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: The objective of this study was to evaluate the efficacy , pharmacokinetics , and safety of adalimumab in patients with polyarticular juvenile idiopathic arthritis ( JIA ) in Japan . Patients aged 4 to 17 years were enrolled in a single-arm , open-label , multicentre study of adalimumab .  Patients weighing < 30 kg received 20 mg every other week ( eow ) , and those ≥30 kg received 40 mg eow . Concomitant methotrexate ( MTX ) was allowed ( ≤10 mg/m2 per week ) . The primary efficacy outcome was the percent of patients with American College of Rheumatology Pediatric 30 response  ( ACR Pedi 30 ) at week 16 . JIA core variables , serum adalimumab concentrations , and anti-adalimumab antibodies ( AAAs ) were analysed . Patients were monitored for adverse events ( AEs ) . Twenty-five patients ( 20 with concomitant MTX at baseline and 5 without ) were enrolled : 24 patients completed 16 weeks of therapy and 22 patients completed 60 weeks . At week 16 , 90 % of patients with MTX and 100 % without MTX  achieved ACR Pedi 30 ; response rates were maintained through week 60 in 94 and 80 % of patients , respectively . Each JIA core variable improved over time . Six patients became AAA positive ( two each at weeks 8 , 16 , and 60 ) , some of which were transient . All six AAA-positive patients achieved ACR Pedi 30 at week 16 , and four maintained that response at week 60 . Six patients ( all with MTX ) experienced nine serious AEs ( JIA , pyrexia , arthralgia , pneumonia , hepatitis B infection , pharyngitis , dehydration , pharyngeal pain , and pneumonia ) . In pediatric patients with polyarticular JIA in Japan , adalimumab was safe and effective for reducing disease activity for up to 60 weeks BACKGROUND We did a r and omised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn 's disease who respond to a single infusion of infliximab .  METHODS 573 patients with a score of at least 220 on the Crohn 's disease activity index ( CDAI ) received a 5 mg/kg intravenous infusion of infliximab at week 0 . After assessment of response at week 2 , patients were r and omly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 ( group I ) , repeat infusions of 5 mg/kg infliximab at the same timepoints ( group II ) , or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg ( group III ) . The prespecified co- primary endpoints were the proportion of patients who responded at week 2 and were in remission ( CDAI < 150 ) at week 30 and the time to loss of response up to week 54 in patients who responded . Analyses of the co- primary endpoints were by intention to treat . FINDINGS 335 ( 58 % ) patients responded to a single infusion of infliximab within 2 weeks . At week 30 , 23 of 110 ( 21 % ) group I patients were in remission , compared with 44 of 113 ( 39 % ) group II ( p=0.003 ) and 50 of 112 ( 45 % ) group III ( p=0.0002 ) patients . Thus , patients in groups II and III combined were more likely to sustain clinical remission than patients in group I ( odds ratio 2.7 , 95 % CI 1.6 - 4.6 ) . Throughout the 54-week trial , the median time to loss of response was 38 weeks ( IQR 15 to > 54 ) and more than 54 weeks ( 21 to > 54 ) for groups II and III , respectively , compared with 19 weeks ( 10 - 45 ) for group I ( p=0.002 and p=0.0002 , respectively ) .  Infliximab safety was consistent with that seen in other trials of infliximab in Crohn 's disease and rheumatoid arthritis . In particular , the incidence of serious infections was similar across treatment groups . INTERPRETATION Patients with Crohn 's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54 , to discontinue corticosteroids , and to maintain their response for a longer period of time , if infliximab treatment is maintained every 8 weeks Background : Data regarding the effectiveness of anti‐tumor necrosis factor ( TNF ) agents for resolution of extraintestinal manifestations ( EIMs ) are scarce . The CARE study evaluated clinical effectiveness , EIM resolution , and safety of adalimumab in a large pan‐European cohort of patients with moderate to severe Crohn 's disease ( CD ) . Methods : In all , 945 patients with a Harvey – Bradshaw Index ( HBI ) ≥7 enrolled in this multicenter , open‐label phase IIIb trial . Patients received subcutaneous adalimumab , 160/80 mg at weeks 0/2 , then 40 mg every other week . Dose adjustments were allowed for CD‐related