A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis Double‐blind, placebo‐controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid‐refractory ulcerative colitis Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study Cyclosporine in severe ulcerative colitis refractory to steroid therapy. Response of Refractory Colitis to Intravenous or Oral Tacrolimus (FK506) Oral tacrolimus as maintenance therapy for refractory ulcerative colitis--an analysis of outcomes in two London tertiary centres. The use of infliximab in the prevention of postsurgical recurrence in polysurgery Crohn's disease patients: a pilot open-labeled prospective study Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn's disease: A single‐center experience Tacrolimus (FK506) as primary immunosuppressant after lung transplantation. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis.
Background and aims : Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis ( UC ) , while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies . Methods : Patients with refractory active UC were r and omly assigned to a high trough concentration ( 10–15 ng/ml ) group ( HT group ) ( n = 21 ) , low trough concentration ( 5–10 ng/ml ) group ( LT group ) ( n = 22 ) , or placebo group ( n = 20 ) . Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily . Efficacy was evaluated in 60 patients based on a disease activity index ( DAI ) score .  Fifty eight patients had additional treatment with tacrolimus  and were evaluated for efficacy in a 10 week open label extension . Results : An improvement in DAI score ( ⩾4 points , all categories improved ) was observed for 68.4 % of cases in the HT group compared with 10.0 % in the placebo group ( p<0.001 ) . In the HT group , 20.0 % of patients had clinical remission and 78.9 % had mucosal healing . In the open label extension , 55.2 % of all patients had an improved DAI score at week 10 . Mean dose of prednisolone  was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10 . The incidence of side effects in the HT group was significantly higher than that of the placebo group ( p = 0.043 ) . The most common event was mild finger tremor . Conclusions : Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC . The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy Background : We report a multicenter study of oral tacrolimus ( FK506 ) therapy in steroid‐refractory ulcerative colitis ( UC ) . Methods : In a placebo‐controlled , double‐blind study , 62 patients with steroid‐refractory , moderate‐to‐severe UC were r and omized into either a tacrolimus group or a placebo for 2 weeks . Patients were evaluated using the Disease Activity Index ( DAI ) . As an entry criterion , patients had to have a total DAI score of 6 or more as well as a mucosal appearance subscore of 2 or 3 .  Clinical response was defined as improvement in all DAI subscores . Mucosal healing was defined as mucosal appearance subscore of 0 or 1 . Clinical remission was defined as a total DAI score ≤2 with an individual subscore of 0 or 1 . Results : The mean total DAI score at study entry was 9.8 ± 1.61 in the tacrolimus group and 9.1 ± 1.05 in the placebo group . At week 2 the clinical response rate was 50.0 % ( 16/32 ) in the tacrolimus group and 13.3 % ( 4/30 ) in the placebo group ( P = 0.003 ) . The rate of mucosal healing observed was 43.8 % ( 14/32 ) in the tacrolimus group and 13.3 % ( 4/30 ) in the placebo group ( P = 0.012 ) and the rate of clinical remission observed was 9.4 % ( 3/32 ) in the tacrolimus group and 0.0 % ( 0/30 ) in the placebo group ( P = 0.238 ) . The therapies in this study were well tolerated , with only minor side effects . Conclusions : Oral tacrolimus therapy in patients with steroid‐refractory UC shortened the acute phase and induced rapid mucosal healing . These results suggest that tacrolimus therapy is useful as an alternative therapy for steroid‐refractory UC . ( Inflamm Bowel Dis 2011 ; BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids . We compared the efficacy and safety of these drugs for this indication . METHODS In this parallel , open-label , r and omised controlled trial , patients were aged at least 18 years , had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points , and had been given an unsuccessful course of high-dose intravenous steroids . None of the patients had previously received ciclosporin or infliximab .  