Change in Erythrocyte Mean Corpuscular Volume During Combination Therapy with Azathioprine and Infliximab Is Associated with Mucosal Healing: A Post hoc Analysis from SONIC Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. Infliximab, azathioprine, or combination therapy for Crohn's disease. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease. Infliximab maintenance therapy for fistulizing Crohn's disease. Maintenance therapy with certolizumab pegol for Crohn's disease. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. Infliximab for the treatment of fistulas in patients with Crohn'S disease. Serum Adalimumab Concentration and Clinical Remission in Patients with Crohn's Disease Certolizumab pegol for the treatment of Crohn's disease. Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD‐subgroup analyses across four randomized trials
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 adalimumab on clinical outcome . METHODS A total of 168 patients with Crohn 's disease treated with adalimumab in a tertiary center were included in a prospect i ve follow-up program . Trough serum concentration and antibodies against adalimumab  were measured at predefined time points using enzyme-linked immunosorbent assays . RESULTS A total of 71 % and 67 % of patients responded by weeks 4 and 12 , respectively ; among them , 61.5 % demonstrated sustained clinical benefit until the end of follow-up ( median [ interquartile range ] , 20.4 [ 11.7 - 30.0 ] months ) . Of the 156 patients receiving maintenance therapy , 102 ( 65.4 % ) had to step up to 40 mg weekly and 60 ( 38.5 % ) eventually stopped adalimumab therapy mainly due to loss of response . Significantly lower  adalimumab trough serum concentrations were measured throughout the follow-up period in patients who discontinued therapy as compared with patients who stayed on adalimumab . Antibodies against adalimumab were present in 9.2 % of the patients and affected trough serum concentration . Serious adverse events occurred in 12 % of the patients . CONCLUSIONS Introduction of adalimumab after failure of infliximab therapy result ed in a sustained clinical benefit in two thirds of patients during a median follow-up period of almost 2 years . Discontinuation was directly related to low adalimumab trough serum concentration , which was observed more frequently in patients who developed antibodies against adalimumab BACKGROUND Infliximab , a monoclonal antibody against tumor necrosis factor , is an effective maintenance therapy for patients with Crohn 's disease without fistulas . It is not known whether infliximab is an effective maintenance therapy for patients with fistulas . METHODS We performed a multicenter , double-blind , r and omized , placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn 's disease and one or more draining abdominal or perianal fistulas of at least three months ' duration . Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0 , 2 , and 6 . A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then r and omly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54 . The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent r and omization . RESULTS The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance ( more than 40 weeks vs. 14 weeks , P<0.001 ) . At week 54 , 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas , as compared with 36 percent of patients in the infliximab maintenance group ( P=0.009 ) . CONCLUSIONS Patients with fistulizing Crohn 's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks BACKGROUND Certolizumab pegol is a pegylated humanized Fab ' fragment with a high binding affinity for tumor necrosis factor alpha that does not induce apoptosis of T cells or monocytes . METHODS In our r and omized , double-blind , placebo-controlled trial , we evaluated the efficacy of certolizumab pegol maintenance therapy in adults with moderate-to-severe Crohn 's disease . As induction therapy , 400 mg of certolizumab pegol was administered subcutaneously at weeks 0 , 2 , and 4 . Patients with a clinical response ( defined as reduction of at least 100 from the baseline score on the Crohn 's Disease Activity Index [ CDAI ] ) at week 6 were stratified according to their baseline C-reactive protein level and were r and omly assigned to receive 400 mg of certolizumab pegol or placebo every 4 weeks through week 24 , with follow-up through week 26 . RESULTS Among patients with a response to induction therapy at week 6 ( 428 of 668 [ 64 % ] ) , the response was maintained through