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. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial. Adalimumab for the treatment of Crohn’s disease Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Efficacy and safety of repeated infliximab infusions for Crohn's disease: 1-year clinical experience. Infliximab induces potent anti‐inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn’s disease Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis: correlation of TNF-alpha serum level with clinical response and benefit from changing dose or frequency of infliximab infusions. Maintenance therapy with certolizumab pegol for Crohn's disease. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. 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 Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Infliximab in Crohn's disease: first anniversary clinical experience
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 : Adalimumab induced clinical remission after four weeks in patients with active Crohn ’s disease in the CLASSIC I trial . Objective : To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn ’s disease in a follow-on r and omised controlled trial ( CLASSIC II ) . Methods : In the preceding CLASSIC I trial , 299 patients with moderate to severe Crohn ’s disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg , 80 mg/40 mg , or 160 mg/80 mg , or placebo , at weeks 0 and 2 . In all , 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 ( week 4 of CLASSIC I ) and 2 ; 55 patients in remission at both weeks 0 and 4 were re-r and omised to adalimumab 40 mg every other week , 40 mg weekly , or placebo for 56 weeks . Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week . With non-response or flare , these patients could have their dosages increased to 40 mg weekly . Patients in the r and omised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly . The primary end point was maintenance of remission ( CDAI < 150 ) in r and omised patients through week 56 . Results : Of 55 patients r and omised at week 4 , 79 % who received adalimumab 40 mg every other week and 83 % who received 40 mg weekly were in remission at week 56 , v 44 % for placebo ( p<0.05 ) . In all , 204 patients entered the open-label arm . Of these , 93 ( 46 % ) were in clinical remission at week 56 . Adalimumab was generally well-tolerated in all patients . Conclusions : Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn ’s disease naive to anti-TNF treatment BACKGROUND & AIMS We assessed the relationship between antibodies to infliximab ( ATI ) and the loss of response postinfliximab , infusion reactions and , in a r and omized trial , investigated whether intravenous hydrocortisone premedication can reduce ATI . METHODS Initially , we prospect ively evaluated clinical response , adverse events , and ATI levels in 53 consecutive patients with Crohn 's disease who received 199 infliximab ( 5 mg/kg ) infusions . Subsequently , 80 patients with Crohn 's disease were r and omized to intravenous hydrocortisone 200 mg or placebo immediately before their first and subsequent infliximab infusions . The primary endpoint was reduction in median ATI levels at week 16 . Analysis was by intention to treat . RESULTS Nineteen of our initial 53 patients ( 36 % ) developed ATI , including all 7 patients with serious infusion reactions ( median ATI level , 19.6 microg/mL ) . Eleven of 15 patients ( 73 % ) who lost their initial response were ATI positive compared with none of 21 continuous responders , ( 8.9 vs. 0.7 microg/mL , P < 0.0001 ) . Administering a second infusion within 8 weeks of the first ( OR , 0.13 ; 95 % CI , 0.03 - 0.5 ; P = 0.0007 ) or concurrent immunosuppressants ( OR , 0.19 ; 95 % CI , 0.04 - 1.03 ; P = 0.007 ) significantly reduced ATI formation . In the placebo-controlled trial , ATI levels were lower at week 16 among hydrocortisone-treated patients ( 1.6 vs. 3.4 microg/mL , P = 0.02 ) , and 26 % of hydrocortisone-treated patients developed ATI compared with 42 % of placebo-treated patients , P = 0.06 . CONCLUSIONS Loss of initial response and infusion reactions post-infliximab is strongly related to ATI formation and level . Administering a second infusion within 8 weeks of the first and concurrent immunosuppressant therapy significantly reduce ATI formation . Intravenous hydrocortisone premedication significantly reduces ATI levels but does not eliminate ATI formation or infusion reactions Introduction : Crohn ’s disease ( CD ) is a chronic inflammatory bowel disease characterized by a relapsing-remitting course with trans-mural inflammation of potentially any section of the digestive tract . Adalimumab ( ADA ) is a subcutaneously administered , recombinant , fully human , IgG1 monoclonal antibody that binds with high affinity and specificity to human TNF-alpha , thus modulating its biologic functions and its proinflammatory effects . Aims : To review the available data on ADA in CD for biological properties , efficacy , and safety . Methods : Electronic search es were conducted using the Pubmed and SCOPUS data bases from the earliest records to April 2008 . The search terms used were “ adalimumab ” , “ anti-TNF ” , “ TNF-alpha ” , “ biologicals ” , “ inflammatory bowel disease ” , and “ Crohn ’s disease ” . Reference lists of all relevant articles were search ed for further studies . Results : Available studies suggest that ADA has the potential to induce and maintain clinical response and remission in moderate-severe CD , both in anti-TNF-naïve patients and in subjects who lost their response and /or became intolerant to infliximab ( IFX ) . ADA seems also effective in maintaining corticosteroid-free remission and obtaining complete fistula closure ( although no specific r and omized trials are available ) . No concomitant immunosuppressors seem to be necessary . Side effects appear similar to IFX , while site-injection reactions are frequent and specific . Data on immunogenicity and its clinical impact are uncertain . Conclusions : ADA appears to be effective in inducing and maintain clinical remission in CD , including patients not manageable with IFX . Successive clinical practice and further on going trials will confirm a positive role for ADA as a new anti-TNF treatment in CD . The impact on clinical management or on re sources should be more studied OBJECTIVE Infliximab , an anti-tumor necrosis factor alpha ( anti-TNFalpha ) antibody , is effective in the treatment of several immunoinflammatory diseases . However , many patients experience primary or secondary response failure , suggesting that individualization of treatment regimens may be beneficial . This study was undertaken to investigate whether serologic monitoring of infliximab  bioavailability and immunogenicity in individual patients would be useful in optimizing treatment regimens to improve efficacy and tolerability . METHODS To avoid the use of solid-phase assays , two radioimmunoassays were developed : one for measurement of levels of anti-infliximab antibody , and a functional one for measurement of TNFalpha binding due to infliximab . Sera from 106 r and omly selected rheumatoid arthritis patients were tested within 6 months of therapy initiation , and associations between findings of serum assays and disease activity , infusion reactions , and treatment failure occurring within 18 months were assessed . RESULTS Trough serum infliximab levels after the first 2 intravenous infusions of infliximab at 3 mg/kg varied considerably between patients ( range 0 - 22 microg/ml ) . At this stage , only 13 % of the patients were anti-infliximab antibody positive . With subsequent infusions , the frequency of antibody positivity rose to 30 % and 44 % ( at 3 months and 6 months , respectively ) , accompanied by diminished trough levels of infliximab .  Indeed , low  infliximab levels at 1.5 months predicted antibody development and later treatment failure . There were highly significant correlations between high levels of antibodies and later dose increases , side effects , and cessation of therapy . High baseline disease activity , judged by C-reactive protein level and Disease Activity Score , was associated with low levels of  infliximab  at the early stage of treatment and later development of anti-infliximab antibodies . Cotreatment with methotrexate result ed in slightly reduced antibody levels after 6 months ; other disease-modifying antirheumatic drugs and prednisolone had no effect . CONCLUSION Development of anti-infliximab antibodies , heralded by low preinfusion serum infliximab levels , is associated with increased risk of infusion reaction and treatment failure . Early monitoring may help optimize dosing regimens for individual patients , diminish side effects , and prevent prolonged use of inadequate infliximab therapy Data from clinical trials suggest the efficacy of the chimeric tumor necrosis factor alpha monoclonal antibody infliximab in improving clinical , endoscopic , and histologic outcomes in patients with moderately to severely active Crohn 's disease ( CD ) and fistulizing CD . To determine whether the efficacy and safety record of infliximab reported in clinical trials would be reflected in clinical use , clinical experience with infliximab was assessed in patients with CD at the University of Chicago , Chicago , Illinois . All patients with CD at this institution receiving infliximab in the first year of its release were prospect ively followed up for 1 year . Disease activity was scored at the time of the initial infusion and at 1 , 3 , 7 , and 12 weeks after infusion . Results were analyzed separately for patients with luminal or fistulous CD .  