Between June 1 , 2007 , and Aug 31 , 2010 , patients at 27 European centres were r and omly assigned ( via computer-derived permutation tables ; 1:1 ) to receive either intravenous ciclosporin ( 2 mg/kg per day for 1 week , followed by oral drug until day 98 ) or infliximab ( 5 mg/kg on days 0 , 14 , and 42 ) . In both groups , azathioprine was started at day 7 in patients with a clinical response . Neither patients nor investigators were masked to study treatment . The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7 , a relapse between day 7 and day 98 , absence of steroid-free remission at day 98 , a severe adverse event leading to treatment interruption , colectomy , or death . Analysis was by intention to treat . This trial is registered with EudraCT ( 2006 - 005299 - 42 ) and Clinical Trials.gov ( NCT00542152 ) . FINDINGS 115 patients were r and omly assigned ; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab .  Treatment failure occurred in 35 ( 60 % ) patients given ciclosporin and 31 ( 54 % ) given infliximab ( absolute risk difference 6 % ; 95 % CI -7 to 19 ; p=0·52 ) . Nine ( 16 % ) patients in the ciclosporin group and 14 ( 25 % ) in the infliximab group had severe adverse events .  INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids . In clinical practice , treatment choice should be guided by physician and centre experience . FUNDING Association François Aupetit , Société Nationale Française de Gastroentérologie , and the International Organization for the study of Inflammatory Bowel Disease BACKGROUND In previous comparative studies tacrolimus was superior to the st and ard formulation of ciclosporin in preventing acute rejection  after renal transplantation . We have compared the microemulsion formulation of ciclosporin with tacrolimus in a multicentre r and omised trial . METHODS The 6-month open study involved 560 patients in 50 European centres . 287 patients were r and omly assigned tacrolimus and 273 ciclosporin microemulsion plus azathioprine and corticosteroids .  The initial oral daily doses were 0.30 mg/kg for tacrolimus and 8 - 10 mg/kg for ciclosporin . The primary endpoint was the proportion of patients with biopsy-proven acute rejection and the time to this event . FINDINGS The two study groups were similar in terms of baseline characteristics . Three patients did not receive study treatment or did not undergo transplantation ( one tacrolimus , two ciclosporin ) . The rate of biopsy-confirmed acute rejection was significantly lower with tacrolimus than with ciclosporin microemulsion ( 56 patients [ 19.6 % ] vs 101 [ 37.3 % ] ; 17.7 % difference [ 95 % CI 10.3 - 25.1 ] ; p<0.0001 ) . Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus ( 27 [ 9.4 % ] vs 57 [ 21.0 % ] ; 11.6 % difference [ 5.7 - 17.5 ] ; p<0.0001 ) . Cross-over between therapies because of biopsy-proven rejection was judged necessary in one of 286 ( 0.3 % ) tacrolimus-group patients and 27 of 271 ( 10.0 % ) ciclosporin-group patients ( p<0.0001 ) . There were no significant differences in survival of patients or grafts or in renal function . The overall frequency of adverse events was similar in the two groups , though hypertension and hypercholesterolaemia were more common in the ciclosporin group and tremor and hypomagnesaemia were more frequent in the tacrolimus group . INTERPRETATION Tacrolimus was significantly more effective than ciclosporin microemulsion in preventing acute rejection after renal transplantation and had a superior cardiovascular-risk profile BACKGROUND There has been no new effective drug therapy for patients with severe ulcerative colitis since corticosteroids were introduced almost 40 years ago . In an uncontrolled study , 80 percent of 32 patients with active ulcerative colitis refractory to corticosteroid therapy had a response to cyclosporine therapy . METHODS We conducted a r and omized , double-blind , controlled trial in which cyclosporine ( 4 mg per kilogram of body weight per day ) or placebo was administered by continuous intravenous infusion to 20 patients with severe ulcerative colitis whose condition had not improved after at least 7 days of intravenous corticosteroid therapy .  