A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. Controlled trial of azathioprine in Crohn's disease. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Thiopurine Methyltransferase (TPMT) Activity and Adverse Effects of Azathioprine in Inflammatory Bowel Disease: Long-Term Follow-Up Study of 394 Patients Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial. Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn's disease: increased relapse rate the following year Management of Crohn's Disease in Adults Cyclosporine in severe ulcerative colitis refractory to steroid therapy. Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee DOUBLE-BLIND WITHDRAWAL TRIAL OF AZATHIOPRINE AS MAINTENANCE TREATMENT FOR CROHN'S DISEASE Azathioprine in Ulcerative Colitis: Final Report on Controlled Therapeutic Trial A controlled double blind study of azathioprine in the management of Crohn's disease. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn's disease. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. Treatment of Crohn's disease with azathioprine: a controlled evaluation. Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial. A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term remission on azathioprine.
We r and omly assigned 71 patients with active chronic Crohn 's disease who were resistant to or intolerant of corticosteroids to treatment with oral cyclosporine ( 5 to 7.5 mg per kilogram of body weight per day ) or placebo for three months . Disease activity was assessed on a clinical grading scale without knowledge of the treatment given . At the end of the treatment period , 22 of the 37 cyclosporine-treated patients ( 59 percent ) had improvement , as compared with 11 of the 34 placebo-treated patients ( 32 percent ) ( P = 0.032 ) . During cyclosporine treatment , there was significant improvement in plasma orosomucoid levels ( P = 0.0025 ) and the Crohn 's Disease Activity Index ( P = 0.00012 ) . The effect of treatment became evident after two weeks . In the subsequent three months , during which the patients were gradually withdrawn from treatment , the improvement continued in 14 of the 37 patients ( 38 percent ) in the cyclosporine group and in 5 of the 34 ( 15 percent ) in the placebo group ( P = 0.034 ) . No serious adverse events were observed . We conclude that cyclosporine has a beneficial therapeutic effect in patients with active chronic Crohn 's disease and resistance to or intolerance of corticosteroids The effect of azathioprine in patients with active Crohn 's disease has been evaluated in a double-blind cross-over trial . Fifteen patients were treated with both azathioprine and placebo : only two improved while on azathioprine , six got worse , and in seven there was no change . The drug seemed to be the cause of deterioration in two of the patients . Although the drug may be of some value in a few patients , it should be used with caution and only when other measures have failed BACKGROUND & AIMS Uncontrolled studies have suggested that methotrexate may be effective in patients with active ulcerative colitis . The aim of this study was to evaluate the effectiveness of oral methotrexate in chronic steroid-dependent ulcerative colitis in a r and omized , double-blind multicenter trial . METHODS Patients with active ulcerative colitis who have received steroids and /or immunosuppressives for at least 4 months during the preceding 12 months with a current Mayo Clinic score of > or = 7 were included in the study .  Methotrexate ( 12.5 mg ) or placebo was added to their treatment once weekly for 9 months . RESULTS Sixty-seven patients were included ( methotrexate , 30 patients , placebo , 37 patients ) . The proportion of patients entering first remission  ( methotrexate , 46.7 % ; placebo , 48.6 % ) , the time to reach first remission  ( methotrexate , 4.1 + /- 1.9 months ; placebo , 3.4 + /- 1.7 months ) , as well as the proportions of patients having a relapse after first remission  ( methotrexate , 64.3 % ; placebo , 44.4 % ) were not significantly different between the two groups . The mean Mayo Clinic score , the mean monthly steroid dose , and the proportion of abnormal laboratory results during the study were also similar . CONCLUSIONS Methotrexate at a weekly oral dose of 12.5 mg was not found to be better than placebo in the induction or maintenance of remission in patients with chronic active ulcerative colitis AIM : To prospect ively evaluate whether a relationship between thiopurine methyltransferase ( TPMT ) activity and incidence of adverse effects ( especially myelotoxicity ) exists , in a long-term follow-up study of a large group of patients with inflammatory bowel disease treated with azathioprine .  