Clinical response , remission , corticosteroid tapering , and adverse event data were collected . A total of 129 patients with luminal ( n = 81 ) or fistulous ( n = 48 ) disease received a mean of 2.38 and 3.23 infusions of infliximab per patient , respectively . After the initial infusion course , clinical response and remission rates at 3 weeks were 65 % and 31 % for patients with luminal disease and 78 % and 24 % for patients with fistulous disease , respectively . Clinical response and remission after the first infusion occurred at a median of 8 days and 9 days , respectively . In those patients who subsequently relapsed , relapses occurred after a mean of 8.5 weeks and 12.2 weeks in patients with luminal and fistulizing disease , respectively . Corticosteroid tapering was possible in > 90 % of patients ( luminal disease ) after the initial infusion and complete withdrawal in 54 % after the second infusion , with a sustained median steroid dose of 0 mg from the 4-month time-point onward . Infusion reactions or adverse events occurred in 5 - 13 % of patients during or immediately after the initial infusion of infliximab ; most were mild and easily managed and did not increase in incidence with subsequent infusions . Clinical experience with infliximab closely mirrors the findings of controlled clinical trials . Repeated administration of infliximab was efficacious and relatively well tolerated in patients with CD and demonstrated corticosteroid-sparing benefits Anti‐TNFα therapy with infliximab is effective for Crohn ’s disease .  Infliximab neutralizes the biological activities of TNFα , a cytokine involved in host‐defence against certain infections 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 & 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 OBJECTIVE To determine the relationship between serum TNF-alpha level and clinical response in rheumatoid arthritis patients treated by infliximab .  This could be of value to predict clinical response to infliximab and to determine the optimal dose and interval between dosing of infliximab .  RA patients who did not respond adequately to conventional doses ( 3 mg/kg ) of infliximab  were studied to see if increasing the dose or frequency of infliximab infusions would be more effective . METHODS Fifty-five RA patients who fulfilled the American College of Rheumatology criteria and were receiving treatment by anti-TNF-alpha ( infliximab 3 mg/kg body weight every 8 weeks ) were evaluated by : clinical disease activity using the Richie score index before receiving their scheduled infliximab infusion . Serum level of TNF-alpha , as measured by competitive ELISA assay , was determined immediately before and 9 - 11 days after receiving infliximab .  RA patients who did not respond adequately to treatment with infliximab  were given either a larger dose of infliximab or given the infusion at six-week intervals . Their clinical response was then evaluated sixteen months later . RESULTS Patients were divided into 2 groups according to Richie score , active group with score > 10 ( score 20.3 + /- 7.7 mean + /- st and ard deviation , n = 25 ) and inactive group with scores < or = 10 ( score 4.1 + /- 3.2 , n = 30 ) . TNF-alpha serum levels pre-infliximab infusion were significantly higher in the active group 76.1 pg/ml than the inactive group 38.0 pg/ml ( P < 0.02 ) . Whereas TNF serum level significantly dropped post infliximab in the inactive group ( P < 0.05 ) , it did not drop in the active group . The mean level of the post-infusion TNF-alpha serum level was higher ( 76.6 + /- 93.4 ng/ml ) in the-active than the mean level of the post-infusion serum TNF-alpha levels in the inactive group ( 26.4 ng/ml + /- 7.9 ) P < 0.01 using the t-test . Increasing the frequency was superior in RA patients ' clinical outcome than increasing the dose of infliximab infusions . CONCLUSION RA patients who responded well to  infliximab  and had inactive disease at the time of the study have lower levels of serum TNF-alpha which could be further suppressed by the recommended doses of infliximab .  RA patients with active disease have higher serum levels of TNF-alpha which could not be suppressed after the recommended doses of infliximab infusion . Changing the frequency of infliximab infusions in the active group was more effective than increasing the dose of infliximab in inducing improved clinical outcome . We suggest that the lack of suppression of TNF-alpha in the active group could be due to inadequate dosing of infliximab or to the presence of a neutralizing antibody directed against infliximab . It remains to be seen if serum TNF-alpha levels could be used as a guide in determining the dose and intervals between dosing of anti-TNF therapy in RA in order to achieve the desired clinical response 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 The effect of different treatment regimens on antibody responses to infliximab  and their clinical significance was examined by using data from ACCENT I. METHODS Patients with Crohn 's disease ( n = 573 ) received 5 mg/kg infliximab ( week 0 ) and then were r and omly assigned to blinded infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo ( group I ) , 5 mg/kg infliximab ( group II ) , or 5 mg/kg infliximab at weeks 2 and 6 , followed by 10 mg/kg thereafter ( group III ) . At week 14 or later , patients losing response could cross over to episodic infliximab treatment increased by 5 mg/kg . Sample s for antibody determination were collected before the first infusion and at weeks 14 , 22 , 54 , 62 , 72 , and , if applicable , before and after crossover . RESULTS Through week 72 , antibodies to infliximab  were detected in 30 % , 10 % , and 7 % of groups I , II , and III , respectively ( P < 0.0001 ) . Patients receiving immunomodulators had a lower incidence