A response to therapy was defined as an improvement in a numerical symptom score ( 0 indicated no symptoms , and 21 severe symptoms ) leading to discharge from the hospital and treatment with oral medications . Failure to respond to therapy result ed in colectomy , but some patients in the placebo group who had no response and no urgent need for surgery were subsequently treated with cyclosporine . RESULTS Nine of 11 patients ( 82 percent ) treated with cyclosporine had a response within a mean of seven days , as compared with 0 of 9 patients who received placebo ( P < 0.001 ) . The mean clinical -activity score fell from 13 to 6 in the cyclosporine group , as compared with a decrease from 14 to 13 in the placebo group . All five patients in the placebo group who later received cyclosporine therapy had a response . CONCLUSIONS Intravenous cyclosporine therapy is rapidly effective for patients with severe corticosteroid-resistant ulcerative colitis Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis , whereas the experience with FK506 is limited . In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative ( n = 33 ) or indeterminate ( n = 5 ) colitis .  FK506 was started intravenously in the first group ( n = 18 ) at a dose of 0.01 to 0.02 mg/kg up to 14 days , followed by 0.1 to 0.2 mg/kg orally , or was started orally at this dose in a second group ( n = 20 ) . Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients , followed by a dose reduction of FK506 . Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety . Primary objectives were the induction of remission ( Truelove index of mild ) and colectomy-free survival . Treatment lasted for a mean of 7.6 months , and the mean observation period was 16.2 months . Eighteen of 38 patients improved within 14 days , and a complete remission was achieved in 13 patients after 1 month . A colectomy within 1 month was performed in 3 of 38 patients . The overall colectomy rate was 34 % . One-half of the patients with a minimum follow-up of 2 years required a colectomy . Intravenous and per oral administration were equally safe and effective . The most frequent adverse events included tremor , hyperglycemia , hypertension , and infection , but none were severe . Renal impairment was rare and subsided upon drug withdrawal . In conclusion , FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration BACKGROUND The medical management of refractory ulcerative colitis ( UC ) remains a significant challenge . Two r and omised controlled studies have demonstrated tacrolimus therapy is effective for the induction of remission of moderate to severe UC . However , the long term outcomes of UC patients treated with tacrolimus as maintenance therapy are not certain . AIMS This study aims to assess the efficacy of tacrolimus maintenance therapy for refractory UC . METHODS A retrospective review of patients with UC treated with tacrolimus at two London tertiary centres was performed . Clinical outcomes were assessed at six months , at the end of tacrolimus treatment , or at the last follow-up for patients continuing tacrolimus treatment . Modified Truelove-Witts score ( mTW ) and Mayo endoscopy subscores were calculated . RESULTS 25 patients with UC , treated with oral tacrolimus between 2005 and 2011 , were identified . The median duration of tacrolimus treatment was 9 months ( IQR 3.7 - 18.2 months ) . The median duration of follow-up was 27 months ( range 3 - 66 months ) . At six months thirteen ( 52 % ) patients had achieved and maintained clinical response and eleven ( 44 % ) were in clinical remission . The mean mTW score decreased from 10+/-0.5 before therapy , to 5.8+/-0.8 ( p≤0.001 95 % CI 2.7 - 5.8 ) at cessation of treatment or last follow-up . Mayo endoscopy subscore decreased from 2.6+/-0.1 to 1.2+/-0.2 ( p≤0.001 mean reduction 1.4 , 95 % CI 0.8 - 1.9 ) . Eight patients ( 32 % ) subsequently underwent a colectomy within a mean time of 17 months ( range 2 - 45 months ) . CONCLUSION Tacrolimus is effective for the maintenance of refractory UC and can deliver sustained improvement in mucosal inflammation Purpose Crohn 's disease ( CD ) commonly recurs after surgery , and a number of patients need repeated surgery , especially smokers and those with repeated surgeries or penetrating disease . Whether infliximab prevents postsurgical recurrence in high-risk CD remains unknown . In the present pilot open-labeled study , we investigated the safety and efficacy of scheduled infliximab , which was started early after surgery , in