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 : The adequacy of exposure of purine analogs as measured by 6-thioguanine nucleotides concentrations in the setting of combination therapy remains poorly understood . The aim of this study was to investigate the relationship between the mean corpuscular volume ( MCV ) value ( as a surrogate marker of 6-thioguanine nucleotides concentration ) and Crohn 's disease outcomes in the setting of combination therapy with infliximab . Methods : The SONIC trial was a r and omized controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine in 508 Crohn 's disease patients . An increase of at least 7 femtoliter ( fL ) of the MCV ( & Dgr;MCV ) was used for statistical analysis . Results : At week 26 , the mean increase of MCV was similar among patients treated with azathioprine alone ( mean of 7.9 fL ) or in combination with infliximab ( mean of 8.5 fL ) . In the azathioprine group , 63.6 % of patients with & Dgr;MCV > 7 were in steroid-free clinical remission at week 26 as compared with 33.3 % of patients without & Dgr;MCV > 7 ( P = 0.0046 ) . In the combination therapy group , & Dgr;MCV above 7 was associated with mucosal healing ( 75.0 % for & Dgr;MCV > 7 versus 47.1 % for & Dgr;MCV < 7 , P = 0.0172 ) but not with steroid-free clinical remission . Patients with a & Dgr;MCV above 7 were more likely to have  infliximab trough level above 3 & mgr;g/mL at week 30 ( 68.4 % versus 38.8 % for & Dgr;MCV < 7 , P = 0.0032 ) . Conclusions : These results suggest that & Dgr;MCV above 7 ( which is a surrogate for a higher 6-thioguanine nucleotides concentration ) leads to improved Crohn 's disease outcomes , even when combined with infliximab . It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy 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 & 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 CONTEXT Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels , and a diminished treatment response . Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up . OBJECTIVE To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term ( 3-year ) follow-up of patients with rheumatoid arthritis ( RA ) . DESIGN , SETTING , AND PATIENTS Prospect i ve cohort study February 2004-September 2008 ; end of follow-up was September 2010 . All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic . MAIN OUTCOME MEASURES Disease activity was monitored and trough serum sample s were obtained at baseline and 8 time points to 156 weeks . Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up . Treatment discontinuation , minimal disease activity , and clinical remission were compared for patients with and without antiadalimumab antibodies . RESULTS After 3 years , 76 of 272 patients ( 28 % ) developed antiadalimumab antibodies--51 of these ( 67 % ) during the first 28 weeks of treatment . Patients without antiadalimumab antibodies had much higher adalimumab concentrations ( median , 12 mg/L ; IQR , 9 - 16 mg/L ) compared with patients with antibody titers from 13 to 100 AU/mL ( median , 5 mg/L ; IQR , 3 - 9 mg/L ; regression coefficient , -4.5 ; 95 % CI , -6.0 to -2.9 ; P < .001 ) and also those greater than 100 AU/mL ( median , 0 mg/L ; IQR , 0 - 3 mg/L ; regression coefficient , -7.1 ; 95 % CI , -8.4 to -5.8 ; P < .001 ) . Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure ( n = 29 [ 38 % ] ; hazard ratio [ HR ] , 3.0 ; 95 % CI , 1.6 - 5.5 ; P < .001 ) compared with antiadalimumab antibody-negative ones ( n = 28 [ 14 % ] ) . Ninety-five of 196 patients ( 48 % ) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients ( 13 % ) with antiadalimumab antibodies ; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints ( DAS28 ) ( < 3.2 ; HR , 3.6 ; 95 % CI , 1.8 - 7.2 ; P < .001 ) compared with antiadalimumab antibody-negative ones . Three of 76 patients ( 4 % ) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 ( 34 % ) antiadalimumab antibody-negative ones ; patients with antiadalimumab antibodies less often achieved remission ( DAS28 < 2.6 ; HR , 7.1 ; 95 % CI , 2.1 - 23.4 ; P < .001 ) compared with antiadalimumab antibody-negative ones . CONCLUSION Among out patients with RA in whom adalimumab was started over 3 years , the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission 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 oral azathioprine per kilogram daily plus a placebo infusion on the st and ard schedule ; or combination therapy with the two drugs . Patients received study medication through week 30 and could continue in a blinded study extension through week 50 . RESULTS Of the 169 patients receiving combination therapy , 96 ( 56.8 % ) were in corticosteroid-free clinical remission at week 26 ( the primary end point ) , as compared with 75 of 169 patients ( 44.4 % ) receiving infliximab alone ( P=0.02 ) and 51 of 170 patients ( 30.0 % ) receiving azathioprine alone ( P<0.001 for the comparison with combination therapy and P=0.006 for the comparison with infliximab ) . Similar numerical trends were found at week 50 . At week 26 , mucosal healing had occurred in 47 of 107 patients ( 43.9 % ) receiving combination therapy , as compared with 28 of 93 patients ( 30.1 % ) receiving infliximab ( P=0.06 ) and 18 of 109 patients ( 16.5 % ) receiving azathioprine ( P<0.001 for the comparison with combination therapy and P=0.02 for the comparison with infliximab ) . Serious infections developed in 3.9 % of patients in the combination-therapy group , 4.9 % of those in the infliximab group , and 5.6 % of those in the azathioprine group . CONCLUSIONS Patients with moderate-to-severe Crohn 's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy . ( Clinical Trials.gov number , NCT00094458 . BACKGROUND & AIMS Adalimumab is an efficacious therapy for active Crohn 's disease , but long-term data are scarce . We conducted an observational study to assess the long-term clinical benefit of adalimumab in patients who failed to respond to infliximab  , specifically focusing on the influence of trough serum concentration and antibodies against adal 
