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 induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Infliximab prevents Crohn's disease recurrence after ileal resection. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study Efficacy and safety of adalimumab in Japanese patients with moderately to severely active ulcerative colitis Adalimumab for the induction and maintenance of clinical remission in Japanese patients with Crohn's disease. Infliximab, azathioprine, or combination therapy for Crohn's disease. Certolizumab pegol for active Crohn's disease: a placebo-controlled, randomized trial. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study. Infliximab maintenance therapy for fistulizing Crohn's disease. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial Maintenance therapy with certolizumab pegol for Crohn's disease. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Infliximab for the treatment of fistulas in patients with Crohn'S disease. Certolizumab pegol for the treatment of Crohn's disease. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis.
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 Objective The aim of this study was to assess the efficacy and safety of adalimumab ( ADA ) , a recombinant human monoclonal antibody against tumour necrosis factor α ( TNF ) , for the induction of clinical remission in anti-TNF naïve patients with moderately to severely active ulcerative colitis . Methods This 8-week , multicentre , r and omised , double-blind , placebo-controlled study ( NCT00385736 ) , conducted at 94 centres in North America and Europe , enrolled ambulatory adult patients with Mayo score of ≥6 points and endoscopic subscore of ≥2 points despite treatment with corticosteroids and /or immunosuppressants . Under the original study protocol , 186 patients were r and omised ( 1:1 ) to subcutaneous treatment with ADA160/80 ( 160 mg at week 0 , 80 mg at week 2 , 40 mg at weeks 4 and 6 ) or placebo . Subsequently , at the request of European regulatory authorities , the protocol was amended to include a second induction group ( ADA80/40 : 80 mg at week 0 , 40 mg at weeks 2 , 4 and 6 ) . The primary efficacy endpoint was clinical remission ( Mayo score ≤2 with no individual subscore > 1 ) at week 8 , assessed in 390 patients r and omised ( 1:1:1 ) to ADA160/80 , ADA80/40 , or placebo . Safety was assessed in all enrolled patients . Patients , study site personnel , investigators , and the sponsor were blinded to treatment assignment . Results At week 8 , 18.5 % of patients in the ADA160/80 group ( p=0.031 vs placebo ) and 10.0 % in the ADA80/40 group ( p=0.833 vs placebo ) were in remission , compared with 9.2 % in the placebo group . Serious adverse events occurred in 7.6 % , 3.8 % and 4.0 % of patients in the placebo , ADA80/40 , and ADA160/80 groups , respectively . There were two malignancies in the placebo group , none in the ADA groups . There were no cases of tuberculosis and no deaths . Conclusions ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and /or immunosuppressants . Clinical trial NCT00385736 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 BACKGROUND & AIMS Crohn 's disease commonly recurs after intestinal resection . We evaluated whether the administration of infliximab after resective intestinal surgery for Crohn 's disease reduces postoperative recurrence . METHODS We r and omly assigned 24 patients with Crohn 's disease who had undergone ileocolonic resection to receive intravenous infliximab ( 5 mg/kg ) , administered within 4 weeks of surgery and continued for 1 year , or placebo . The primary end point was the proportion of patients with endoscopic recurrence at 1 year . Secondary end points were clinical recurrence and remission and histologic recurrence . RESULTS The rate of endoscopic recurrence at 1 year was significantly lower in the infliximab group ( 1 of 11 patients ; 9.1 % ) compared with the placebo group ( 11 of 13 patients ; 84.6 % ) ( P = .0006 ) . There was a nonsignificant higher proportion of patients in clinical remission in the infliximab group ( 8 of 10 ; 80.0 % ) compared with the placebo group ( 7 of 13 ; 53.8 % ) ( P = .38 ) . The histologic recurrence rate at 1 year was significantly lower in the infliximab group ( 3 of 11 patients ; 27.3 % ) compared with the placebo group ( 11 of 13 patients ; 84.6 % ) ( P = .01 ) . The occurrence of adverse events was similar between the placebo and infliximab groups , and none occurred in the immediate postoperative period . CONCLUSIONS Administration of infliximab after intestinal resective surgery was effective at preventing endoscopic and histologic recurrence of Crohn 's disease BACKGROUND Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial . We assessed this risk in a prospect i ve observational cohort study . METHODS 19,486 patients with inflammatory bowel disease , of whom 11,759 ( 60.3 % ) had Crohn 's disease and 7727 ( 39.7 % ) had ulcerative colitis or unclassified inflammatory bowel disease , were enrolled in a nationwide French cohort by 680 gastroenterologists , who reported details of immunosuppressive therapy during the observation period , cases of cancer , and deaths . The risk of lymphoproliferative disorder was assessed according to thiopurine exposure . Median follow-up was 35 months ( IQR 29 - 40 ) . FINDINGS At baseline , 5867 ( 30.1 % ) of patients were receiving , 2809 ( 14.4 % ) had discontinued , and 10,810 ( 55.5 % ) had never received thiopurines . 23 new cases of lymphoproliferative disorder were diagnosed , consisting of one case of Hodgkin 's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder . The incidence rates of lymphoproliferative disorder were 0.90 per 1000 ( 95 % CI 0.50 - 1.49 ) patient-years in those receiving , 0.20/1000 ( 0.02 - 0.72 ) patient-years in those who had discontinued , and 0.26/1000 ( 0.10 - 0.57 ) patient-years in those who had never received thiopurines ( p=0.0054 ) . The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 ( 2.01 - 13.9 , p=0.0007 ) . Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease . INTERPRETATION Patients receiving thiopurines  for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders . FUNDING Programme Hospitalier de Recherche Clinique National ( AOM05157 ) , Association François Aupetit , Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris ( AP-HP ) , Ligue contre le Cancer , and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie Background Adalimumab is a fully human , monoclonal antibody against tumor necrosis factor that is approved in Western countries for the treatment of moderately to severely active ulcerative colitis ( UC ) . Methods This 52-week , phase 2/3 , r and omized , double-blind study evaluated adalimumab for induction and maintenance treatment in 273 anti-TNF – naive Japanese patients with UC who were refractory to corticosteroids , immunomodulators , or both . Patients received placebo , adalimumab 80/40 ( 80 mg at week 0 , then 40 mg every other week ) , or adalimumab 160/80 ( 160/80 mg at weeks 0/2 , then 40 mg every other week ) in addition to background UC therapy . Results At week 8 , remission rates were similar among treatment arms , but more patients treated with adalimumab 160/80 achieved response ( placebo , 35 % ; 80/40 , 43 % ; 160/80 , 50 % ; P = 0.044 for 160/80 vs placebo ) and mucosal healing ( placebo , 30 % ; 80/40 , 39 % ; 160/80 , 44 % ; P = 0.045 for 160/80 vs placebo ) compared with placebo . At week 52 , more patients receiving adalimumab 40 mg every other week achieved response ( 18 vs 31 % ; P = 0.021 ) , remission ( 7 vs 23 % ; P = 0.001 ) , and mucosal healing ( 16 vs 29 % ; P = 0.015 ) compared with placebo . Week 8 response to adalimumab was associated with greater rates of response ( 61 % ) , remission ( 46 % ) , and mucosal healing ( 57 % ) at week 52 relative to the overall population . Rates of serious adverse events were similar between treatment arms . Conclusions Induction with adalimumab 160/80 mg led to early response and mucosal healing . Maintenance adalimumab had greater rates of long-term response , remission , and mucosal healing compared with placebo . No new safety signals were identified BACKGROUND AND AIMS Adalimumab has been shown to be efficacious and well-tolerated