maintaining remission of CD patients who have undergone multiple surgeries due to penetrating disease . Methods Eleven patients ( nine male , two female ; age range , 26–48 years ) who had undergone repeated surgeries ( median , 4 ; range , 2–5 ) for penetrating disease were enrolled . Two to 4 weeks after surgery , the patients were started on intravenous infliximab ( 5 mg/kg ) at an 8-week interval . The primary end points were the proportion of patients in clinical remission at the end of the study , the rate of endoscopic/radiologic remission at 24 months , and the rate of adverse effects . Results One patient dropped out due to non-compliance , and ten patients were eligible for analysis . Clinical remission was maintained in six of ten patients ( 60.0 % ) at the end of the study . At 24 months , four out of ten patients were in endoscopic or radiological remission ( 40.0 % ) . Two patients experienced adverse effects ( 18.2 % ) , one of whom elected to withdraw from the study . Conclusion The findings of no major safety concern and possible clinical benefit in our study suggest that further investigation of infliximab as a treatment for prevention of postsurgical recurrence in high-risk CD is warranted Background : The published experience regarding the use of tacrolimus in Crohn 's disease ( CD ) and ulcerative colitis ( UC ) refractory to more commonly used medical therapy has been fairly limited . Our objective was to describe our experience with its use in a cohort of patients which , to our knowledge , represents the largest North American cohort described to date . Methods : This was a retrospective , single‐center chart analysis . Patients were identified by compiling all hospital discharges with principle diagnoses of ICD‐9 codes for 555.0‐555.9 ( regional enteritis ) and 556.0‐556.9 ( ulcerative colitis ) from January 1 , 2000 , to October 31 , 2005 , and then cross‐referencing the electronic charts for tacrolimus serum concentrations ordered during this time period . Additional patients were identified through verbal communication with participating clinicians . Information abstract ed included proportion with clinical response and remission ( using a modified disease activity index ) , ability to wean from steroids , need for surgery / time to surgery , and side‐effect profile . Results : In all , 32 UC patients and 15 CD patients were identified . The mean disease duration was : UC 81 months ( range , 1 month to 37 years ) , CD 100 months ( range , 1 month to 35 years ) . The disease distribution for UC was : pancolitis 12 ( 37.5 % ) , extensive colitis 6 ( 18.8 % ) , left‐sided 11 ( 34.4 % ) , and proctitis 3(9.4 % ) . For CD this was : TI 2 ( 13.3 % ) , small bowel 2 ( 13.3 % ) , colonic 3 ( 20.7 % ) , ileocolonic 7(46.7 % ) , and perianal 1 ( 6.7 % ) .  The duration of tacrolimus treatment for UC was mean , 29 weeks . For CD it was mean , 9.9 weeks . In all , 30/32 UC and 7/15 CD patients were on steroids ; 4/30 UC and 0/7 CD patients were able to subsequently wean off steroids . In all , 12/32 UC patients proceeded to colectomy . Mean time to colectomy was 28 weeks and 6/15 CD patients proceeded to a resective surgery . The mean time to surgery was 22 weeks . In all , 22/32 UC patients achieved a clinical response ; 3/32 achieved remission and 8/15 CD patients achieved a clinical response ; 1/15 achieved remission . Adverse reactions were generally mild . In 6 patients the drug had to be discontinued because of an adverse reaction . There were no opportunistic infections identified , no cases of renal insufficiency related to drug administration , and no deaths while on the medicine . Conclusions : Our experience with tacrolimus in UC and CD indicates that it is safe and relatively well tolerated , although its clinical efficacy is quite variable . More prospect i ve studies assessing its use are necessary BACKGROUND Our positive experience with tacrolimus ( FK 506 ) in heart transplantation has led to our assessing the use of this medication as a primary immunosuppressant in lung transplantation . 