Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Methotrexate for the treatment of refractory Crohn's disease. Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis. Long-term Methotrexate for Crohn's Disease: Safety and Efficacy in Clinical Practice Low-dose oral methotrexate in refractory inflammatory bowel disease Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial. Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee Azathioprine or methotrexate in the treatment of patients with steroid‐dependent or steroid‐resistant ulcerative colitis: results of an open‐label study on efficacy and tolerability in inducing and maintaining remission Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. 6‐Mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid‐dependent inflammatory bowel disease Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn's disease: a randomised, investigator-blind study. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. Methotrexate in Crohn's disease: long-term efficacy and toxicity Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Methotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study. Mucosal healing with methotrexate in Crohn’s disease: a prospective comparative study with azathioprine and infliximab Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.
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 BACKGROUND : Previous studies suggested that methotrexate has beneficial effects in patients with Crohn 's disease . We report our experience with this agent in patients with chronic active Crohn 's disease who previously failed to improve with conventional treatment , including azathioprine  in most cases . METHODS : Between June 1988 and June 1992 , 39 patients with refractory Crohn 's disease were treated with methotrexate .  In patients with active disease , clinical remission was defined by a Harvey‐Bradshaw index of less than 4 . For patients also taking corticosteroids , the date s of remission and complete steroid withdrawal were recorded . For patients who achieved clinical remission , and those in clinical remission when methotrexate was started , the relapse rate on methotrexate therapy was noted . RESULTS : In the 37 patients with active disease at methotrexate initiation , the probability of remission was 72 % at 3 months . The probability of remission and steroid withdrawal was 42 % at 12 months . In patients on clinical remission , the probability of relapse  on methotrexate was 58 % at 12 months . Twenty‐two patients experienced side‐effects , but these only warranted methotrexate discontinuation in four cases . CONCLUSIONS : Methotrexate appears effective in most patients with refractory Crohn 's disease and its short‐term toxicity is acceptable , but the long‐term benefit seems more limited BACKGROUND & AIMS Parenteral methotrexate is an effective treatment for patients with Crohn 's disease , but has never been adequately evaluated in patients with ulcerative colitis ( UC ) . We conducted a r and omized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC . METHODS We performed a double-blind , placebo-controlled trial to evaluate the efficacy of parenteral methotrexate ( 25 mg/wk ) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013 . Patients were given prednisone ( 10 to 40 mg/d ) when the study began and were r and omly assigned to groups ( 1:1 ) given placebo or methotrexate ( intramuscularly or subcutaneously , 25 mg weekly ) for 24 weeks . The primary end point was steroid-free remission ( defined as a Mayo score ≤2 with no item > 1 and complete withdrawal of steroids ) at week 16 . Secondary endpoints included clinical remission ( defined as a Mayo clinical subscore ≤2 with no item > 1 ) and endoscopic healing without steroids at weeks 16 and /or 24 , remission without steroids at week 24 , and remission at both weeks 16 and 24 . RESULTS Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate ( 31.7 % ) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1 % ( 95 % confidence interval [ CI ] : -4.0 % to 28.1 % ; P = .15 ) . The proportion of patients in steroid-free clinical remission at week 16 was 41.7 % in the methotrexate group and 23.5 % in the placebo group , for a difference of 18.1 % ( 95 % CI : 1.1 % to 35.2 % ; P = .04 ) . The proportions of patients with steroid-free endoscopic healing at week 16 were 35 % in the methotrexate group and 25.5 % in the placebo group -- a