in Western patients with Crohn 's disease . These 2 r and omized , double-blind clinical trials evaluated adalimumab efficacy and safety in Japanese patients with moderate to severe Crohn 's disease . METHODS 90 patients enrolled in the induction trial and were r and omized to receive adalimumab 160/80 mg , adalimumab 80/40 mg or placebo at Weeks 0/2 . At Week 4 , patients who achieved a decrease in CDAI ≥ 70 points versus Baseline entered the maintenance trial and were r and omized to adalimumab 40 mg every other week or placebo for 52 weeks . All other patients received 4 more weeks of blinded adalimumab before entering the open-label portion of the maintenance trial . At/after Week 4 of the maintenance trial , blinded patients who flared/failed to respond entered the open-label portion . Open-label maintenance patients received adalimumab 40 mg every other week with the option of 80 mg every other week for flare/non-response . RESULTS Clinical remission rates at Week 4 in the induction trial were 33.3 % , 17.6 % and 13.0 % in the adalimumab 160/80 mg , adalimumab 80/40 mg and placebo groups , respectively . Maintenance remission rates were 38.1 % for adalimumab and 9.1 % for placebo at Week 52 . Anti-TNF naïve patients achieved greater efficacy than anti-TNF exposed patients . Patients r and omized to adalimumab achieved greater quality of life improvement versus placebo . There were no clinical ly relevant differences in safety between adalimumab and placebo . CONCLUSIONS Adalimumab is effective and well-tolerated for inducing and maintaining clinical remission in Japanese patients with moderate to severe Crohn 's disease 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 Certolizumab pegol ( CZP ) is a pegylated-conjugated Fab ' against tumor necrosis factor ( TNF ) . Additional data are needed regarding the efficacy of induction therapy with CZP in active Crohn 's disease ( CD ) . METHODS A placebo-controlled trial evaluated the efficacy of CZP therapy in 439 adults with moderate to severe CD naive to anti-TNF therapy . Patients were r and omized to receive CZP ( 400 mg subcutaneously ) or placebo at weeks 0 , 2 , and 4 . The primary end point was clinical remission at week 6 . RESULTS Clinical remission rates at week 6 in the CZP and placebo groups were 32 % and 25 % ( P = .174 ) , respectively . Remission rates at weeks 2 and 4 in the CZP and placebo groups were 23 % and 16 % ( P = .033 ) and 27 % and 19 % ( P = .063 ) , respectively . Clinical response rates at weeks 2 , 4 , and 6 in the CZP and placebo groups were 33 % and 20 % ( P = .001 ) , 35 % and 26 % ( P = .024 ) , and 41 % and 34 % ( P = .179 ) , respectively . There were significantly greater rates of clinical remission at week 6 for CZP in patients with increased concentrations of C-reactive protein ( ≥5 mg/L ) at entry . Serious adverse events developed in 5 % and 4 % of patients in the CZP and placebo groups , respectively . CONCLUSIONS The primary end point did not reach statistical significance . Significant differences between CZP and placebo were observed in patients who had increased concentrations of C-reactive protein when the study began . Future clinical trials should emphasize the treatment of patients who have objective evidence of inflammation in addition to symptoms of active disease BACKGROUND & AIMS Inflammatory bowel diseases ( IBD ) are becoming more common in Asia , but epidemiologic data are lacking . The Asia-Pacific Crohn 's and Colitis Epidemiology Study aim ed to determine the incidence and phenotype of IBD in 8 countries across Asia and in Australia . METHODS We performed a prospect i ve , population -based study of IBD incidence in predefined catchment areas , collecting data for 1 year , starting on April 1 , 2011 . New cases were ascertained from multiple overlapping sources and entered into a Web-based data base . Cases were confirmed using st and ard criteria . Local endoscopy , pathology , and pharmacy records were search ed to ensure completeness of case capture . RESULTS We identified 419 new cases of IBD ( 232 of ulcerative colitis [ UC ] , 166 of Crohn 's disease [ CD ] , and 21 