week 26 in 62 % of patients with a baseline C-reactive protein level of at least 10 mg per liter ( the primary end point ) who were receiving certolizumab pegol ( vs. 34 % of those receiving placebo , P<0.001 ) and in 63 % of patients in the intention-to-treat population who were receiving certolizumab pegol ( vs. 36 % receiving placebo , P<0.001 ) . Among patients with a response to induction therapy at week 6 , remission ( defined by a CDAI score of < or = 150 ) at week 26 was achieved in 48 % of patients in the certolizumab group and 29 % of those in the placebo group ( P<0.001 ) . The efficacy of certolizumab pegol was also shown in patients taking and those not taking glucocorticoids or immunosuppressants and in patients who had and those who had not previously taken infliximab . Infectious serious adverse events ( including one case of pulmonary tuberculosis ) occurred in 3 % of patients receiving certolizumab pegol and in less than 1 % of patients receiving placebo .  Antinuclear antibodies developed in 8 % of the patients in the certolizumab group ; antibodies against certolizumab pegol developed in 9 % of all patients who entered the induction phase . CONCLUSIONS Patients with moderate-to-severe Crohn 's disease who had a response to induction therapy with 400 mg of certolizumab pegol were more likely to have a maintained response and a remission at 26 weeks with continued certolizumab pegol treatment than with a switch to placebo . ( Clinical Trials.gov number , NCT00152425 [ Clinical Trials.gov ] . ) BACKGROUND & AIMS Tumor necrosis factor blockade has been shown to be an effective treatment strategy in Crohn 's disease ( CD ) . Adalimumab is a human immunoglobulin G1 ( IgG(1 ) ) monoclonal antibody targeting tumor necrosis factor ( TNF ) . A r and omized , double-blind , placebo-controlled , dose-ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD . METHODS A total of 299 patients with moderate to severe CD naive to anti-TNF therapy  were r and omized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg , 80 mg/40 mg , or 160 mg/80 mg or placebo . The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 ( defined as a Crohn 's Disease Activity Index score < 150 points ) among the 80 mg/40 mg , 160 mg/80 mg , and placebo groups . RESULTS The rates of remission at week 4 in the adalimumab 40 mg/20 mg , 80 mg/40 mg , and 160 mg/80 mg groups were 18 % ( P = .36 ) , 24 % ( P = .06 ) , and 36 % ( P = .001 ) , respectively , and 12 % in the placebo group . Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions , which were more common in adalimumab-treated patients . CONCLUSIONS Adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn 's disease naive to anti-TNF therapy . The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2 . Adalimumab was well tolerated BACKGROUND & AIMS Infliximab , an anti-tumor necrosis factor monoclonal antibody , rapidly reduces signs and symptoms of active Crohn 's disease . The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit . METHODS The efficacy , safety , pharmacokinetics , and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a r and omized , double-blind , placebo-controlled , parallel group trial . Seventy-three patients with active Crohn 's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response ( > /=70-point decrease in the Crohn 's Disease Activity Index ) to an initial infusion of infliximab ( or placebo )  were studied . RESULTS Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab . Median values for Crohn 's Disease Activity Index , inflammatory bowel disease question naire ( a quality of life measurement ) , and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment , but not with placebo retreatment . Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity . One case of lymphoma and 1 case of suspected lupus were reported ; the complete long-term safety profile of infliximab requires additional clinical investigation . CONCLUSIONS Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn 's disease not responding to conventional treatments BACKGROUND & AIMS To investigate the efficacy and safety of certolizumab pegol ( a polyethylene-glycolated Fab ' fragment of anti-tumor necrosis factor , CDP870 ) in Crohn 's disease . METHODS In a placebo-controlled , phase II study , 292 patients with moderate to severe Crohn 's disease received subcutaneous certolizumab 100 , 200 , or 400 mg or placebo at weeks 0 , 4 , and 8 . The primary end point was the percentage of patients with a clinical response  at week 12 ( a Crohn 's Disease Activity Index decrease of > or = 100 points or remission [ Crohn 's Disease Activity Index < or = 150 points ] ) in the intent-to-treat population . RESULTS All certolizumab doses produced significant clinical benefit over placebo at week 2 ( placebo , 15.1 % ; certolizumab 100 mg , 29.7 % [ P = .033 ] ; 200 mg , 30.6 % [ P = .026 ] ; 400 mg , 33.3 % [ P = .010 ] ) . At all time points , the clinical response rates were highest for certolizumab 400 mg , greatest at week 10 ( certolizumab 400 mg , 52.8 % ; placebo , 30.1 % ; P = .006 ) but not significant at week 12 ( certolizumab 400 mg , 44.4 % ; placebo , 35.6 % ; P = .278 ) . Patients with baseline C-reactive protein levels of 10 mg/L or greater ( n = 119 ) showed clearer separation between active treatment and placebo ( week 12 clinical response : certolizumab 400 mg , 53.1 % ; placebo , 17.9 % ; P = .005 ; post hoc analysis ) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups . CONCLUSIONS Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn 's disease . High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo . Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab BACKGROUND Studies in animals and an open-label trial have suggested a role for antibodies to tumor necrosis factor alpha , specifically chimeric monoclonal antibody cA2 , in the treatment of Crohn 's disease . METHODS We conducted a 12-week multicenter , double-blind , placebo-controlled trial of cA2 in 108 patients with moderate-to-severe Crohn 's disease that was resistant to treatment . All had scores on the Crohn 's Disease Activity Index between 220 and 400 ( scores can range from 0 to about 600 , with higher scores indicating more severe illness ) . Patients were r and omly assigned to receive a single two-hour intravenous infusion of either placebo or cA2 in a dose of 5 mg per kilogram of body weight , 10 mg per kilogram , or 20 mg per kilogram . Clinical response , the primary end point , was defined as a reduction of 70 or more points in the score on the Crohn 's Disease Activity Index at four weeks that was not accompanied by a change in any concomitant medications . RESULTS At four weeks , 81 percent of the patients given 5 mg of cA2 per kilogram ( 22 of 27 patients ) , 50 percent of those given 10 mg of cA2 per kilogram ( 14 of 28 ) , and 64 percent of those given 20 mg of cA2 per kilogram ( 18 of 28 ) had had a clinical response , as compared with 17 percent of patients in the placebo group ( 4 of 24 ) ( p<0.001 for the comparison of the cA2 group as a whole with placebo ) . Thirty-three percent of the patients given cA2 went into remission ( defined as a score below 150 on the Crohn 's Disease Activity Index ) , as compared with 4 percent of the patients given placebo ( P=0.005 ) . At 12 weeks , 41 percent of the cA2-treated patients ( 34 of 83 ) had had a clinical response , as compared with 12 percent of the patients in the placebo group ( 3 of 25 ) ( P=0.008 ) . The rates of adverse effects were similar in the groups . CONCLUSIONS A single infusion of cA2 was an effective short-term treatment in many patients with moderate-to-severe , treatment-resistant Crohn 's disease Objective : To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn9s disease ( CD ) . Design : A Phase III , multicentre , r and omised , double-blind , placebo-controlled study with an open-label extension . Setting : 92 sites . Patients : A subgroup of adults with moderate to severely active CD ( CD Activity Index [ CDAI ] 220 - 450 ) for ≥4 months who had draining fistulas at baseline . Interventions : All patients received initial open-label adalimumab induction therapy ( 80 mg/40 mg at Week 0/2 ) . At Week 4 , all patients were r and omised to receive double-blind placebo or adalimumab 40 mg every other week or weekly through Week 56 ( irrespective of fistula status ) . Patients completing Week 56 of therapy were then eligible to enroll in an open-label extension . Main outcome measures : Complete fistula healing/closure ( assessed at every visit ) was defined as no drainage , either spontaneous or with gentle compression . Results : Of 854 patients enrolled , 117 had draining fistulas at both screening and baseline ( 70 r and omised to adalimumab and 47 r and omised to placebo ) . The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period . Of all patients with healed fistulas at Week 56 ( both adalimumab and placebo groups ) , 90 % ( 28 of 31 ) maintained healing following 1 year of open-label adalimumab therapy ( observed analysis ) . Conclusions : In patients with active CD  , adalimumab therapy was more effective than placebo for inducing fistula healing . Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial Background : Drug concentration monitoring may be useful to guide therapeutic adjustments for anti – tumor necrosis factor agents in Crohn 's disease . The relationship between serum adalimumab concentrations and clinical outcomes was assessed using data from CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn 's Disease ( CLASSIC ) I/II . Methods : Serum adalimumab concentrations at week 4 of CLASSIC I and weeks 4 , 24 , and 56 of CLASSIC II were compared by clinical remission status ( yes/no ) . Logistic regression and Classification and Regression Tree analyses explored factors associated with remission at weeks 4 , 24 , and 56 . Threshold analyses and receiver operating characteristic curves evaluated the relationship between serum concentrations and clinical remission/response . Results :  Serum adalimumab concentrations for 275 patients were available . Median adalimumab concentrations were significantly higher in patients who achieved clinical remission than those who did not at week 4 of CLASSIC I ( 8.10 versus 5.05 µg/mL , P < 0.05 ) . At all time points , adalimumab concentrations demonstrated considerable variability and overlap between patients with and without remission . With Classification and Regression Tree analyses , baseline Crohn 's Disease Activity Index , baseline C-reactive protein , and adalimumab concentrations were associated with early remission at week 4 of CLASSIC I and week 4 of CLASSIC II , but not at weeks 24 and 56 . Receiver operating characteristic curves demonstrated low utility of cutoff thresholds to discriminate by clinical response/remission status . Conclusions : A positive association between serum adalimumab concentration and remission was identified at several time points . A threshold concentration reliably associated with remission was not identified . Further prospect i ve evaluations are needed before recommendations for adalimumab concentration monitoring can be made BACKGROUND Certolizumab pegol is a pegylated humanized Fab ' fragment that binds tumor necrosis factor alpha . METHODS In a r and omized , double-blind , placebo-controlled trial , we evaluated the efficacy of certolizumab pegol in 662 adults with moderate-to-severe Crohn 's disease . Patients were stratified according to baseline levels of C-reactive protein ( CRP ) and were r and omly assigned to receive either 400 mg of certolizumab pegol or placebo subcutaneously at weeks 0 , 2 , and 4 and then every 4 weeks . Primary end points were the induction of a response at week 6 and a response at both weeks 6 and 26 . RESULTS Among patients with a baseline CRP level of at least 10 mg per liter , 37 % of patients in the certolizumab group had a response at week 6 , as compared with 26 % in the placebo group ( P=0.04 ) . At both weeks 6 and 26 , the corresponding values were 22 % and 12 % , respectively ( P=0.05 ) . In the overall population , response rates at week 6 were 35 % in the certolizumab group and 27 % in the placebo group ( P=0.02 ) ; at both weeks 6 and 26 , the response rates were 23 % and 16 % , respectively ( P=0.02 ) . At weeks 6 and 26 , the rates of remission in the two groups did not differ significantly ( P=0.17 ) . Serious adverse events were reported in 10 % of patients in the certolizumab group and 7 % of those in the placebo group ; serious infections were reported in 2 % and less than 1 % , respectively . In the certolizumab group , antibodies to the drug developed in 8 % of patients , and antinuclear antibodies developed in 2 % . CONCLUSIONS In patients with moderate-to-severe Crohn 's disease , induction and maintenance therapy with certolizumab pegol was associated with a modest improvement in response rates , as compared with placebo , but with no significant improvement in remission rates . ( Clinical Trials.gov number , NCT00152490 [ Clinical Trials.gov ] . ) Background Benefits and risks of concomitant immunomodulators and maintenance infliximab in inflammatory bowel disease ( IBD ) patients have not been adequately evaluated
BACKGROUND & AIMS There is debate over whether patients with Crohn 's disease who start anti-tumor necrosis factor ( TNF ) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators .
We conducted a meta- analysis of subgroups from r and omized controlled trials ( RCTs ) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy .