The use of methotrexate for treatment of inflammatory bowel disease in clinical practice

BackgroundMethotrexate is considered a treatment for Crohn's disease, whilst few data in ulcerative colitis are available.AimTo evaluate frequency, indications, efficacy and safety of methotrexate in inflammatory bowel disease patients.Methods5420 case histories were reviewed.ResultsMethotrexate was prescribed to 112 patients (2.1%; 89 Crohn's disease, 23 ulcerative colitis). It was the first-line immunosuppressive option in 32 (28.6%), it was an alternative drug due to toxicity or failure of thiopurines in 80 (71.4%). Steroid-dependence represented the main indication both when it was used as first (13/32, 40.6%) and second option (41/80, 51.2%). Efficacy was considered optimal in 39/112 (34.8%), partial in 29/112 (25.9%), absent in 22/112 (19.6%), not assessable in 22/112 (19.6%). Side effects happened in 49 out of 112 patients (43.7%) (39 Crohn's disease, 10 ulcerative colitis), leading to drug discontinuation in 38 (33.9%). The occurrence of side effects was approximately fivefold higher in patients who did not receive folic acid (14/19, 73.7%) than in those who did (35/93, 37.6%): odds ratio 4.64, 95% confidence interval 1.54–14.00; p = 0.005.ConclusionsThe use of methotrexate appears to be negligible in clinical practice. However, our results suggest that, if appropriately used, methotrexate could be more widely administered to inflammatory bowel disease patients with complicated disease.     

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease

OBJECTIVE: Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients. METHODS: Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of > or = 1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk's criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose. RESULTS: In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500-5410 mg), given for a mean of 131.7 wk (range, 66-281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk's grade I and II), and one patient had hepatic fibrosis (Roenigk's grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk's grade IIIB hepatotoxicity. CONCLUSIONS: Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients.     

Low-dose oral methotrexate in refractory inflammatory bowel disease

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.     

Experience with low-dose methotrexate: Toxicity,tolerability and effect on conventional patterns of drug therapy for inflammatory arthritis

Summary This study examines the 10-year experience of a single rheumatologist in the treatment of inflammatory arthritis with low dose methotrexate (MTX). The toxicity and tolerability of MTX has been assessed and the effect of this drug on the conventional pattern of pharmacotherapy for inflammatory arthritis has been examined. The case records of all 99 patients with inflammatory arthritis prescribed MTX in the ten-year period up to the end of 1991 were reviewed. Adverse reactions, duration of therapy, overall efficacy, as well as details of previous and concurrent drug therapy were noted.MTX was clinically beneficial in 85 patients. Of these, on a four point scale, 68 patients claimed moderate or marked benefit. MTX was discontinued in 20 patients; in 12 the cause was an adverse reaction. Many more (47) patients suggered mild reactions not resulting in drug withdrawal. In our patients MTX has a favourable tolerability record and has been continued in 83%, 69% and 50% after 1, 2, and 5 years of treatment respectively. The use of MTX increased markedly towards the end of the 10-year study period. Sixty-two patients were started on MTX either in 1990 or 1991. The mean number of other disease modifying drugs used before MTX has declined from a peak of 2.40 in 1987 in 1987 to 1.52 in 1991. Similarly, the percentage of patients prescribed concurrent oral corticosteroids has declined from 88% to 52% from 1987 to 1991.In our experience MTX is effective, has a favourable toxicity and tolerability record. In this practice we have identified a trend to increased use of MTX earlier in the course of drug treatment of inflammatory arthritis. The concurrent use of oral corticosteroids appears to be declining.     

Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate: a case study of five patients with treatment-resistant inflammatory bowel disease

INTRODUCTION: This study reports the clinical outcome, toxicity, and methotrexate pharmacokinetics after the addition of low-dose cyclosporine to methotrexate in patients with ulcerative colitis or Crohn's disease. METHODS: Three patients with steroid-refractory ulcerative colitis and two patients with steroid refractory Crohn's disease who failed monotherapy with subcutaneous methotrexate 25 mg/week for 16 weeks were treated with the combination of methotrexate and low-dose oral cyclosporine (3 mg/kg/day) for an additional 16 weeks. Clinical response was measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate were also determined. RESULTS: Both patients with Crohn's disease withdrew from the study for toxicity (headaches, seizure). The three patients with ulcerative colitis experienced clinical improvement with a mean increase in the IBDQ score from 164 to 190 points, p = 0.01. The mean serum creatinine in the three patients who completed the study increased from 0.9 mg/dL at baseline to 1.2 mg/dL at week 16. p = 0.04. One patient developed hypertension. There was no significant change from baseline in the concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate. CONCLUSIONS: Combination therapy with methotrexate and low-dose oral cyclosporine did not alter methotrexate pharmacokinetics and resulted in high rates of cyclosporine-associated toxicity.     