difference of 9.5 % ( 95 % CI : -7.5 % to 26.5 % ; P = .28 ) . No differences were observed in other secondary end points . More patients receiving placebo discontinued the study because of adverse events ( 47.1 % ) , mostly caused by UC , than patients receiving methotrexate ( 26.7 % ; P = .03 ) . A higher proportion of patients in the methotrexate group had nausea and vomiting ( 21.7 % ) than in the placebo group ( 3.9 % ; P = .006 ) . CONCLUSIONS In a r and omized controlled trial , parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC . However , methotrexate induced clinical remission without steroids in a significantly larger percentage of patients , result ing in fewer withdrawals from therapy due to active UC . Clinical Trials.gov ID NCT00498589 Goals To assess the efficacy and safety profile of methotrexate ( MTX ) for the treatment of Crohn 's disease ( CD ) in clinical practice . Background MTX is widely used for some chronic immunologic diseases . Although some r and omized controlled trials suggest its efficacy in CD , this drug remains a second-line , underused , immunomodulator . Study Medical records of all patients treated with MTX for CD in our center ( n=44 ) were review ed . Clinical and epidemiologic parameters , including risk factors for hepatotoxicity , were registered . Results MTX was prescribed mainly for steroid-dependency ( n=22 ) and as concomitant treatment to infliximab ( n=18 ) . Mean duration of treatment was 22.9±19 months , with a mean cumulative dose of MTX of 1169±784 mg . Thirty-nine percent of patients developed drug-related side effects , hepatotoxicity being the most frequent [ 13 patients ( 30 % ) ] . However , only 5 patients ( 11 % ) had to discontinue MTX . In steroid-dependent CD patients  , disease remission and complete steroid withdrawal was achieved in 77 % of cases . Seven patients lost their initial response to MTX during follow-up , leading to a cumulative probability of remission of 39 % after 3 years of treatment . Conclusions MTX is well tolerated in most CD patients . Although a great proportion of steroid-dependent CD patients achieve disease remission and steroid withdrawal , there is a trend to a loss of efficacy with time . Larger , long-term studies are necessary to establish the role of MTX in the management of CD The purpose of this study was to evaluate the efficacy and safety of low-dose weekly , oral methotrexate in patients with steroid-dependent or steroid-refractory inflammatory bowel disease ( IBD ) .  Oral methotrexate was given weekly at 15 mg/week . The primary criterion of response was based on steroid withdrawal . Of the 10 patients with Crohn 's disease , daily prednisone dosage dropped from a mean of 37±9.6 mg to 8.3±2.1 mg/day ( P<0.02 ) ; two had a complete withdrawal and four a partial response ( < 7.5 mg/day ) . In the eight patients with ulcerative colitis , daily prednisone dose dropped from a mean of 26.3±3.2 mg/day to 12.7±2.0 mg/day ( P<0.001 ) ; three had a partial response . Adverse effects  due to methotrexate were mild in both groups . We conclude that oral methotrexate may be useful and reasonably safe as a steroid-sparing agent in patients with refractory IBD 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 Biomarkers of intestinal inflammation , such as faecal calprotectin and C-reactive protein , have been recommended for monitoring patients with Crohn 's disease , but whether their use in treatment decisions improves outcomes is unknown . We aim ed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn 's disease who were managed with a tight control algorithm  , using clinical symptoms and biomarkers , versus patients managed with a clinical management algorithm .  METHODS CALM was an open-label , r and omised , controlled phase 3 study , done in 22 countries at 74 hospitals and outpatient centres , which evaluated adult patients ( aged 18 - 75 years ) with active endoscopic Crohn 's disease ( Crohn 's Disease Endoscopic Index of Severity [ CDEIS ] > 6 ; sum of CDEIS subscores of > 6 in one or more segments with ulcers ) , a Crohn 's Disease Activity Index ( CDAI ) of 150 - 450 depending on dose of prednisone at baseline , and no previous use of immunomodulators or biologics . Patients were r and omly assigned at a 1:1 ratio to tight control or clinical management groups , stratified by smoking status ( yes or no ) , weight ( < 70 kg or ≥70 kg ) , and