IBD-undetermined ) . The crude annual overall incidence values per 100,000 individuals were 1.37 for IBD in Asia ( 95 % confidence interval : 1.25 - 1.51 ; 0.76 for UC , 0.54 for CD , and 0.07 for IBD-undetermined ) and 23.67 in Australia ( 95 % confidence interval : 18.46 - 29.85 ; 7.33 for UC , 14.00 for CD , and 2.33 for IBD-undetermined ) . China had the highest incidence of IBD in Asia ( 3.44 per 100,000 individuals ) . The ratios of UC to CD were 2.0 in Asia and 0.5 in Australia . Median time from symptom onset to diagnosis was 5.5 months ( interquartile range , 1.4 - 15 months ) . Complicated CD ( stricturing , penetrating , or perianal disease ) was more common in Asia than Australia ( 52 % vs 24 % ; P = .001 ) , and a family history of IBD was less common in Asia ( 3 % vs 17 % ; P < .001 ) . CONCLUSIONS We performed a large-scale population -based study and found that although the incidence of IBD varies throughout Asia , it is still lower than in the West . IBD can be as severe or more severe in Asia than in the West . The emergence of IBD in Asia will result in the need for specific health care re sources , and offers a unique opportunity to study etiologic factors in developing nations 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 : Tumour necrosis factor production is increased in the mucosa of patients with active ulcerative colitis . The benefits of infliximab in Crohn ’s disease are established . We investigated its efficacy in ulcerative colitis . Methods : We conducted a r and omised placebo controlled trial of infliximab ( 5 mg/kg ) in the treatment of glucocorticoid resistant ulcerative colitis . Infusions were given at weeks 0 and 2 . Disease activity and quality of life were recorded over eight weeks of follow up . Remission was defined as an ulcerative colitis symptom score ( UCSS ) of ⩽2 and /or Baron score of 0 at week 6 . Patients not in remission were offered open label infliximab 10 mg/kg and review ed two weeks later . Results : After two weeks , there was no statistically significant difference between the infliximab and placebo groups in the proportion of patients with a Baron score of 0 ( 13 % ( 3/23 ) v 5 % ( 1/19 ) ( 95 % confidence interval ( CI ) −9 % to 24 % ) ; p=0.74 ) . After six weeks , remission ( UCSS ⩽2 ) rates were 39 % ( 9/23 ) versus 30 % ( 6/20 ) ( 95 % CI −19 to 34 % ; p=0.76 ) . The median improvement in UCSS was 3 for the infliximab group and 2.5 for the placebo group ( p=0.82 , Mann-Whitney U test ) . A Baron score of 0 was likely in either group ( 26 % ( 6/23 ) v 30 % ( 6/20 ) ( 95 % CI −30 % to 23 % ) ; p=0.96 ) . Improvement in the IBDQ and EuroQol was not significantly different between the groups ( p=0.22 and 0.3 , respectively , Mann-Whitney U test ) . Twenty eligible patients were given open labelled infusions . Remission was achieved in 3/11 ( 27 % ) patients initially treated with infliximab and in 1/9 ( 11 % ) patients treated with placebo . Conclusion : These data do not support the use of infliximab in the management of moderately active glucocorticoid resistant ulcerative colitis 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 Infliximab , an anti-tumor necrosis factor monoclonal antibody , rapidly reduces signs and symptoms of active Crohn 's disease . The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit . METHODS The efficacy , safety , pharmacokinetics , and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a r and omized , double-blind , placebo-controlled , parallel group trial . Seventy-three patients with active Crohn 's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response ( > /=70-point decrease in the Crohn 's Disease Activity Index ) to an initial infusion of infliximab ( or placebo )  were studied . RESULTS Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab . Median values for Crohn 's Disease Activity Index , inflammatory bowel disease question naire ( a quality of life measurement ) , and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment , but not with placebo retreatment . Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity . One case of lymphoma and 1 case of suspected lupus were reported ; the complete long-term safety profile of infliximab requires additional clinical investigation . CONCLUSIONS Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn 's disease not responding to conventional treatments BACKGROUND & AIMS To investigate the efficacy and safety of certolizumab pegol ( a polyethylene-glycolated Fab ' fragment of anti-tumor necrosis factor , CDP870 ) in Crohn 's disease . METHODS In a placebo-controlled , phase II study , 292 patients with moderate to severe Crohn 's disease received subcutaneous certolizumab 100 , 200 , or 400 mg or placebo at weeks 0 , 4 , and 8 . The primary end point was the percentage of patients with a clinical response  at week 12 ( a Crohn 's Disease Activity Index decrease of > or = 100 points or remission [ Crohn 's Disease Activity Index < or = 150 points ] ) in the intent-to-treat population . RESULTS All certolizumab doses produced significant clinical benefit over placebo at week 2 ( placebo , 15.1 % ; certolizumab 100 mg , 29.7 % [ P = .033 ] ; 200 mg , 30.6 % [ P = .026 ] ; 400 mg , 33.3 % [ P = .010 ] ) . At all time points , the clinical response rates were highest for certolizumab 400 mg , greatest at week 10 ( certolizumab 400 mg , 52.8 % ; placebo , 30.1 % ; P = .006 ) but not significant at week 12 ( certolizumab 400 mg , 44.4 % ; placebo , 35.6 % ; P = .278 ) . Patients with baseline C-reactive protein levels of 10 mg/L or greater ( n = 119 ) showed clearer separation between active treatment and placebo ( week 12 clinical response : certolizumab 400 mg , 53.1 % ; placebo , 17.9 % ; P = .005 ; post hoc analysis ) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups . CONCLUSIONS Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn 's disease . High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo . Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab BACKGROUND & AIMS The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for ulcerative colitis ( UC ) have not been evaluated previously . METHODS This r and omized , double-blind trial evaluated the efficacy and safety of 16 weeks of treatment with infliximab monotherapy , azathioprine monotherapy , or the 2 drugs combined in  tumor necrosis factor-a antagonist-naive adults with moderate to severe UC . Patients were assigned r and omly to receive intravenous infusions of infliximab 5 mg/kg at weeks 0 , 2 , 6 , and 14 plus daily oral placebo capsules ; oral azathioprine 2.5 mg/kg daily plus placebo infusions on the infliximab schedule ; or combination therapy with the 2 drugs .  Corticosteroid-free clinical remission ( primary end point , week 16 ) was evaluated at weeks 8 and 16 . The study was terminated before the enrollment target was reached . RESULTS A total of 239 patients were included in efficacy analyses . Baseline characteristics were similar between treatment groups . Corticosteroid-free remission at week 16 was achieved by 39.7 % ( 31 of 78 ) of patients receiving infliximab/azathioprine , compared with 22.1 % ( 17 of 77 ) receiving infliximab alone(P = .017 ) and 23.7 % ( 18 of 76 ) receiving azathioprine alone(P = .032 ) . Mucosal healing at week 16 occurred in 62.8 % ( 49 of 78 ) of patients receiving infliximab/azathioprine , compared with 54.6 % ( 42 of 77 ) receiving infliximab ( P = .295 ) and 36.8 % ( 28 of 76 ) receiving azathioprine ( P = .001 ) . Serious infections occurred in 2 patients ( 1 patient receiving infliximab , and 1 patient receiving azathioprine ) . CONCLUSIONS Anti – tumor necrosis factor-a – naive patients with moderate to severe UC treated with infliximab plus azathioprine were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy . Combination therapy led to significantly better mucosal healing than azathioprine monotherapy . Clinical Trials.gov number , NCT00537316 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 Certolizumab pegol is a pegylated humanized Fab ' fragment that binds tumor necrosis factor alpha . METHODS In a r and omized , double-blind , placebo-controlled trial , we evaluated the efficacy of certolizumab pegol in 662 adults with moderate-to-severe Crohn 's disease . Patients were