Efficacy, pharmacokinetics, and safety of adalimumab in pediatric patients with juvenile idiopathic arthritis in Japan Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn's disease: Results from CARE Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab 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. Influence of immunogenicity on the long-term efficacy of infliximab in 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. Predictors of adalimumab dose escalation in patients with crohn's disease at a tertiary referral center Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn's disease: A single centre experience. Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial. Efficacy and safety of adalimumab in Canadian patients with moderate to severe Crohn's disease: results of the Adalimumab in Canadian SubjeCts with ModErate to Severe Crohn's DiseaSe (ACCESS) trial. 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. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease Adalimumab sustains steroid‐free remission after 3 years of therapy for Crohn’s disease Serum Adalimumab Concentration and Clinical Remission in Patients with Crohn's Disease
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 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 Treatment with infliximab , a chimeric monoclonal IgG1 antibody against tumor necrosis factor , can result in the formation of antibodies against infliximab . We evaluated the clinical significance of these antibodies in patients with Crohn 's disease . METHODS In a cohort of 125 consecutive patients with Crohn 's disease who were treated with infliximab infusions  , we evaluated the concentrations of infliximab and of antibodies against infliximab  , clinical data , side effects ( including infusion reactions ) , and the use of concomitant medications before and 4 , 8 , and 12 weeks after each infusion . RESULTS A mean of 3.9 infusions ( range , 1 to 17 ) per patient were administered over a mean period of 10 months . Antibodies against infliximab  were detected in 61 percent of patients . The presence of concentrations of 8.0 microg per milliliter or greater before an infusion predicted a shorter duration of response ( 35 days , as compared with 71 days among patients with concentrations of less than 8.0 microg per milliliter ; P<0.001 ) and a higher risk of infusion reactions ( relative risk , 2.40 ; 95 percent confidence interval , 1.65 to 3.66 ; P<0.001 ) .  Infliximab concentrations were significantly lower at four weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction ( median , 1.2 vs. 14.1 microg per milliliter ; P<0.001 ) . Patients who had infusion reactions had a median duration of clinical response of 38.5 days , as compared with 65 days among patients who did not have an infusion reaction ( P<0.001 ) . Concomitant immunosuppressive therapy was predictive of low titers of antibodies against infliximab  ( P<0.001 ) and high concentrations of  infliximab  four weeks after an infusion ( P<0.001 ) . CONCLUSIONS The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment . Concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response 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 : Pivotal trials for adalimumab ( ADA ) demonstrated effectiveness versus placebo for induction and maintenance of remission in moderate to severely active Crohn 's disease ( CD ) . Although the approved maintenance regimen in the U.S. is 40 mg subcutaneously every 14 days , some patients require dose‐escalation ( [ DE ] either an increase in the delivered dose or decrease in the interval of treatment ) . Our objective was to determine which patient‐ , disease‐ , and therapy‐related factors were associated with DE in CD patients treated with ADA .  Methods : This retrospective medical record review of patients included all patients treated with ADA for CD at the University of Chicago Inflammatory Bowel Disease Center between 2003 and 2008 .  Patient‐related factors , disease‐related factors , and therapy‐related factors were analyzed . Survival and logistic regression analyses were performed . Results : In all , 75 patients treated with ADA between December 2003 and June 2008 were identified . Thirty‐one subjects ( 41 % ) required DE ( 32 % male , median age 37.6 , median disease duration 22.7 years ) after a median 20 weeks of therapy ( range 2–75 ) . Patient‐ , clinical ‐ , and therapy‐related factors were similar between DE and non‐DE . Need for DE was predicted by a family history of inflammatory bowel disease ( IBD ) ( P = 0.0187 ) . Time to DE was predicted by male gender , isolated colonic disease , and smoking history ( all P < 0.05 ) ; however , only male gender was an independent predictor of time to DE . Conclusions : In all , 41 % of CD patients required ADA DE , with shorter time to DE in smokers , men , and patients with isolated colonic disease . Patients , caregivers , and insurers should anticipate DE when utilizing ADA in CD . ( Inflamm Bowel Dis 2011 ; BACKGROUND AND AIMS Non-response , loss of response , or intolerance to anti-tumour necrosis factor alpha ( anti-TNFα ) therapy is well recognised in Crohn 's disease ( CD ) patients . Data concerning outcomes following the use of a second anti-TNFα therapy , particularly in patients who do not respond to a first anti-TNFα agent  , are still emerging . The aim of this study was to assess response and tolerability to adalimumab following infliximab failure in a single centre cohort of CD patients . METHODS Data were collected prospect ively on 44 patients who received