disease duration ( ≤2 years or > 2 years ) after 8 weeks of prednisone induction therapy , or earlier if they had active disease . In both groups , treatment was escalated in a stepwise manner , from no treatment , to adalimumab induction followed by adalimumab every other week , adalimumab every week , and lastly to both weekly adalimumab and daily azathioprine . This escalation was based on meeting treatment failure criteria , which differed between groups ( tight control group before and after r and om assignment : faecal calprotectin ≥250 μg/g , C-reactive protein ≥5mg/L , CDAI ≥150 , or prednisone use in the previous week ; clinical management group before r and om assignment : CDAI decrease of < 70 points compared with baseline or CDAI > 200 ; clinical management group after r and om assignment : CDAI decrease of < 100 points compared with baseline or CDAI ≥200 , or prednisone use in the previous week ) . De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met . The primary endpoint was mucosal healing ( CDEIS < 4 ) with absence of deep ulcers 48 weeks after r and omisation . Primary and safety analyses were done in the intention-to-treat population . This trial has been completed , and is registered with Clinical Trials.gov , number NCT01235689 . FINDINGS Between Feb 11 , 2011 , and Nov 3 , 2016 , 244 patients ( mean disease duration : clinical management group , 0·9 years [ SD 1·7 ] ; tight control group , 1·0 year [ 2·3 ] ) were r and omly assigned to monitoring groups ( n=122 per group ) . 29 ( 24 % ) patients in the clinical management group and 32 ( 26 % ) patients in the tight control group discontinued the study , mostly because of adverse events . A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 ( 56 [ 46 % ] of 122 patients ) than in the clinical management group ( 37 [ 30 % ] of 122 patients ) , with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1 % ( 95 % CI 3·9 - 28·3 ; p=0·010 ) . 105 ( 86 % ) of 122 patients in the tight control group and 100 ( 82 % ) of 122 patients in the clinical management group reported treatment-emergent adverse events ; no treatment-related deaths occurred . The most common adverse events were nausea ( 21 [ 17 % ] of 122 patients ) , nasopharyngitis ( 18 [ 15 % ] ) , and headache ( 18 [ 15 % ] ) in the tight control group , and worsening Crohn 's disease ( 35 [ 29 % ] of 122 patients ) , arthralgia ( 19 [ 16 % ] ) , and nasopharyngitis ( 18 [ 15 % ] ) in the clinical management group . INTERPRETATION CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn 's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone . Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage , surgeries , hospital admissions , and disability . FUNDING AbbVie BACKGROUND Healing of mucosal lesions appears to offer significant benefit and is an important end point in clinical trials of treatment for Crohn 's disease . The only vali date d endoscopic activity score at present is the Crohn 's Disease Endoscopic Index of Severity , which is complicated and time consuming and , hence , is unsuitable for routine use . The aim of this study was to develop and to prospect ively vali date a simpler endoscopic score of disease activity , the Simple Endoscopic Score for Crohn 's Disease . METHODS Selected endoscopic parameters ( ulcer size , ulcerated and affected surfaces , stenosis ) were scored from 0 to 3 . Reproducibility for scoring of these parameters was evaluated through 71 examinations in which the endoscopist was paired with an observer . The simplest score ( Simple Endoscopic Score for Crohn 's Disease ) that was highly correlated with both the Crohn 's Disease Endoscopic Index of Severity and Crohn 's Disease Activity Index was derived for 70 patients and then was prospect ively vali date d in 121 different patients with Crohn 's disease . RESULTS The interobserver agreement for all selected endoscopic variables was excellent ( kappa coefficient 0.791 - 1.000 ) . Based on multiple linear regression , the Simple Endoscopic Score  for Crohn 's Disease result ed in the sum of the scores for ulcer size , ulcerated surface , affected surface , and luminal narrowing . In the validation phase of the study , a strong correlation was demonstrated for the Simple Endoscopic Score for Crohn 's Disease with Crohn 's Disease Endoscopic Index of Severity ( r = 0.920 ) . In addition , the Simple Endoscopic Score for Crohn 's Disease was