    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 : The adequacy of exposure of purine analogs as measured by 6-thioguanine nucleotides concentrations in the setting of combination therapy remains poorly understood . The aim of this study was to investigate the relationship between the mean corpuscular volume ( MCV ) value ( as a surrogate marker of 6-thioguanine nucleotides concentration ) and Crohn 's disease outcomes in the setting of combination therapy with infliximab . Methods : The SONIC trial was a r and omized controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine in 508 Crohn 's disease patients . An increase of at least 7 femtoliter ( fL ) of the MCV ( & Dgr;MCV ) was used for statistical analysis . Results : At week 26 , the mean increase of MCV was similar among patients treated with azathioprine alone ( mean of 7.9 fL ) or in combination with infliximab ( mean of 8.5 fL ) . In the azathioprine group , 63.6 % of patients with & Dgr;MCV > 7 were in steroid-free clinical remission at week 26 as compared with 33.3 % of patients without & Dgr;MCV > 7 ( P = 0.0046 ) . In the combination therapy group , & Dgr;MCV above 7 was associated with mucosal healing ( 75.0 % for & Dgr;MCV > 7 versus 47.1 % for & Dgr;MCV < 7 , P = 0.0172 ) but not with steroid-free clinical remission . Patients with a & Dgr;MCV above 7 were more likely to have  infliximab trough level above 3 & mgr;g/mL at week 30 ( 68.4 % versus 38.8 % for & Dgr;MCV < 7 , P = 0.0032 ) . Conclusions : These results suggest that & Dgr;MCV above 7 ( which is a surrogate for a higher 6-thioguanine nucleotides concentration ) leads to improved Crohn 's disease outcomes , even when combined with infliximab . It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy 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 & 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 CONTEXT Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels , and a diminished treatment response . Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up . OBJECTIVE To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term ( 3-year ) follow-up of patients with rheumatoid arthritis ( RA ) . DESIGN , SETTING , AND PATIENTS Prospect i ve cohort study February 2004-September 2008 ; end of follow-up was September 2010 . All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic . MAIN OUTCOME MEASURES Disease activity was monitored and trough serum sample s were obtained at baseline and 8 time points to 156 weeks . Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up . Treatment discontinuation , minimal disease activity , and clinical remission were compared for patients with and without antiadalimumab antibodies . RESULTS After 3 years , 76 of 272 patients ( 28 % ) developed antiadalimumab antibodies--51 of these ( 67 % ) during the first 28 weeks of treatment . Patients without antiadalimumab antibodies had much higher adalimumab concentrations ( median , 12 mg/L ; IQR , 9 - 16 mg/L ) compared with patients with antibody titers from 13 to 100 AU/mL ( median , 5 mg/L ; IQR , 3 - 9 mg/L ; regression coefficient , -4.5 ; 95 % CI , -6.0 to -2.9 ; P < .001 ) and also those greater than 100 AU/mL ( median , 0 mg/L ; IQR , 0 - 3 mg/L ; regression coefficient , -7.1 ; 95 % CI , -8.4 to -5.8 ; P < .001 ) . Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure ( n = 29 [ 38 % ] ; hazard ratio [ HR ] , 3.0 ; 95 % CI , 1.6 - 5.5 ; P < .001 ) compared with antiadalimumab antibody-negative ones ( n = 28 [ 14 % ] ) . Ninety-five of 196 patients ( 48 % ) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients ( 13 % ) with antiadalimumab antibodies ; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints ( DAS28 ) ( < 3.2 ; HR , 3.6 ; 95 % CI , 1.8 - 7.2 ; P < .001 ) compared with antiadalimumab antibody-negative ones . Three of 76 patients ( 4 % ) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 ( 34 % ) antiadalimumab antibody-negative ones ; patients with antiadalimumab antibodies less often achieved remission ( DAS28 < 2.6 ; HR , 7.1 ; 95 % CI , 2.1 - 23.4 ; P < .001 ) compared with antiadalimumab antibody-negative ones . CONCLUSION Among out patients with RA in whom adalimumab was started over 3 years , the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission 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 oral azathioprine per kilogram daily plus a placebo infusion on the st and ard schedule ; or combination therapy with the two drugs . Patients received study medication through week 30 and could continue in a blinded study extension through week 50 . RESULTS Of the 169 patients receiving combination therapy , 96 ( 56.8 % ) were in corticosteroid-free clinical remission at week 26 ( the primary end point ) , as compared with 75 of 169 patients ( 44.4 % ) receiving infliximab alone ( P=0.02 ) and 51 of 170 patients ( 30.0 % ) receiving azathioprine alone ( P<0.001 for the comparison with combination therapy and P=0.006 for the comparison with infliximab ) . Similar numerical trends were found at week 50 . At week 26 , mucosal healing had occurred in 47 of 107 patients ( 43.9 % ) receiving combination therapy , as compared with 28 of 93 patients ( 30.1 % ) receiving infliximab ( P=0.06 ) and 18 of 109 patients ( 16.5 % ) receiving azathioprine ( P<0.001 for the comparison with combination therapy and P=0.02 for the comparison with infliximab ) . Serious infections developed in 3.9 % of patients in the combination-therapy group , 4.9 % of those in the infliximab group , and 5.6 % of those in the azathioprine group . CONCLUSIONS Patients with moderate-to-severe Crohn 's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy . ( Clinical Trials.gov number , NCT00094458 . BACKGROUND & AIMS Adalimumab is an efficacious therapy for active Crohn 's disease , but long-term data are scarce . We conducted an observational study to assess the long-term clinical benefit of adalimumab in patients who failed to respond to infliximab  , specifically focusing on the influence of trough serum concentration and antibodies against adal 
    Output:
    