concomitant medications ( from week 8) and adalimumab ( from week 12 ) . Clinical endpoints were analyzed through week 20 for all patients , and after stratification by prior infliximab exposure and by reason for discontinuing infliximab ( primary nonresponse [ PNR ] or other ) . Results : The remission rate ( HBI < 5 ) at week 20 was 52 % ( 95 % confidence interval , 49%–55 % ) overall , and was higher for infliximab‐naïve versus infliximab‐exposed patients ( 62 % versus 42 % , P < 0.001 ) . Remission rates were similar for PNR ( 37 % ) and other reasons ( 43 % ; P = 0.278 ) . Of 497 patients with baseline EIMs , 51 % were free of EIM signs and symptoms at week 20 . Serious infectious adverse events were reported in 5 % of patients . Opportunistic infections and malignancies were rare ( ≤1 % ) . There was one case of demyelinating disease , but no occurrences of lupus , tuberculosis , or death . Conclusions : In this large cohort of patients , adalimumab treatment result ed in rates of clinical remission and EIM resolution exceeding 50 % , and substantial rates of effectiveness in patients who had PNR to  infliximab . Adalimumab was well tolerated , with safety consistent with prior reports . ( Inflamm Bowel Dis 2011 Objective CONCERTO was a r and omised , double-blind , parallel-armed study of methotrexate ( MTX ) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis ( RA ) . Methods Early , biologic and MTX-naive RA patients ( N=395 ) were evenly r and omised to open-label adalimumab ( 40 mg every other week ) plus weekly blinded 2.5 , 5 , 10 or 20 mg MTX for 26 weeks . Clinical , radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance . Results Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint , 28-joint count disease activity score with C reactive protein ( DAS28(CRP ) ) < 3.2 ( 42.9 % , 44.0 % , 56.6 % and 60.2 % for 2.5 , 5 , 10 or 20 mg/week MTX , respectively ) , DAS28(CRP ) < 2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab . No statistical differences in minimal clinical ly important differences in physical function were detected . Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by vali date d clinical indices ; differences comparing 10 and 20 mg MTX were minimal .  Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX . More patients experienced infectious adverse events with increasing MTX dose . Conclusions Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile . In early RA patients initiating adalimumab combination therapy , efficacy of 10 and 20 mg/week MTX appeared equivalent BACKGROUND & AIMS This study evaluated the efficacy and safety of adalimumab , a fully human , anti-tumor necrosis factor monoclonal antibody administered subcutaneously , in the maintenance of response and remission in patients with moderate to severe Crohn 's disease ( CD ) . METHODS Patients received open-label induction therapy with adalimumab 80 mg ( week 0 ) followed by 40 mg ( week 2 ) . At week 4 , patients were stratified by response ( decrease in Crohn 's Disease Activity Index > or = 70 points from baseline ) and r and omized to double-blind treatment with placebo , adalimumab 40 mg every other week ( eow ) , or adalimumab 40 mg weekly through week 56 . Co- primary end points were the percentages of r and omized responders who achieved clinical remission ( Crohn 's Disease Activity Index score < 150 ) at weeks 26 and 56 . RESULTS The percentage of r and omized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 ( 40 % , 47 % , and 17 % , respectively ; P < .001 ) and week 56 ( 36 % , 41 % , and 12 % , respectively ; P < .001 ) . No significant differences in efficacy between adalimumab eow and weekly were observed . More patients receiving placebo discontinued treatment because of an adverse event ( 13.4 % ) than those receiving adalimumab ( 6.9 % and 4.7 % in the 40-mg eow and 40-mg weekly groups , respectively ) . CONCLUSIONS Among patients who responded to adalimumab  , both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks . Adalimumab was well-tolerated , with a safety profile consistent with previous experience with the drug Objective To characterise the temporal evolution of antibodies to infliximab ( ATI ) . Design Prospect i ve observational study of  infliximab-treated patients with inflammatory bowel disease between 2009 and 2012 . Interventions Trough levels of infliximab and ATI were measured before each