METHODS : TPMT activity in red blood cells ( RBC ) was measured by a radiochemical method in 394 consecutive patients with Crohn 's disease ( 238 ) or ulcerative colitis ( 156 ) starting treatment with azathioprine .  The relationship among several variables and TPMT values was assessed , and the correlation between such levels and the incidence of adverse effects was evaluated . RESULTS : Mean TPMT value was 18.6 ± 4 U/mL RBCs ( range 9.4–33.7 ) . No patient had low levels ( < 5 ) , 7.1 % had intermediate levels ( 5–13.7 ) , and 92.9 % had high levels ( > 13.8 ) . Differences ( P < 0.001 ) were demonstrated in TPMT activity depending on the type of inflammatory bowel disease , but not on the remaining variables ( including treatment with 5-aminosalycilates ) . Adverse effects were reported in 74 patients ( 18.8 % ) , the most frequent being gastrointestinal intolerance ( 9.1 % ) and myelotoxicity ( 4.3 % ) . No patient having adverse effects had low TPMT levels . However , mean TPMT activity was lower in those with adverse effects ( 16.6 ± 3 vs 19.1 ± 4 U/mL , P < 0.001 ) . Moreover , the probability of suffering myelotoxicity in the high TPMT group was only 3.5 % , compared with 14.3 % in the TPMT intermediate group ( 95 % CI = 1.37–14.9 ; OR = 4.5 ) . CONCLUSIONS : The strategy of determining TPMT activity in all patients prior to initiating treatment with azathioprine could help to minimize the risk of myelotoxicity , as patients with intermediate TPMT activity had fourfold more risk than high TPMT activity patients BACKGROUND / AIMS Immunosuppression with methotrexate may be useful in the treatment of Crohn 's disease . We tested the efficacy of methotrexate in refractory Crohn 's disease in a r and omized , controlled trial . METHODOLOGY R and omized , double-blind placebo-controlled trial of methotrexate in 33 patients with steroid-dependent Crohn 's disease , 33 % of whom had previously failed therapy with 6-mercaptopurine .  Patients were given placebo or oral methotrexate 15 mg/week , or adjusted up to 22.5 mg/week , for up to 1 year or until treatment failure . Outcome was assessed by reduction in prednisone dosage , Crohn 's Disease Activity Index , hospital admission , and laboratory parameters . RESULTS Four patients were dropped from the study for non-compliance and one because of intercurrent illness , and 28 patients could be evaluated . Fewer methotrexate-treated patients ( 6/13 or 46 % ) had flares of Crohn 's disease as compared to placebo-treated patients ( 12/15 or 80 % ) , but this did not achieve statistical significance ( p<0.1 ) . There was a non-significant trend toward an increased number of significant side effects in the methotrexate-treated patients ( 3/13 or 23 % ) as compared to the placebo-treated patients ( 0/15 or 0 % ) ( p<0.2 ) . Laboratory indices of inflammation did not differ between the two groups . CONCLUSIONS The  methotrexate-treated  group showed a trend toward fewer Crohn 's disease flares , balanced by an increased number of significant side effects BACKGROUND & AIMS No therapy has been shown to reliably prevent the evolution of postoperative recurrence of Crohn 's disease . The aim of the current trial was to compare 6-mercaptopurine ( 6-MP ) and mesalamine with placebo for the prevention of clinical , endoscopic , and radiographic recurrence of Crohn 's disease after resection and ileocolic anastomosis . METHODS Five centers r and omized 131 patients to receive 6-MP ( 50 mg ) , mesalamine  ( 3 g ) , or placebo daily in a double-blind , double-dummy trial . Patients had clinical assessment s at 7 weeks and then every 3 months ; colonoscopy at 6 , 12 , and 24 months ; and small bowel series at 12 and 24 months . End points were clinical , endoscopic , and radiographic recurrence rates at 24 months . RESULTS Clinical recurrence rates ( intent to treat ) by life-table analysis at 24 months were 50 % ( 95 % confidence interval [ CI ] , 34%-68 % ) , 58 % ( 95 % CI , 41%-75 % ) , and 77 % ( 95 % CI , 61%-91 % ) in patients receiving 6-MP , mesalamine , and placebo , respectively . Endoscopic recurrence rates were 43 % ( 95 % CI , 28%-63 % ) , 63 % ( 95 % CI , 47%-79 % ) , and 64 % ( 95 % CI , 46%-81 % ) , and radiographic recurrence rates were 33 % ( 95 % CI , 19%-54 % ) , 46 % ( 95 % CI , 29%-66 % ) , and 49 % ( 95 % CI , 30%-72 % ) , respectively . 6-MP was more effective than placebo ( P < 0.05 ) at preventing clinical and endoscopic recurrence over 2 years . Patient withdrawals result ed in 69 % of the study population evaluable for the clinical recurrence end point . CONCLUSIONS 6-MP , 50 mg daily , was more effective than placebo at preventing postoperative recurrence of Crohn 's disease and should be considered as a maintenance therapy after ileocolic resection Introduction : Azathioprine is effective for maintenance of remission in Crohn 's disease , however , duration of efficacy and the dose response relationship has not been fully evaluated Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research , derived from extensive review of published literature . When data that will withst and objective scrutiny are not available , a recommendation may be made based on a consensus of experts . Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty . Guidelines are intended to be flexible , not necessarily indicating the only acceptable approach , and should be distinguished from st and ards of care that are inflexible and rarely violated . Given the wide range of choices in any health-care problem , the physician should select the course best suited to the individual patient and the clinical situation presented . These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee . Expert opinion is solicited from the outset for the document . The quality of evidence upon which a specific recommendation is based is as follows : Grade A : Homogeneous evidence from multiple well- design ed r and omized ( therapeutic ) or cohort ( descriptive ) controlled trials , each involving a number of participants to be of sufficient statistical power . Grade B : Evidence from at least one large well- design ed clinical trial with or without r and omization , from cohort or case – control analytic studies , or well- design ed meta- analysis . Grade C : Evidence based on clinical experience , descriptive studies , or reports of expert committees . The Committee review s guidelines in depth , with participation from experienced clinicians and others in related fields . The final recommendations are based on the data available at the time of the production of the document and may be up date d with pertinent scientific developments at a later time 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 Guidelines for clinical practice are aim ed to indicate preferred approaches to medical problems as established by scientifically valid research . Double-blind placebo controlled studies are preferable , but compassionate-use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine . When only data that will not withst and objective scrutiny are available , a recommendation is identified as a consensus of experts . Guidelines are applicable to all physicians who address the subject regardless of specialty training or interests and are aim ed to indicate the preferable but not necessarily the only acceptable approach to a specific problem . Guidelines are intended to be flexible and must be distinguished from st and ards of care , which are inflexible and rarely violated . Given the wide range of specifics in any health-care problem , the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision . Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the board of trustees . Each has been intensely review ed and revised by the Committee , other experts in the field , physicians who will use them , and specialists in the science of decision analysis . The recommendations of each guideline are therefore considered valid at the time of composition based on the data available . New developments in medical research and practice pertinent to each guideline will be review ed at a time established and indicated at publication to assure continued validity . The recommendations made are based on the level of evidence found . Grade A recommendations imply that there is consistent level 1 evidence ( r and omized controlled trials ) , grade B indicates that the evidence would be level 2 or 3 , which are cohort studies or case – control studies . Grade C recommendations are based on level 4 studies , meaning case series or poor- quality cohort studies , and grade D recommendations are based on level 5 evidence , meaning expert opinion 51 patients with Crohn 's disease who were in good health while taking azathiprine , 2 mg/kg body-weight/day , for at least six months were allocated either to a group in which azathioprine was continued or to one in which a control tablet was substituted . The trial lasted one year unless relapse recurred earlier . The cumulative probability of relapse was nil at six months and 5 % ( + /-5 S.D. ) at a year among those on azathioprine , compared with 25 % ( + /-9 S.D. ) at six months and 41 % ( + /-11 S.D. ) at a year among those in the control group ( P less than 0.01 ) . 