correlated to clinical parameters and serum C-reactive protein level . CONCLUSIONS Simple Endoscopic Score for Crohn 's Disease is a simple , reproducible , and easy-to-use endoscopic scoring system for Crohn 's disease 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 Background : The role of azathioprine and methotrexate in inducing and maintaining remission in patients with ulcerative colitis is still controversial BACKGROUND Although corticosteroids are highly effective in improving symptoms of Crohn 's disease , they may have substantial toxicity . In some patients , attempts to discontinue corticosteroids are unsuccessful . METHODS We conducted a double-blind , placebo-controlled multicenter study of weekly injections of methotrexate in patients who had chronically active Crohn 's disease despite a minimum of three months of prednisone therapy . Patients were r and omly assigned to treatment with intramuscular methotrexate ( 25 mg once weekly ) or placebo for 16 weeks . The patients also received prednisone ( 20 mg once a day ) , which was tapered over 10 weeks unless their condition worsened . The primary outcome measure was clinical remission at the end of the 16-week trial . Remission was defined by the discontinuation of prednisone and a score of < or = 150 points on the Crohn 's Disease Activity Index . RESULTS A total of 141 patients were r and omly assigned in a 2:1 ratio to  methotrexate ( 94 patients ) or placebo ( 47 patients ) . After 16 weeks , 37 patients ( 39.4 percent ) were in clinical remission in the methotrexate group , as compared with 9 patients ( 19.1 percent ) in the placebo group ( P = 0.025 ; relative risk , 1.95 ; 95 percent confidence interval , 1.09 to 3.48 ) . The patients in the methotrexate group received less  prednisone  overall than those in the placebo group ( P = 0.026 ) . The mean ( + /- SE ) score on the Crohn 's Disease Activity Index after 16 weeks of treatment was significantly lower in the methotrexate group ( 162 + /- 12 ) than in the placebo group ( 204 + /- 17 , P = 0.002 ) . The changes in quality -of-life scores and serum orosomucoid concentrations were similar . In the methotrexate group , 16 patients ( 17 percent ) withdrew from treatment because of adverse events ( including asymptomatic elevation of serum aminotransferase in 7 and nausea in 6 ) , as compared with 1 patient ( 2 percent ) in the placebo group . CONCLUSIONS In a group of patients with chronically active Crohn 's disease , methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone Background As treatment of steroid‐dependent patients with inflammatory bowel disease ( IBD ) is controversial , we analysed the efficacy and tolerance of 6‐mercaptopurine ( 6‐MP ) and methotrexate ( MTX ) added to prednisone in increasing and maintaining the disease remission rate . Methods Seventy‐two steroid‐dependent IBD patients , 34 with ulcerative colitis ( UC ) and 38 with Crohn 's disease ( CD ) , receiving treatment with prednisone  were r and omly assigned in a 2:2:1 ratio to additionally receive , orally , over a period of 30 weeks 1.5 mg/kg/day of 6‐MP ( group A ) or 15 mg/week of MTX ( group B ) , or 3 g/day of 5‐aminosalicylic acid ( 5‐ASA ) ( group C ) . All patients who achieved remission were included in a maintaining remission study for 76 weeks . Remission was defined after stopping prednisone as a CD activity index of < 150 and normal serum orosomucoid concentration for CD patients and a Mayo Clinic score < 7 for UC patients . Results With regard to achieved remission , a significantly higher ( P < 0.05 ) rate existed for UC patients in group A ( 78.6 % ) than in group C ( 25 % ) , with no statistical differences in group B ( 58.3 % ) versus C. For CD patients , the rates were significantly higher ( P < 0.001 and 0.01 , respectively ) in groups A ( 93.7 % ) and B ( 80 % ) versus C ( 14 % ) . With regard to maintaining remission , UC patients in group A ( 63.6 % ) presented significantly higher rates ( P < 0.0015 and P < 0.001 , respectively ) versus 14.3 % in group B and none in group C. For CD patients , statistical differences ( P < 0.001 ) existed when comparing rates in groups A ( 53.3 % ) and B ( 66.6 % ) versus none in group C. Noticeable side effects appeared in 13.3 % of patients from group A and 11.5 % from group B. Conclusions These results suggest that 6‐MP or MTX added to prednisone could be effective in steroid sparing , as well as in achieving and maintaining remission in steroid‐dependent IBD patients . MTX was less effective in maintaining remission in UC patients BACKGROUND AND AIMS The efficacy of azathioprine in the treatment of chronic active Crohn 's disease is well established . However , this drug has a long onset of action . Methotrexate has also been shown to be effective in chronic active Crohn 's disease . The aim of this study was to evaluate the efficacy and safety of methotrexate in comparison with azathioprine , and to establish whether methotrexate has a shorter onset of action in this setting . METHODS Patients with chronic active Crohn 's disease were admitted to this investigator-blind study . Chronicity was defined as the need for steroid therapy of > or = 10 mg/day for at least 4 months during the preceding 12 months , with at least one attempt to discontinue treatment . The disease had to be clinical ly active at entry , with a Crohn 's Disease Activity Index of > or = 200 . Six patients treated with azathioprine and methotrexate , respectively , were found to have enterocutaneous and perianal fistulas . At entry , all patients received prednisolone ( 40 mg once a day ) which was tapered over a period of 12 weeks unless their clinical condition deteriorated . All patients were r and omised to receive i.v . methotrexate 25 mg/week , or oral azathioprine 2 mg/kg per day , for a 6-month follow-up period . After the first 3 months , methotrexate was switched to oral administration maintaining the same dose . The primary efficacy outcome considered was the proportion of patients entering first remission after 3 and 6 months of therapy . Clinical remission was defined as the lack of need for steroid treatment and a Crohn 's Disease Activity Index score of < or = 150 points at each scheduled visit . RESULTS In the 54 patients ( 26 F , 28 M , mean age 34 years , range 18 - 60 ) r and omly assigned to methotrexate ( n=27 ) or azathioprine ( n=27 ) , no statistically significant difference was found between the two treatment regimens with respect to remission rate after 3 ( methotrexate 44 % , azathioprine 33 % , p=0.28 , ( 95 % CI , 0.369 - 0.147 ) , and 6 months ( methotrexate 56 % , azathioprine 63 % , p=0.39 , 95 % CI , 0.187 - 0.335 ) , respectively . Six patients withdrew from therapy due to adverse events : 3/27 ( 11 % ) in methotrexate and 3/27 ( 11 % ) in azathioprine .  Drug-related adverse events ( asthenia , nausea and vomiting ) that did not require withdrawal from therapy were more frequent in the methotrexate group ( azathioprine : 2/27 ( 7 % ) ; methotrexate : 12/27 ( 44 % ) , p=0.00009 ) . The frequency of these adverse events was comparable during the intravenous or oral administration of the drug . CONCLUSIONS This study confirms that methotrexate is effective in inducing remission in patients with chronic active Crohn 's disease , therapeutic efficacy being comparable , but not faster , than that of azathioprine 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 OBJECTIVE : A 16-wk , placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn 's disease . The long-term efficacy and safety of this antimetabolite drug , however , are not yet well established and are assessed in this study . METHODS : A total of 49 patients with Crohn 's disease who were treated with methotrexate for ≥6 months were studied . All patients had been chronically treated with steroids ; but at the time of initiation , only 27 were still on steroids . Of the 49 patients , 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure .  Clinical remission was defined as a Harvey-Bradshaw index of < 4 . RESULTS : In all , 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months ( range , 7–59 months ) . In these patients the probabilities of relapse were 29 % , 41 % , and 48 % at 1 , 2 , and 3 yr , respectively . A higher rate of relapse was observed in women and in patients with ileocolitis . Adverse reactions were recorded in 24 patients , requiring discontinuation of methotrexate in five . A liver biopsy was performed in 11 patients ; a mild steatosis was found in five , a slight dilation of the sinusoids in one , a granulomatous hepatitis with a mild portal fibrosis in one , and a slight periportal fibrosis in one patient . CONCLUSIONS : This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn 's disease , with side effects that are usually only moderate The aim of this study was to develop and vali date an endoscopic index for assessing the severity of Crohn 's disease .  Endoscopic findings were prospect ively collected by a multicentre group in 75 patients with Crohn 's colitis according to a previously vali date d procedure . The presence of nine preselected lesions was recorded in the following segments ( 1 ) rectum , ( 2 ) sigmoid and left colon , ( 3 ) transverse colon , ( 4 ) right colon , and ( 5 ) ileum . In addition the extent of the diseased and ulcerated areas were estimated in each segment . These segmental data were recorded on a st and ard form , together with the endoscopist 's global estimate of lesion severity . A stepwise multiple regression was used to derive an index which was correlated with the endoscopist 's global evaluation of lesion severity . Four mucosal lesions : deep and superficial ulcerations , ulcerated and non-ulcerated stenosis , and both estimates of extent involved were selected and weighted to obtain a Crohn 's Disease Endoscopic Index of Severity which correlated with the endoscopist 's global appraisal of lesion severity ( r = 0.83 ) . This index was then prospect ively shown to be valid in a further series of 113 colonoscopies ( r = 0.81 ) . The index was calculated in 54 patients with active Crohn 's disease , before and at the end of a course of corticosteroids : index variations correctly reflected changes in colitis severity as evaluated by the endoscopists ( r = 0.72 ) . For endoscopists familiar with the data collection procedure , this Crohn 's Disease Endoscopic Index of Severity should be of value in the follow up of patients , especially in clinical trials 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 We assessed oral 5-aminosalicylic acid ( 5-ASA ) prepared with a pH-sensitive polymer coating in 87 patients with mildly to moderately active ulcerative colitis in a double-blind , placebo-controlled trial . Patients were r and omly assigned to receive 5-ASA at a dosage of either 4.8 or 1.6 g per day or placebo for six weeks . The outcome was monitored by flexible proctosigmoidoscopic examinations and physicians ' assessment s at three-week intervals and by patients ' recordings of daily symptoms . Results showed 24 percent complete and 50 percent partial responses in those receiving 4.8 g of 5-ASA per day as compared with 5 percent complete and 13 percent partial responses in those receiving placebo ( P less than 0.0001 , rank-sum test ) . At a dosage of 1.6 g per day , the response was twice as good as with placebo , but the difference did not reach statistical significance ( P = 0.51 ) . Age , sex , duration of disease , duration of active symptoms , or extent of disease did not affect the clinical outcome . We conclude that oral 5-ASA administered in a dosage of 4.8 g per day is effective therapy , at least in the short term , for mildly to moderately active ulcerative colitis STUDY OBJECTIVE To determine whether methotrexate has anti-inflammatory activity in refractory inflammatory bowel disease . DESIGN Nonr and omized , open-label , preliminary trial of methotrexate along with st and ard medications for 12 weeks . SETTING Referral-based gastroenterology practice . PATIENTS Twenty-one patients with refractory inflammatory bowel disease ( 14 , Crohn disease ; 7 , chronic ulcerative colitis ) ; 17 taking variable doses of corticosteroids and 14 on sulfasalazine or metronidazole . Of the 21 patients , 10 had previously failed azathioprine or 6-mercaptopurine trials . INTERVENTIONS Sulfasalazine and metronidazole were continued and prednisone dose was tapered according to clinical response . Methotrexate was given as a 25-mg intramuscular injection weekly for 12 weeks , then switched to a tapering oral dose if a clinical and objective improvement was noted . MEASUREMENTS AND MAIN RESULTS Sixteen of twenty-one patients ( 11 of 14 patients with Crohn disease , 5 of 7 patients with chronic ulcerative colitis ) had an objective response as measured by disease activity indices ( modified Crohn 's Disease Activity Index , 13.3 to 5.4 [ P = 0.0001 ] , Ulcerative Colitis Activity Index , 13.3 to 6.3 [ P = 0.007 ] ) .  