of antibodies compared with patients receiving  infliximab alone ( 10 % and 18 % , respectively ; P = 0.02 ) . Antibodies were associated with a 12 % absolute increase in infusion reactions but no increase in serious infusion reactions or serum sickness-like reactions . In the overall population , similar proportions of antibody-positive and antibody-negative patients achieved clinical response ( 64 % and 62 % , respectively ; P = NS ) or clinical remission ( 41 % and 39 % , respectively ; P = NS ) at week 54 . Notably , 86 % of patients responded to retreatment , and 63 % were in clinical response at week 54 ; however , fewer antibody-positive group I patients attained clinical remission ( 31 % ) compared with those who were antibody negative ( 37 % ) or antibody inconclusive ( 54 % ) ( P = NS ) . CONCLUSIONS Reduced antibody formation and greater clinical benefit were observed with an induction regimen followed by maintenance treatment compared with a single dose followed by episodic retreatment in Crohn 's disease patients treated with infliximab 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 BACKGROUND & AIMS This analysis of Crohn 's disease patients treated with infliximab in ACCENT I compared episodic and scheduled treatment strategies under conditions that simulate clinical practice . METHODS After 5 mg/kg infliximab at week 0 , 573 patients were r and omized to infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo ( episodic ) , infliximab 5 mg/kg at weeks 2 and 6 followed by 5 mg/kg ( 5 mg/kg scheduled ) every 8 weeks , or infliximab 5 mg/kg at weeks 2 and 6 followed by 10 mg/kg ( 10 mg/kg scheduled ) every 8 weeks . At or after week 14 , treatment could be given with a dose of infliximab 5 mg/kg higher upon loss of response . RESULTS The efficacy of scheduled infliximab therapy was better than episodic treatment . Crohn 's Disease Activity Index ( CDAI ) scores were consistently significantly better in the 10 mg/kg scheduled maintenance group from weeks 10 to 54 , and response and remission rates ( combined scheduled ) were significantly higher from weeks 10 to 30 . A greater proportion of patients achieved complete mucosal healing at week 54 ( P = 0.041 ) . A lower proportion developed antibodies to infliximab  in the scheduled groups than in the episodic group ( 9 % [ 5 mg/kg ] , 6 % [ 10 mg/kg ] , 28 % [ episodic ] , respectively ) . Scheduled strategy patients had fewer Crohn 's disease-related hospitalizations ( P = 0.014 ) and surgeries ( P = 0.01 ) than episodic strategy patients . CONCLUSIONS The scheduled infliximab groups , particularly the 10 mg/kg group , had better CDAI and Inflammatory Bowel Disease Question naire ( IBDQ ) responses than those in the episodic group . Both scheduled groups had fewer hospitalizations , higher rates of mucosal healing , and fewer developed antibodies than those in the episodic group , with no increase in side effects OBJECTIVE The aim of this study is to report on the first year experience with infliximab for Crohn 's disease . METHODS All Crohn 's patients receiving infliximab at our institution in the first year of release were prospect ively registered . Disease activity was scored at initial infusion , and at 1 , 3 , 7 , and 12 wk . Results were tabulated separately for patients with luminal ( L ) or fistulous ( F ) Crohn 's disease .  Steroid withdrawal and adverse events were tabulated . RESULTS One hundred twenty-nine patients were treated ( 81 L , 48 F ) .  Mean number of infusions/patient were 2.38 L , 3.23 F. Median time to response and remission was 8 and 9 days L ; 9 and 10 days F , respectively . Initial infusion course response and remission rates at 3 wk were 65 % and 31 % L ; 78 % and 24 % F , respectively . Rates were higher if concurrently treated with 6-mercaptopurine or azathioprine and improved with subsequent infusions . Relapse occurred in 78 % at a mean 8.5 wk L and in 71 % at a mean of 12.2 wk F. Steroid tapering was seen in > 90 % , with 54 % completely off steroids after a second infusion . Infusion-related reactions were seen in up to 24 % of patients . The incidence of side effects did not differ if on concurrent immunomodulatory therapy . CONCLUSIONS Clinical experience with infliximab closely parallels the results of the controlled clinical trials , and includes steroid-sparing effects
BACKGROUND Infliximab ( IFX ) is a chimeric ( mouse/human ) anti-TNF-alpha monoclonal antibody approved for the treatment of refractory luminal and fistulizing Crohn 's disease ( CD ) .
It is a source of potential immunogenicity for humans , with the occurrence of anti-infliximab antibodies ( ATIs ) , which are thought to interfere with the pharmacodynamics and /or pharmacokinetics of the compound .
It remains unclear whether ATIs have any clinical importance for drug efficacy or safety .
We review studies specifically evaluating the incidence of ATIs in CD and their impact on the efficacy and safety of IFX .
RESULTS The biological and clinical mechanisms of ATI development are poorly understood .
The incidence of ATIs in vivo depends on multiple analytical and clinical factors , both patient- and treatment-related .