1 patient in whom azathioprine was continued died of pancytopenia in the fourth month of the trial . Azathioprine is potentially toxic but appears to reduce the relapse-rate in Crohn 's disease Eighty patients , all of whom were suffering from a frank clinical attack of ulcerative colitis , were admitted to the trial . The attack was treated with a st and ard course of corticosteroids and the patients were immediately placed on treatment with either azathioprine in a dose of 2·5 mg/kg body weight or dummy tablets . The trial tablets were continued for one year while the patients were maintained under regular clinical , sigmoidoscopic , histological , haematological , and biochemical surveillance . If a patient relapsed during such maintenance treatment he or she was treated with a further course of corticosteroids without interrupting maintenance treatment . In the treatment of an actual attack of ulcerative colitis the results in the attacks which brought the 80 patients into the trial show that no benefit came from the addition of azathioprine to a st and ard course of corticosteroid therapy . Patients admitted in their first attack of ulcerative colitis showed no benefit from the one-year maintenance treatment with azathioprine  , the benefits of which were confined to patients admitted in a relapse of established disease . Even in these the difference between the treated group and the control group failed to reach statistical significance , but the difference was big enough to suggest that there is a prima facie case for regarding azathioprine as of some benefit in this group of patients While immunosuppressive agents are used widely in the management of Crohn 's disease , their efficacy has not been well established in r and omised controlled trials . This study was design ed to examine whether azathioprine increases remission rate when used in conjunction with a diminishing dose regimen of prednisolone over a period of 12 weeks . It further examined whether azathioprine offers any therapeutic advantage over placebo in the maintenance of remission in Crohn 's disease over a period of 15 months . Sixty three patients with active Crohn 's disease were treated with a 12 weeks diminishing dose of prednisolone and at the same time entered into a r and omised , double blind 15 month trial of either azathioprine ( 2.5 mg/kg ) or placebo .  Remission rates between the two groups were compared at 12 weeks and at 15 months . There was no significant difference in the proportion of patients who had achieved and maintained remission by week 12 but at 15 months there was a highly significant difference in the proportion of patients in remission ( 42 % receiving azathioprine v 7 % receiving placebo ) , p = 0.001 . Using life tables this beneficial effect was reflected as the difference in the median number of days on the trial ( p = 0.02 ) . There were significantly greater decreases over the trial period in the median erythrocyte sedimentation rate , C reactive protein , and leucocyte count in the azathioprine group . There were no cases of severe bone marrow suppression or clinical pancreatitis . In conclusion , azathioprine offers a therapeutic advantage over placebo in the maintenance of remission in Crohn 's disease BACKGROUND The role of azathioprine ( AZA ) in the treatment of active Crohn 's disease ( CD ) is still controversial . This study examined whether AZA combined with st and ard prednisolone therapy improved the therapeutic outcome compared with monotherapy with prednisolone . METHODS Forty-two patients with a Crohn 's Disease Activity Index ( CDAI ) of > 150 were r and omized into two groups . Both received 60 mg of prednisolone daily in a tapering regimen to a maintenance dose of 10 mg . In addition , group 1 received 2.5 mg AZA/kg body wt and group 2 received a placebo over the whole study period of 4 months . RESULTS At the end of the trial , 16 of 21 patients ( 76 % ) in group 1 were in remission ( CDAI < 150 ) , compared with 8 of 21 ( 38 % ) in group 2 ( P = 0.03 ) . The CDAI in group 1 dropped from 290 + /- 97 ( SD ) to 72 + /- 84 and from 285 + /- 110 to 155 + /- 105 in group 2 . The differences between activity indices in groups 1 and 2 became statistically significant after 8 weeks . The average prednisolone dose per day was 20.9 mg in group 1 and 26.7 mg in group 2 ( P = 0.02 ) . No major side effects were observed in this study . CONCLUSION The combination of prednisolone and AZA was superior to the treatment with prednisolone alone in active CD . Patients receiving AZA showed remission more frequently , more quickly , and with lower doses of prednisolone BACKGROUND At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn 's disease ( CD ) . AIM To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD . PATIENTS Patients with active CD , who have received steroids and /or immunosuppressives for at least 4 months during the preceding 12 months and with a current Harvey-Bradshaw index of > or = 7 were studied . METHODS Methotrexate ( 12.5 mg weekly ) or 6-mercaptopurine ( 50 mg daily ) , or placebo were given during the 9 months of the trial in addition to steroids and 5-aminosalicylic acid as clinical ly indicated . RESULTS Eighty-four patients were included ( methotrexate , 26 patients ; 6-mercaptopurine , 32 patients ; placebo , 26 patients ) . The proportion of patients entering first remission as well as the proportions of patients relapsing after first remission were not significantly different between the groups . The mean Harvey-Bradshaw index and the mean monthly steroid dose were also similar . However , when each patient was evaluated as his or her own control , the reduction in steroid dose , the general well being , and the reduction in abdominal pain were significantly better in the methotrexate treated patients . CONCLUSIONS Methotrexate at a weekly oral dose of 12.5 mg was found to be moderately better than 6-mercaptopurine and placebo in patients with chronic active CD To determine whether azathioprine is an effective drug in the treatment of Crohn 's disease a double-blind study was performed . Twenty-seven patients with involvement of either small or large intestine or both were r and omized to either a treatment group ( azathioprine 3 mg per kg of body weight ) or a placebo group for 4 months . During the subsequent 4-month period , the treatment schedule of the two groups was reversed . Although some patients improved dramatically on azathioprine , others improved during the placebo period . This study does not provide evidence to support the effectiveness of  azathioprine  in the treatment of Crohn 's disease OBJECTIVE To investigate the efficacy of azathioprine in treating patients with severe ulcerative colitis . DESIGN One-year , r and omized , placebo-controlled trial . SUBJECTS 83 patients with severe ulcerative colitis were enrolled . Fifty patients who relapsed within two months on corticosteroid withdrawal were r and omized into two groups . The azathioprine group received oral sulfasalazine ( 6 - 8 g/day ) , oral prednisolone ( 1 mg/Kg/day ) and oral azathioprine ( 2 mg/Kg/day ) . The placebo group received oral sulfasalazine ( 6 - 8 g/day ) , oral prednisolone ( 1 mg/Kg/day ) and placebo . Corticosteroids were tapered over 12 - 16 weeks . RESULTS Five patients ( 2 in azathioprine group , 3 in placebo group ) dropped out of the study . Three patients in the azathioprine group had side effects . The number of patients going into complete remission and partial remission was not significantly different in the two groups . The proportion of relapses in the azathioprine group was lower than in the placebo group ( p < 0.05 ) . CONCLUSIONS In patients with ulcerative colitis , azathioprine had no effect in achieving remission , when given in combination with prednisolone ; however , it lowers the proportion of relapses . Side effects like pancreatitis and hepatitis are mild and respond promptly to drug withdrawal BACKGROUND & AIMS An open study reported that patients with Crohn 's disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued . To confirm this observation , we performed a multicenter , double-blind , noninferiority withdrawal study . METHODS Patients who were in clinical remission on azathioprine for > or = 42 months were r and omized to continue azathioprine or to receive an equivalent placebo for 18 months . The primary end point was clinical relapse at 18 months . RESULTS Forty patients were r and omly assigned to receive azathioprine and 43 to receive placebo . Characteristics of patients at entry were similar in the 2 study groups . At 18 months , 3 patients had a relapse in the azathioprine group , and 9 had a relapse in the placebo group . Kaplan-Meier estimates of the relapse rate at 18 months were 8 % + /- 4 % and 21 % + /- 6 % , respectively . The hypothesis that placebo was inferior to azathioprine was not rejected ( P = .195 ) . Among the baseline variables , C-reactive protein level > 20 mg/L , time without steroids < 50 months , and hemoglobin level < 12 g/dL were found to be predictive of relapse in the multivariate analysis . CONCLUSIONS This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn 's disease who have been in remission on azathioprine  for > or = 3.5 years . Thus , azathioprine maintenance therapy should be continued beyond 3.5 years
OBJECTIVES : There remains controversy regarding the efficacy of thiopurine analogs ( azathioprine ( AZA ) and 6-mercaptopurine ( 6-MP ) ) , methotrexate ( MTX ) , and cyclosporine for the treatment of inflammatory bowel disease ( IBD ) .
We performed an up date d systematic review of the literature to clarify the efficacy of immunosuppressive therapy at inducing remission and preventing relapse in ulcerative colitis ( UC ) and Crohn 's disease ( CD ) .