Prednisone dosage decreased from 21.4 mg + /- 5.6 ( SEM ) to 5.5 mg + /- 2.0 ; P = 0.006 and 38.6 mg + /- 6.35 to 12.9 mg + /- 3.4 ; P = 0.01 , respectively . Five patients with Crohn colitis had colonoscopic healing and 4 had normal histology at 12 weeks . In contrast , none of the 7 patients with ulcerative colitis had normal flexible sigmoidoscopies , despite histologic improvement in 5 . Side effects included mild rises in transaminase levels in 2 patients , transient leukopenia in 1 , self-limited diarrhea and nausea in 2 patients , and 1 case each of brittle nails and atypical pneumonitis . CONCLUSIONS Although this pilot study is encouraging , further work is needed before methotrexate can be recommended for inflammatory bowel disease Needing a single index of degree of illness in Crohn 's disease , the National Cooperative Crohn 's Disease Study group collected data prospect ively from 187 visits of 112 patients with Crohn 's disease of the small bowel , colon , or both . Information on 18 predictor variables was gathered at each visit . In addition , the attending physician rated his over-all evaluation of how well the patient was doing and compared the patient 's status with that at the previous visit . A multiple regression computer program was utilized to derive an equation for prediction of the physician 's over-all ratings from a subset of the predictor variables fulfilling a combination of constraints . This equation , numerically simplified and utilizing eight selected variables , is the Crohn 's Disease Activity Index . Index values of 150 and below are associated with quiescent disease ; values above that indicate active disease , and values above 450 are seen with extremely severe disease BACKGROUND & AIMS Parenteral methotrexate induces clinical remission but not endoscopic improvement of mucosal inflammation in patients with ulcerative colitis ( UC ) . We performed a r and omized , placebo-controlled trial to assess the efficacy of parenteral methotrexate in maintaining steroid-free response or remission in patients with UC after induction therapy with methotrexate and steroids . METHODS We performed a 48-week trial , from February 2012 through May 2016 , of 179 patients with active UC ( Mayo score of 6 - 12 with endoscopy subscore ≥ 2 ) despite previous conventional or biological therapy . The study comprised a 16-week open label methotrexate induction period followed by a 32-week double-blind , placebo-controlled maintenance period . Patients were given subcutaneous methotrexate ( 25 mg/wk ) and a 12-week steroid taper . At week 16 , steroid-free responders were r and omly assigned to groups that either continued methotrexate ( 25 mg/wk , n = 44 ) or were given placebo ( n = 40 ) until week 48 . We compared the efficacy of treatment by analyzing the proportion of patients who remained relapse free and were in remission at week 48 without use of steroids or other medications to control disease activity . RESULTS Ninety-one patients ( 51 % ) achieved response at week 16 , and 84 patients were included in the maintenance period study . During this period , 60 % of patients in the placebo group ( 24/40 ) and 66 % in the methotrexate group ( 29/44 ) had a relapse of UC ( P = .75 ) . At week 48 , 30 % of patients in the placebo group ( 12/40 ) and 27 % of patients in the methotrexate group ( 12/44 ) were in steroid-free clinical remission without need for additional therapies ( P = .86 ) . No new safety signals for methotrexate were detected . CONCLUSIONS Parenteral methotrexate ( 25 mg/wk ) was not superior to placebo in preventing relapses of UC in patients who achieved steroid-free response during induction therapy . Clinical Trials.gov , Number : NCT01393405 BACKGROUND Anti-TNF drugs are effective treatments for the management of Crohn 's disease but treatment failure is common . We aim ed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment , non-remission at week 54 , and adverse events leading to drug withdrawal . METHODS The personalised anti-TNF therapy in Crohn 's disease study ( PANTS ) is a prospect i ve observational UK-wide study . We enrolled  anti-TNF-naive patients ( aged ≥6 years ) with active luminal Crohn 's disease at the time of first exposure to infliximab or adalimumab between March 7 , 2013 , and July 15 , 2016 . Patients were evaluated for 12 months or until drug withdrawal . Demographic data , smoking status , age at diagnosis , disease duration , location , and behaviour , previous medical and drug history , and previous Crohn 's disease-related surgeries were recorded at baseline . At every visit , disease activity score , weight , therapy , and adverse events were recorded ; drug and total anti-drug antibody concentrations were also measured . Treatment failure endpoints were primary non-response at week 14 , non-remission at week 54 , and adverse events leading to drug withdrawal . We used regression analyses to identify which factors were associated with treatment failure . FINDINGS We enrolled 955 patients treated with infliximab ( 753 with originator ; 202 with biosimilar ) and 655 treated with adalimumab .  