infusion by anti-λ ELISA . Patients were monitored for disease activity by clinical activity indexes and for dose-intensification or infliximab cessation . The occurrence of transient ATI disappearing spontaneously without intervention was recorded separately . Results 125 patients were included ( 98 Crohn 's disease , 27 ulcerative colitis , median follow-up 11.5±22 months ) and 1119 sera were analysed for infliximab and ATI levels . Kaplan-Meier analysis showed that 42 % of patients remained ATI-free by 4 years of treatment . Most ( 90 % ) of the patients who developed ATI did so within the first 12 months of therapy , whereas transient ATI were detected throughout the duration of infliximab therapy ( p<0.001 ) . ATI incidence was similar between patients who received infliximab  previously ( episodic/interrupted therapy patients , n=14 ) and scheduled-therapy patients ( n=111 ) . In the scheduled group , combination immunomodulator+infliximab result ed in longer ATI-free survival compared with monotherapy ( p=0.003 , logrank test ) . Survival free of clinical loss of response was enjoyed by 51 % of patients , and serial measurements showed that ATI development often preceded the onset of clinical flare . Conclusions When followed prospect ively , most patients who develop ATI do so within the first 12 months of therapy . This incidence is reduced by concomitant immunomodulator even in scheduled-therapy patients . In contrast , transient ATI , which are of little clinical significance , can appear haphazardly at any time during treatment . The onset of clinical loss of response may lag behind the appearance of anti-infliximab antibodies BACKGROUND The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn 's disease are unknown . METHODS In this r and omized , double-blind trial , we evaluated the efficacy of infliximab monotherapy , azathioprine monotherapy , and the two drugs combined in 508 adults with moderate-to-severe Crohn 's disease who had not undergone previous immunosuppressive or biologic therapy . Patients were r and omly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0 , 2 , and 6 and then every 8 weeks plus daily oral placebo capsules ; 2.5 mg of 
    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: The objective of this study was to evaluate the efficacy , pharmacokinetics , and safety of adalimumab in patients with polyarticular juvenile idiopathic arthritis ( JIA ) in Japan . Patients aged 4 to 17 years were enrolled in a single-arm , open-label , multicentre study of adalimumab .  Patients weighing < 30 kg received 20 mg every other week ( eow ) , and those ≥30 kg received 40 mg eow . Concomitant methotrexate ( MTX ) was allowed ( ≤10 mg/m2 per week ) . The primary efficacy outcome was the percent of patients with American College of Rheumatology Pediatric 30 response  ( ACR Pedi 30 ) at week 16 . JIA core variables , serum adalimumab concentrations , and anti-adalimumab antibodies ( AAAs ) were analysed . Patients were monitored for adverse events ( AEs ) . Twenty-five patients ( 20 with concomitant MTX at baseline and 5 without ) were enrolled : 24 patients completed 16 weeks of therapy and 22 patients completed 60 weeks . At week 16 , 90 % of patients with MTX and 100 % without MTX  achieved ACR Pedi 30 ; response rates were maintained through week 60 in 94 and 80 % of patients , respectively . Each JIA core variable improved over time . Six patients became AAA positive ( two each at weeks 8 , 16 , and 60 ) , some of which were transient . All six AAA-positive patients achieved ACR Pedi 30 at week 16 , and four maintained that response at week 60 . Six patients ( all with MTX ) experienced nine serious AEs ( JIA , pyrexia , arthralgia , pneumonia , hepatitis B infection , pharyngitis , dehydration , pharyngeal pain , and pneumonia ) . In pediatric patients with polyarticular JIA in Japan , adalimumab was safe and effective for reducing disease activity for up to 60 weeks BACKGROUND We did a r and omised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn 's disease who respond to a single infusion of infliximab .  