Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial. Safety of infliximab in Crohn's disease: A large single‐center experience Infliximab, azathioprine, or combination therapy for Crohn's disease. Infliximab maintenance therapy for fistulizing Crohn's disease. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Infliximab for the treatment of fistulas in patients with Crohn's disease. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease Frequency of glucocorticoid resistance and dependency in Crohn's disease. Infliximab for the treatment of fistulas in patients with Crohn'S disease. Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD‐subgroup analyses across four randomized trials Mucosal healing with methotrexate in Crohn’s disease: a prospective comparative study with azathioprine and infliximab Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.
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 The aim of this study was to evaluate the usefulness of short-term infliximab combined with azathioprine ( AZA ) or 6-mercaptopurine ( 6-MP ) in steroid-dependent Crohn 's disease patients . METHODS Patients with active disease despite prednisone given for more than 6 months were eligible and were stratified as follows : the failure stratum consisted of patients receiving AZA/6-MP at a stable dose for more than 6 months , and the naive stratum consisted of patients not treated previously with AZA/6-MP . Patients were r and omized to infliximab 5 mg/kg or placebo at weeks 0 , 2 , and 6 . All patients were treated with AZA/6-MP maintained at a stable dose throughout the 52 weeks of the study . The primary end point was remission off steroids at week 24 . RESULTS Among the 113 enrolled patients ( 55 in the failure stratum ) , 57 were assigned to infliximab . At week 24 , the success rate ( intent-to-treat analysis ) was higher in the infliximab group than in the placebo group ( 57 % vs 29 % ; P = .003 ) ; at weeks 12 and 52 , the corresponding rates were 75 % vs 38 % ( P < .001 ) and 40 % vs 22 % ( P = .04 ) , respectively . In each stratum , the success rate was significantly higher in the infliximab group at weeks 12 and 24 , and a trend was found at week 52 . In the failure stratum , only 27 % of the patients in the infliximab group were still in remission off steroids , compared with 52 % in the naive stratum . Steroid resistance was less common and the cumulative dose of prednisone was lower in the infliximab group . CONCLUSIONS Infliximab plus AZA/6-MP is more effective than AZA/6-MP alone in steroid-dependent Crohn 's disease patients Background : The aim of this study was to evaluate the short‐ and long‐term safety experience of infliximab treatment in patients with Crohn 's disease ( CD ) in clinical practice . Methods : The medical records of 297 consecutive patients with CD treated with infliximab at the Beth Israel Deaconess Medical Center were review ed for demographic features and adverse events . Results : The 297 patients received a total of 1794 infusions . Patients received a median of four infusions and had a median follow‐up of 14.3 months . Forty‐four patients ( 15 % ) experienced a serious adverse event , requiring the infusion to be stopped in 33 patients ( 11 % ) . Acute infusion reactions occurred in 18 patients ( 6 % ) including respiratory problems in 10 patients ( 3 % ) and an anaphylactoid reaction in 1 patient ( 0.3 % ) . Serum sickness‐like disease occurred in one patient ( 0.3 % ) and three patients ( 1 % ) developed drug‐induced lupus . One patient developed a probable new demyelination disorder . Eight patients ( 2.7 % ) , all of whom were on concurrent immunosuppressants , developed a serious infection , one result ing in fatal sepsis . Six patients ( 2 % ) developed malignancies including two lymphomas and two skin cancers . A total of four ( 1.3 % ) deaths were observed ( median age 72.5 years ) ; two due to gastrointestinal bleeding , one due to sepsis , and one due to malignancy . Conclusions : While short‐ and long‐term infliximab therapy was generally well tolerated , serious adverse events occurred in 15 % of patients including drug‐induced lupus , fatal sepsis , and malignancy . Concomitant immunosuppressants were significantly associated with infections and deaths , particularly among elderly patients . ( Inflamm Bowel Dis 2010 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 