Primary non-response occurred in 295 ( 23·8 % , 95 % CI 21·4 - 26·2 ) of 1241 patients who were assessable at week 14 . Non-remission at week 54 occurred in 764 ( 63·1 % , 60·3 - 65·8 ) of 1211 patients who were assessable , and adverse events curtailed treatment in 126 ( 7·8 % , 6·6 - 9·2 ) of 1610 patients . In multivariable analysis , the only factor independently associated with primary non-response was low drug concentration at week 14 ( infliximab : odds ratio 0·35 [ 95 % CI 0·20 - 0·62 ] , p=0·00038 ; adalimumab : 0·13 [ 0·06 - 0·28 ] , p<0·0001 ) ; the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab . Continuing st and ard dosing regimens after primary non-response was rarely helpful ; only 14 ( 12·4 % [ 95 % CI 6·9 - 19·9 ] ) of 113 patients entered remission by week 54 . Similarly , week 14 drug concentration was also independently associated with non-remission at week 54 ( 0·29 [ 0·16 - 0·52 ] for infliximab ; 0·03 [ 0·01 - 0·12 ] for adalimumab ; p<0·0001 for both ) . The proportion of patients who developed anti-drug antibodies ( immunogenicity ) was 62·8 % ( 95 % CI 59·0 - 66·3 ) for infliximab and 28·5 % ( 24·0 - 32·7 ) for adalimumab . For both drugs , suboptimal week 14 drug concentrations predicted immunogenicity , and the development of anti-drug antibodies predicted subsequent low drug concentrations . Combination immunomodulator ( thiopurine or methotrexate ) therapy mitigated the risk of developing anti-drug antibodies ( hazard ratio 0·39 [ 95 % CI 0·32 - 0·46 ] for infliximab ; 0·44 [ 0·31 - 0·64 ] for adalimumab ; p<0·0001 for both ) . For infliximab , multivariable analysis of immunododulator use , and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission ( odds ratio 0·56 [ 95 % CI 0·38 - 0·83 ] , p=0·004 ) . INTERPRETATION Anti-TNF treatment failure is common and is predicted by low drug concentrations , mediated in part by immunogenicity . Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes . FUNDING Guts UK , Crohn 's and Colitis UK , Cure Crohn 's Colitis , AbbVie , Merck Sharp and Dohme , Napp Pharmaceuticals , Pfizer , and Celltrion Aliment Pharmacol Ther 2011 ; 33 : 714–721 BACKGROUND & AIMS Methotrexate and infliximab are effective therapies for Crohn 's disease ( CD ) . In the combination of maintenance methotrexate-infliximab trial , we evaluated the potential superiority of combination therapy over infliximab alone . METHODS In a 50-week , double-blind , placebo-controlled trial , we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy ( 15 - 40 mg/day ) within the preceding 6 weeks . Patients were assigned r and omly to groups given methotrexate at an initial weekly dose of 10 mg , escalating to 25 mg/week ( n = 63 ) , or placebo ( n = 63 ) . Both groups received infliximab ( 5 mg/kg of body weight ) at weeks 1 , 3 , 7 , and 14 , and every 8 weeks thereafter . Prednisone was tapered , beginning at week 1 , and discontinued no later than week 14 . The primary outcome was time to treatment failure , defined as a lack of prednisone-free remission ( CD Activity Index , < 150 ) at week 14 or failure to maintain remission through week 50 . RESULTS Patients ' baseline characteristics were similar between groups . By week 50 , the actuarial rate of treatment failure was 30.6 % in the combination therapy group compared with 29.8 % in the infliximab monotherapy group ( P = .63 ; hazard ratio , 1.16 ; 95 % confidence interval , 0.62 - 2.17 ) . Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein . No clinical ly meaningful differences were observed in secondary outcomes . Combination therapy was well tolerated . CONCLUSIONS The combination of infliximab and methotrexate , although safe , was no more effective than infliximab alone in patients with CD receiving treatment with prednisone . ClincialTrials.gov number , NCT00132899
Background The therapeutic role of methotrexate ( MTX ) for management of inflammatory bowel disease ( IBD ) remains unclear .