62 of our patients after lung transplantation were included in this study . The first 34 patients were treated with cyclosporine A ( CyA ) , the remaining 28 with tacrolimus . No meaningful differences were found in baseline characteristics . The actuarial one-year survival rate was 70.6 % for the CyA group and 92.3 % for the tacrolimus group . The number of acute rejection episodes per patient was 1.50 for the CyA group versus 1.18 for the tacrolimus group ( p < 0.05 ) . The incidence of infection and their spectrum were comparable in both groups . The most frequently reported adverse events were diabetes mellitus 57 % ( tacrolimus ) vs 23 % ( CyA ) , and renal insufficiency ( 27 % vs 15 % ) . Tacrolimus seems to be a more potent immunosuppressant after lung transplantation than CyA ; on the other h and , diabetes and nephrotoxicity were diagnosed more frequently using tacrolimus . Although our results are very promising , further follow-up on the incidence of obliterative bronchiolitis is warranted BACKGROUND Tacrolimus ( FK 506 ) , a macrolide compound isolated from a bacterium , is a potent immunosuppressant with activity in solid-organ transplants . Most immunosuppressive regimens for liver transplantation are based on cyclosporine . METHODS We conducted an open-label , r and omized , multicenter trial to compare the efficacy and safety of tacrolimus-based and cyclosporine-based immunosuppressive regimens for patients receiving a first liver transplant . A total of 478 adults and 51 children ( < or = 12 years of age ) were r and omly assigned at the time of transplantation to receive tacrolimus ( n = 263 ) or cyclosporine ( n = 266 ) and were followed for one year . The primary end points were patient and graft survival at one year . The secondary end points were the incidence of acute rejection , corticosteroid-resistant rejection , and refractory rejection ( continued rejection after two courses of corticosteroids and an intervening course of muromonab-CD3 ) . RESULTS According to Kaplan-Meier analysis , actuarial patient-survival rates at day 360 were 88 percent for both the tacrolimus and cyclosporine groups ( P = 0.85 ; 95 percent confidence interval for the difference , -5.4 to 6.6 percent ) , and graft-survival rates were 82 percent and 79 percent , respectively ( P = 0.55 ; 95 percent confidence interval for the difference , -4.8 to 9.7 percent ) . Acute rejection occurred in 154 patients in the tacrolimus group and 173 patients in the cyclosporine group ( P < 0.002 ) , corticosteroid-resistant rejection occurred in 43 and 82 patients , respectively ( P < 0.001 ) , and refractory rejection occurred in 6 and 32 patients , respectively ( P < 0.001 ) . Tacrolimus was associated with a higher incidence of adverse events requiring withdrawal from the study , primarily nephrotoxicity and neurotoxicity ; 37 patients in the tacrolimus group and 13 in the cyclosporine group discontinued the study because of adverse events ( P < 0.001 ) . CONCLUSIONS After one year , immunosuppressive regimens based on tacrolimus and cyclosporine were comparable in terms of patient and graft survival .  Tacrolimus was associated with significantly fewer episodes of acute , corticosteroid-resistant , or refractory rejection , but substantially more adverse events requiring discontinuation of the drug AIM To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis ( UC ) patients . METHODS This was a prospect i ve , multicenter , observational study . Between May 2010 and August 2012 , 49 steroid-refractory UC patients ( 55 flare-ups ) were consecutively enrolled . All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1 mg/kg per day . The dose was adjusted to maintain trough whole-blood levels of 10 - 15 ng/mL for the first 2 wk . Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger 's clinical activity index ( CAI ) . RESULTS The mean CAI was 12.6 ± 3.6 at onset . Within the first 7 d , 93.5 % of patients maintained high trough levels ( 10 - 15 ng/mL ) . The CAI significantly decreased beginning 2 d after treatment initiation . At 2 wk , 73.1 % of patients experienced clinical responses . After tacrolimus initiation , 31.4 % and 75.6 % of patients achieved clinical remission at 2 and 4 wk , respectively . Treatment was well tolerated . CONCLUSION Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation . Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC
BACKGROUND Approximately 25 % of patients with ulcerative colitis [ UC ] experience a severe flare requiring steroid therapy to avoid colectomy .
We performed a systematic review and meta- analysis to assess the efficacy of tacrolimus as a rescue therapy for active UC .