the significant difference in radiographic progression reported with ETN and MTX treatment vs TT at week 102 . The radiographic difference was noted despite the fact that X-rays were not done in patients who withdrew early ; in other studies , results at the time of exit have been extrapolated to the final endpoint to allow comparison . In this case , radiological data are only in those observed or study completers ; by definition , such patients usually fare quite well and patients who do well have less progression of joint damage . Initial TT and initial MTX monotherapy with step-up had similar ACR20/50/70 response rates at 2 years , OBJECTIVE To determine the efficacy , safety , and tolerability of 3 different dosages of CP-690,550 , a potent , orally active JAK inhibitor , in patients with active rheumatoid arthritis ( RA ) in whom methotrexate , etanercept , infliximab , or adalimumab caused an inadequate or toxic response . METHODS Patients ( n = 264 ) were r and omized equally to receive placebo , 5 mg of CP-690,550 , 15 mg of CP-690,550 , or 30 mg of CP-690,550 twice daily for 6 weeks , and were followed up for an additional 6 weeks after treatment . The primary efficacy end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at 6 weeks . RESULTS By week 6 , the ACR20 response rates were 70.5 % , 81.2 % , and 76.8 % in the 5 mg , 15 mg , and 30 mg twice daily groups , respectively , compared with 29.2 % in the placebo group ( P < 0.001 ) . Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1 . ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4 . The most common adverse events reported were headache and nausea . The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4 % ( versus 26.2 % in the placebo group ) . No opportunistic infections or deaths occurred . Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels , and increases in mean serum creatinine level ( 0.04 - 0.06 mg/dl ) were seen in all CP-690,550 treatment arms . CONCLUSION Our findings indicate that CP-690,550 is efficacious in the treatment of RA , result ing in rapid , statistically significant , and clinical ly meaningful reductions in the signs and symptoms of RA . Further studies of CP-690,550 in RA are warranted OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA 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 pred 
    Output:
    