METHODS 573 patients with a score of at least 220 on the Crohn 's disease activity index ( CDAI ) received a 5 mg/kg intravenous infusion of infliximab at week 0 . After assessment of response at week 2 , patients were r and omly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 ( group I ) , repeat infusions of 5 mg/kg infliximab at the same timepoints ( group II ) , or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg ( group III ) . The prespecified co- primary endpoints were the proportion of patients who responded at week 2 and were in remission ( CDAI < 150 ) at week 30 and the time to loss of response up to week 54 in patients who responded . Analyses of the co- primary endpoints were by intention to treat . FINDINGS 335 ( 58 % ) patients responded to a single infusion of infliximab within 2 weeks . At week 30 , 23 of 110 ( 21 % ) group I patients were in remission , compared with 44 of 113 ( 39 % ) group II ( p=0.003 ) and 50 of 112 ( 45 % ) group III ( p=0.0002 ) patients . Thus , patients in groups II and III combined were more likely to sustain clinical remission than patients in group I ( odds ratio 2.7 , 95 % CI 1.6 - 4.6 ) . Throughout the 54-week trial , the median time to loss of response was 38 weeks ( IQR 15 to > 54 ) and more than 54 weeks ( 21 to > 54 ) for groups II and III , respectively , compared with 19 weeks ( 10 - 45 ) for group I ( p=0.002 and p=0.0002 , respectively ) .  Infliximab safety was consistent with that seen in other trials of infliximab in Crohn 's disease and rheumatoid arthritis . In particular , the incidence of serious infections was similar across treatment groups . INTERPRETATION Patients with Crohn 's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54 , to discontinue corticosteroids , and to maintain their response for a longer period of time , if infliximab treatment is maintained every 8 weeks Background : Data regarding the effectiveness of anti‐tumor necrosis factor ( TNF ) agents for resolution of extraintestinal manifestations ( EIMs ) are scarce . The CARE study evaluated clinical effectiveness , EIM resolution , and safety of adalimumab in a large pan‐European cohort of patients with moderate to severe Crohn 's disease ( CD ) . Methods : In all , 945 patients with a Harvey – Bradshaw Index ( HBI ) ≥7 enrolled in this multicenter , open‐label phase IIIb trial . Patients received subcutaneous adalimumab , 160/80 mg at weeks 0/2 , then 40 mg every other week . Dose adjustments were allowed for CD‐related concomitant medications ( from week 8) and adalimumab ( from week 12 ) . Clinical endpoints were analyzed through week 20 for all patients , and after stratification by prior infliximab exposure and by reason for discontinuing infliximab ( primary nonresponse [ PNR ] or other ) . Results : The remission rate ( HBI < 5 ) at week 20 was 52 % ( 95 % confidence interval , 49%–55 % ) overall , and was higher for infliximab‐naïve versus infliximab‐exposed patients ( 62 % versus 42 % , P < 0.001 ) . Remission rates were similar for PNR ( 37 % ) and other reasons ( 43 % ; P = 0.278 ) . Of 497 patients with baseline EIMs , 51 % were free of EIM signs and symptoms at week 20 . Serious infectious adverse events were reported in 5 % of patients . Opportunistic infections and malignancies were rare ( ≤1 % ) . There was one case of demyelinating disease , but no occurrences of lupus , tuberculosis , or death . Conclusions : In this large cohort of patients , adalimumab treatment result ed in rates of clinical remission and EIM resolution exceeding 50 % , and substantial rates of effectiveness in patients who had PNR to  infliximab . Adalimumab was well tolerated , with safety consistent with prior reports . ( Inflamm Bowel Dis 2011 Objective CONCERTO was a r and omised , double-blind , parallel-armed study of methotrexate ( MTX ) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis ( RA ) . Methods Early , biologic and MTX-naive RA patients ( N=395 ) were evenly r and omised to open-label adalimumab ( 40 mg every other week ) plus weekly blinded 2.5 , 5 , 10 or 20 mg MTX for 26 weeks . Clinical , radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance . Results Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint , 28-joint count disease activity score with C reactive protein ( DAS28(CRP ) ) < 3.2 ( 42.9 % , 44.0 % , 56.6 % and 60.2 % for 2.5 , 5 , 10 or 20 mg/week MTX , respectively ) , DAS28(CRP ) < 2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab . No statistical differences in minimal clinical ly important differences in physical function were detected . Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by vali date d clinical indices ; differences comparing 10 and 20 mg MTX were minimal .  Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX . More patients experienced infectious adverse events with increasing MTX dose . Conclusions Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile . In early RA patients initiating adalimumab combination therapy , efficacy of 10 and 20 mg/week MTX appeared equivalent BACKGROUND & AIMS This study evaluated the efficacy and safety of adalimumab , a fully human , anti-tumor necrosis factor monoclonal antibody administered subcutaneously , in the maintenance of response and remission in patients with moderate to severe Crohn 's disease ( CD ) . METHODS Patients received open-label induction therapy with adalimumab 80 mg ( week 0 ) followed by 40 mg ( week 2 ) . At week 4 , patients were stratified by response ( decrease in Crohn 's Disease Activity Index > or = 70 points from baseline ) and r and omized to double-blind treatment with placebo , adalimumab 40 mg every other week ( eow ) , or adalimumab 40 mg weekly through week 56 . Co- primary end points were the percentages of r and omized responders who achieved clinical remission ( Crohn 's Disease Activity Index score < 150 ) at weeks 26 and 56 . RESULTS The percentage of r and omized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 ( 40 % , 47 % , and 17 % , respectively ; P < .001 ) and week 56 ( 36 % , 41 % , and 12 % , respectively ; P < .001 ) . No significant differences in efficacy between adalimumab eow and weekly were observed . More patients receiving placebo discontinued treatment because of an adverse event ( 13.4 % ) than those receiving adalimumab ( 6.9 % and 4.7 % in the 40-mg eow and 40-mg weekly groups , respectively ) . CONCLUSIONS Among patients who responded to adalimumab  , both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks . Adalimumab was well-tolerated , with a safety profile consistent with previous experience with the drug Objective To characterise the temporal evolution of antibodies to infliximab ( ATI ) . Design Prospect i ve observational study of  infliximab-treated patients with inflammatory bowel disease between 2009 and 2012 . Interventions Trough levels of infliximab and ATI were measured before each infusion by anti-λ ELISA . Patients were monitored for disease activity by clinical activity indexes and for dose-intensification or infliximab cessation . The occurrence of transient ATI disappearing spontaneously without intervention was recorded separately . Results 125 patients were included ( 98 Crohn 's disease , 27 ulcerative colitis , median follow-up 11.5±22 months ) and 1119 sera were analysed for infliximab and ATI levels . Kaplan-Meier analysis showed that 42 % of patients remained ATI-free by 4 years of treatment . Most ( 90 % ) of the patients who developed ATI did so within the first 12 months of therapy , whereas transient ATI were detected throughout the duration of infliximab therapy ( p<0.001 ) . ATI incidence was similar between patients who received infliximab  previously ( episodic/interrupted therapy patients , n=14 ) and scheduled-therapy patients ( n=111 ) . In the scheduled group , combination immunomodulator+infliximab result ed in longer ATI-free survival compared with monotherapy ( p=0.003 , logrank test ) . Survival free of clinical loss of response was enjoyed by 51 % of patients , and serial measurements showed that ATI development often preceded the onset of clinical flare . Conclusions When followed prospect ively , most patients who develop ATI do so within the first 12 months of therapy . This incidence is reduced by concomitant immunomodulator even in scheduled-therapy patients . In contrast , transient ATI , which are of little clinical significance , can appear haphazardly at any time during treatment . The onset of clinical loss of response may lag behind the appearance of anti-infliximab antibodies BACKGROUND The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn 's disease are unknown . METHODS In this r and omized , double-blind trial , we evaluated the efficacy of infliximab monotherapy , azathioprine monotherapy , and the two drugs combined in 508 adults with moderate-to-severe Crohn 's disease who had not undergone previous immunosuppressive or biologic therapy . Patients were r and omly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0 , 2 , and 6 and then every 8 weeks plus daily oral placebo capsules ; 2.5 mg of 
    Output:
    