stratified according to baseline levels of C-reactive protein ( CRP ) and were r and omly assigned to receive either 400 mg of certolizumab pegol or placebo subcutaneously at weeks 0 , 2 , and 4 and then every 4 weeks . Primary end points were the induction of a response at week 6 and a response at both weeks 6 and 26 . RESULTS Among patients with a baseline CRP level of at least 10 mg per liter , 37 % of patients in the certolizumab group had a response at week 6 , as compared with 26 % in the placebo group ( P=0.04 ) . At both weeks 6 and 26 , the corresponding values were 22 % and 12 % , respectively ( P=0.05 ) . In the overall population , response rates at week 6 were 35 % in the certolizumab group and 27 % in the placebo group ( P=0.02 ) ; at both weeks 6 and 26 , the response rates were 23 % and 16 % , respectively ( P=0.02 ) . At weeks 6 and 26 , the rates of remission in the two groups did not differ significantly ( P=0.17 ) . Serious adverse events were reported in 10 % of patients in the certolizumab group and 7 % of those in the placebo group ; serious infections were reported in 2 % and less than 1 % , respectively . In the certolizumab group , antibodies to the drug developed in 8 % of patients , and antinuclear antibodies developed in 2 % . CONCLUSIONS In patients with moderate-to-severe Crohn 's disease , induction and maintenance therapy with certolizumab pegol was associated with a modest improvement in response rates , as compared with placebo , but with no significant improvement in remission rates . ( Clinical Trials.gov number , NCT00152490 [ Clinical Trials.gov ] . ) BACKGROUND & AIMS Subcutaneous golimumab , a fully human monoclonal antibody to tumor necrosis factor-α ( TNFα ) , was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis , despite conventional therapy , who responded to golimumab induction therapy . METHODS We performed a phase 3 , double-blind trial of patients who completed golimumab induction trials ( Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment , eg , PURSUIT ) . Patients who responded to induction therapy with golimumab ( n = 464 ) were assigned r and omly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52 . Patients who responded to  placebo in the induction study continued to receive placebo . Nonresponders in the induction study received 100 mg golimumab . The primary end point was clinical response maintained through week 54 ; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54 . RESULTS Clinical response was maintained through week 54 in 47.0 % of patients receiving 50 mg golimumab , 49.7 % of patients receiving 100 mg golimumab , and 31.2 % of patients receiving placebo ( P = .010 and P < .001 , respectively ) . At weeks 30 and 54 , a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing ( 27.8 % and 42.4 % ) than patients given placebo ( 15.6 % and 26.6 % ; P = .004 and P = .002 , respectively ) or 50 mg golimumab ( 23.2 % and 41.7 % , respectively ) . Percentages of serious adverse events were 7.7 % , 8.4 % , and 14.3 % among patients given placebo , 50 mg , or 100 mg golimumab , respectively ; percentages of serious infections were 1.9 % , 3.2 % , and 3.2 % , respectively . Among all patients given golimumab in the study , 3 died ( from sepsis , tuberculosis , and cardiac failure , all in patients who received 100 mg golimumab ) and 4 developed active tuberculosis . CONCLUSIONS Golimumab ( 50 mg or 100 mg ) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis ; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54 . Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications . Clinical Trials.gov number : NCT00488631
Background Anti-tumor necrosis factor-alpha ( TNF-α ) agents have considerable advances in treating inflammatory bowel disease ( IBD ) .
These drugs carry possible risk of adverse symptoms , and no meta- analysis has examined this issue and the potential duration -response relationship .
Purpose The purpose of this study was to assess duration -response relationship between anti-TNF-α agents and risk of adverse symptoms from all available r and omized control trials ( RCTs ) with placebo arms in IBD .