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 & AIMS The benefit to risk ratio of concomitant immunosuppressives with scheduled infliximab ( IFX ) maintenance therapy for Crohn 's disease is an issue of debate . We aim ed to study the influence of immunosuppressives discontinuation in patients in remission with combination therapy in an open-label , r and omized , controlled trial . METHODS Patients with controlled disease > or = 6 months after the start of IFX ( 5 mg/kg intravenously ) combined with immunosuppressives were r and omized to continue ( Con ) or to interrupt ( Dis ) immunosuppressives , while all patients received scheduled IFX maintenance therapy for 104 weeks . Primary end point was the proportion of patients who required a decrease in  IFX dosing interval or stopped IFX therapy . Secondary end points included IFX trough levels , safety , and mucosal healing . RESULTS A similar proportion ( 24/40 , 60 % Con ) and ( 22/40 , 55 % Dis ) of patients needed a change in  IFX dosing interval or stopped IFX  therapy ( 11/40 Con , 9/40 Dis ) . C-reactive protein ( CRP ) was higher and IFX trough levels were lower in the Dis group ( Dis : CRP , 2.8 mg/L ; interquartile range [ IQR ] , 1.0 - 8.0 ; Con : CRP , 1.6 mg/L ; IQR , 1.0 - 5.6 , P < .005 ; trough IFX : Dis : 1.65 microg/mL ; IQR , 0.54 - 3.68 ; Con : 2.87 microg/mL ; IQR , 1.35 - 4.72 , P < .0001 ) . Low IFX trough levels correlated with increased CRP and clinical score . Mucosal ulcers were absent at week 104 in 64 % ( Con ) and 61 % ( Dis ) of evaluated patients with ongoing response to IFX . CONCLUSIONS Continuation of immunosuppressives beyond 6 months offers no clear benefit over scheduled IFX monotherapy but is associated with higher median IFX trough and decreased CRP levels . The impact of these observations on long-term outcomes needs to be explored further BACKGROUND Enterocutaneous fistulas are a serious complication of Crohn 's disease and are difficult to treat . Infliximab , a chimeric monoclonal antibody to tumor necrosis factor alpha , has recently been developed as a treatment for Crohn 's disease . We conducted a r and omized , multicenter , double-blind , placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn 's disease . METHODS The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months ' duration as a complication of Crohn 's disease . Patients were r and omly assigned to receive one of three treatments : placebo ( 31 patients ) , 5 mg of infliximab per kilogram of body weight ( 31 patients ) , or 10 mg of infliximab per kilogram ( 32 patients ) ; all three were to be administered intravenously at weeks 0 , 2 , and 6 . The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits . A secondary end point was the closure of all fistulas . RESULTS Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point , as compared with 26 percent of the patients in the placebo group ( P=0.002 and P=0.02 , respectively ) . In addition , 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas , as compared with 13 percent of the patients assigned to placebo ( P=0.001 and P=0.04 , respectively ) . The median length of time during which the fistulas remained closed was three months . More than 60 percent of patients in all the groups had adverse events . For patients treated with infliximab , the most common were headache , abscess , upper respiratory tract infection , and fatigue . CONCLUSIONS Infliximab is an efficacious treatment for fistulas in patients with Crohn 's disease Background : Episodic infliximab ( IFX ) treatment is associated with the formation of antibodies to IFX ( ATIs ) in the majority of patients , which can lead to infusion reactions and a shorter duration of response . Concomitant use of immunosuppressives ( IS ) reduces the risk of ATI formation . Aims and methods : To investigate which of the IS — that is , methotrexate ( MTX ) or azathioprine (AZA)—is most effective at reducing the risk of ATI formation , a multicentre cohort of 174 patients with Crohn ’s disease , treated with IFX in an on-dem and schedule , was prospect ively studied . Three groups were studied : no IS ( n = 59 ) , concomitant MTX ( n = 50 ) and concomitant AZA ( n = 65 ) . ATI and IFX concentrations were measured in a blinded manner at Prometheus Laboratories before and 4 weeks after each infusion . Results : ATIs were detected in 55 % ( 96/174 ) of the patients . The concomitant use of IS therapy ( AZA or MTX ) was associated with a lower incidence of ATIs ( 53/115 ; 46 % ) compared with patients not taking concomitant IS therapy ( 43/59 ; 73 % ; p<0.001 ) . The incidence of ATIs was not different for the MTX group ( 44 % ) compared with the AZA group ( 48 % ) . Patients not taking IS therapy had lower IFX levels ( median 2.42 μg/ml ( interquartile range ( IQR ) 1–10.8 ) , maximum 21 μg/ml ) 4 weeks after any follow-up infusion than patients taking concomitant IS therapy ( median 6.45 μg/ml ( IQR 3–11.6 ) , maximum 21 μg/ml ; p = 0.065 ) , but there was no difference between MTX or AZA . In patients who developed significant ATIs > 8 μg/ml during follow-up , the IFX levels 4 weeks after the first infusion were retrospectively found to be significantly lower than in patients who did not develop ATIs on follow-up or had inconclusive ATIs . Conclusion : Concomitant IS therapy reduces ATI formation associated with IFX treatment and improves the pharmacokinetics of IFX . There is no difference between MTX and AZA in reducing these risks . ATI profoundly influences the pharmacokinetics of IFX . The formation of ATIs > 8 μg/ml is associated with lower serum levels of IFX already at 4 weeks after its first administration The outcome of the first steroid treatment course was prospect ively studied in a regional cohort of 196 patients with Crohn 's disease diagnosed 1979 - 1987 . The immediate outcome after 30 days , and the prolonged outcome 30 days after treatment had stopped , are described . In all 109 patients treatment was analysed . Complete remission was obtained in 48 % , partial remission in 32 % , and no response in 20 % within 30 days of treatment . Among primary responders ( complete and partial remission ) , 55 % remained in prolonged response after treatment had finished , while 45 % relapsed or could not be withdrawn from treatment within one year . Localisation of disease , age , sex or clinical symptoms did not significantly correlate with outcome , which can be summarised as prolonged steroid response in 44 % , steroid dependency in 36 % , and steroid resistant in 20 % of the patients 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 Benefits and risks of concomitant immunomodulators and maintenance infliximab in inflammatory bowel disease ( IBD ) patients have not been adequately evaluated Aliment Pharmacol Ther 2011 ; 33 : 714–721 BACKGROUND & AIMS Methotrexate and infliximab are effective therapies for Crohn 's disease ( CD ) . In the combination of maintenance methotrexate-infliximab trial , we evaluated the potential superiority of combination therapy over infliximab alone . METHODS In a 50-week , double-blind , placebo-controlled trial , we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy ( 15 - 40 mg/day ) within the preceding 6 weeks . Patients were assigned r and omly to groups given methotrexate at an initial weekly dose of 10 mg , escalating to 25 mg/week ( n = 63 ) , or placebo ( n = 63 ) . Both groups received infliximab ( 5 mg/kg of body weight ) at weeks 1 , 3 , 7 , and 14 , and every 8 weeks thereafter . Prednisone was tapered , beginning at week 1 , and discontinued no later than week 14 . The primary outcome was time to treatment failure , defined as a lack of prednisone-free remission ( CD Activity Index , < 150 ) at week 14 or failure to maintain remission through week 50 . RESULTS Patients ' baseline characteristics were similar between groups . By week 50 , the actuarial rate of treatment failure was 30.6 % in the combination therapy group compared with 29.8 % in the infliximab monotherapy group ( P = .63 ; hazard ratio , 1.16 ; 95 % confidence interval , 0.62 - 2.17 ) . Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein . No clinical ly meaningful differences were observed in secondary outcomes . Combination therapy was well tolerated . CONCLUSIONS The combination of infliximab and methotrexate , although safe , was no more effective than infliximab alone in patients with CD receiving treatment with prednisone . ClincialTrials.gov number , NCT00132899
OBJECTIVE Infliximab ( IFX ) monotherapy and IFX combined with immunosuppressors have been used in the treatment of Crohn 's disease .
However , the differences between combination therapy and IFX alone remain controversial .
The aim of this meta- analysis was to evaluate the effectiveness and risk associated with combination therapy and IFX monotherapy .