adalimumab therapy following infliximab failure . Initial response to adalimumab therapy at 6weeks following induction was defined using a two point decrease in the Harvey-Bradshaw Index , with remission at this point defined using a Harvey Bradshaw index≤4 . Sustained clinical benefit at the last point of follow up was determined using a physician 's global assessment . Corticosteroid-free sustained clinical benefit was also assessed at this point . RESULTS Thirty-four ( 77 % ) patients had initial response to adalimumab therapy , with 28 ( 64 % ) having sustained clinical benefit . Corticosteroid-free sustained clinical benefit was achieved in nine ( 53 % ) of 17 patients requiring steroids at commencement of adalimumab . Four ( 44 % ) of the 9 patients who were primary non-responders to infliximab responded to adalimumab . The majority of CD patients who failed adalimumab therapy required surgery . CONCLUSIONS Second-line anti-TNFα therapy with adalimumab is effective at both inducing remission and maintaining response in CD patients who have failed infliximab , regardless of the reason for infliximab failure BACKGROUND & AIMS We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohn 's disease ( CD ) . METHODS A r and omized , double-blind , placebo-controlled trial ( extend the safety and efficacy of adalimumab through endoscopic healing [ EXTEND ] ) evaluated adalimumab for induction and maintenance of mucosal healing in 135 adults with moderate to severe ileocolonic CD . The baseline degree of mucosal ulceration was documented by ileocolonoscopy . All patients received induction therapy ( subcutaneous adalimumab 160/80 mg at weeks 0/2 ) . At week 4 , patients were r and omly assigned to groups given 40 mg adalimumab or placebo every other week through week 52 . Open-label adalimumab was given to patients with flares or no response , starting at week 8 . Mucosal healing was reassessed by ileocolonoscopy at weeks 12 and 52 . RESULTS Twenty-seven percent of patients receiving adalimumab  had mucosal healing at week 12 ( the primary end point ) versus 13 % given placebo ( P = .056 ) . At week 52 , rates of mucosal healing were 24 % and 0 , respectively ( P < .001 ) . Remission rates , based on the Crohn 's Disease Endoscopic Index of Severity , were 52 % for adalimumab and 28 % for placebo at week 12 ( P = .006 ) and 28 % and 3 % , respectively , at week 52 ( P < .001 ) . Rates of clinical remission based on the Crohn 's Disease Activity Index were greater among patients given continuous adalimumab therapy versus placebo at weeks 12 ( 47 % vs 28 % ; P = .021 ) and 52 ( 33 % vs 9 % ; P = .001 ) . Five serious ( 1 during induction and 4 during open-label therapy ) and 3 opportunistic infections ( 1 in each group during double-blind therapy and 1 during open-label therapy ) were reported ( n = 135 ) . CONCLUSIONS Following induction therapy with adalimumab , patients with moderately to severely active CD who continue to receive adalimumab are more likely to achieve mucosal healing than those given placebo OBJECTIVE To evaluate open-label adalimumab therapy for clinical effectiveness , fistula healing , patient-reported outcomes and safety in Canadian patients with moderate to severe Crohn 's disease ( CD ) who were either naive to or previously exposed to antitumour necrosis factor ( anti-TNF ) therapy . METHODS Patients with moderate to severe CD ( CD activity index [ CDAI ] score of greater than 220 , or Harvey-Bradshaw index [ HBI ] of 7 or greater ) were eligible . Patients received open-label adalimumab as induction ( 160 mg and 80 mg subcutaneously [ sc ] ) at weeks 0 and 2 , respectively and maintenance ( 40 mg sc every other week ) therapy . At or after eight weeks , patients with flare or nonresponse could have their dosage increased to 40 mg sc weekly . Patients were followed for a minimum of six months or until adalimumab was commercially available in Canada . RESULTS Of the 304 patients enrolled , 160 were infliximab experienced , while 144 were anti-TNF naive .  HBI remission ( HBI score of 4 or lower ) at week 24 was achieved by 53 % of anti-TNF-naive and 36 % of infliximab-experienced patients ( P<0.01 ; P<0.001 for both groups for all visits versus baseline ) . Fistula healing rates at week 12 were 48 % for anti-TNF-naive patients , and 26 % for infliximab-experienced patients . At week 24 , fistula healing rates were significantly greater for the anti-TNF-naive group ( 60 % versus 28 % ; P<0.01 ) . Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients . Serious infections occurred in 2 % of patients . CONCLUSIONS Adalimumab therapy induced and sustained steroidfree remission in both infliximab-experienced and anti-TNF-naive patients with moderate to severe CD . Clinical ly meaningful rates of fistula healing were also observed . Improvements in patient-reported outcomes were sustained throughout the 24-week study period 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 : 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 Aliment Pharmacol Ther 2011 ; 34 : 306–317 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 AND AIMS Combination therapy with infliximab and azathioprine has been shown to be superior to either treatment alone in Crohn 's disease ( CD ) .
However , the benefit of combining adalimumab with an immunomodulator remains controversial .
The aim of this study was to compare the efficacy of adalimumab monotherapy with combination therapy for induction and maintenance of response and remission in CD using a meta- analysis of the current literature .