糖皮质激素在炎症性肠病中的应用

炎症性肠病(IBD)是糖皮质激素(简称激素)治疗的适应证.IBD包括溃疡性结肠炎(UC)和克罗恩病(CD).对UC患者,激素可经静脉、口服、直肠灌注或栓剂给药.直肠灌注或栓剂的成分可以是传统使用的激素、布地奈德或人体生物利用度低的其他激素.对CD患者,传统使用的激素可以口服给药,亦可静脉给药.布地奈德可以口服.     

Vaccines and recommendations for their use in inflammatory bowel disease

The patient with inflammatory bowel disease will be predisposed to numerous infections due their immune status. It is therefore important to understand the immune and serologic status at diagnosis and to put the patient into an adapted vaccination program. This program would be applied differently according to two patient groups: the immunocompromised and the non-immunocom-promised. In general, the first group would avoid the use of live-virus vaccines, and in all cases, inflammatory bowel disease treatment would take precedence over vaccine risk. It is important to individualize vaccination schedules according to the type of patient, the treatment used and the disease pattern.In addition, patient with inflammatory bowel disease should be considered for the following vaccines: varicella vaccine, human papilloma virus, influenza, pneumococcal polysaccharide vaccine and hepatitis B vaccine.     

Alternative strategies for the use of infliximab in pediatric inflammatory bowel disease

Infliximab is approved for the induction and 1-year maintenance of remission in pediatric Crohn’s disease unresponsive to conventional therapy. Despite significant experience with the use of this agent in children and adolescents who have inflammatory bowel disease, many questions about its optimal use remain. Recent safety concerns raised debate over the common practice of using infliximab in combination with conventional immunomodulatory agents. Additionally, although regularly scheduled administration maintains remission more effectively than episodic therapy, it is not known whether all patients who start infliximab must continue it for maintenance. Some patients may be able to use infliximab for induction and another agent for maintenance. Finally, the optimal placement of infliximab in the algorithm for the medical treatment of pediatric inflammatory bowel disease remains an open question.     

Sellar inflammatory mass with inflammatory bowel disease

Inflammatory bowel disease may be associated with different intracranial disorders. An inflammatory sellar mass is very rare but includes a variety of noninfectious causes including lymphocytic hypophysitis, granulomatous inflammation and Wegener’s granulomatosis. A 32-year-old man was diagnosed with an inflammatory sellar mass associated with an extensive colonic inflammatory process clinically characteristic of Crohn’s disease. The concurrent onset of these inflammatory disorders in distinctly separate sites may reflect their common embryological origin or represent an unusual form of metastatic Crohn’s disease. Further studies are needed to determine if less overt or focal sellar inflammatory processes occur in inflammatory bowel disease, particularly in Crohn’s disease because their occurrence may be critically relevant for long-term management.     

Expert opinion:Experience with 6-mercaptopurine in the treatment of inflammatory bowel disease

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn’s disease as well. Not much was ever made of the role of sulfasalazine for Crohn’ s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn’s colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn’s disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn’s disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960’s and 1970’s and its trial for Crohn’s disease published in the New England Journal of Medicine in 1980?     

Adverse events associated with the use of cyclosporine in patients with inflammatory bowel disease

BACKGROUND:  Intravenous cyclosporine (IV CsA) is an effective therapy for patients with inflammatory bowel disease (IBD). However, data regarding its adverse events in these patients are limited.
METHODS:  A retrospective chart review of the initial 111 consecutive patients with IBD treated with IV CsA followed by a predetermined duration of oral therapy.
RESULTS:  One hundred eleven patients (64 UC, 47 CD; mean age 33 yr, range 16–68) received IV CsA at 4 mg/kg/day, then oral CsA at 8 mg/kg/day, with dose adjustment based on serum creatinine. The mean treatment duration was 9.3 months (range 1 wk to 34 months). Major adverse events occurred in 17 (15.3%) patients. Nephrotoxicity (serum creatinine ≥1.4 mg/dL [123 μmol/L] or a rise by at least 33% over baseline not responding to dose adjustment) sufficiently severe to warrant discontinuation of therapy occurred in 6 (5.4%) patients. Serious infection occurred in 7 (6.3%) patients, seizures in 4 (3.6%) patients, anaphylaxis in 1 (0.9%) patient, and death in 2 (1.8%) patients. Minor adverse events (transient effects with complete resolution either spontaneously or with dose adjustment) comprised: paresthesias (51%), hypomagnesemia (42%), hypertension (39%), hypertrichosis (27%), headache (23%), minor nephrotoxicity (defined as above but with restoration of normal serum creatinine with dose adjustment; 19% of patients), abnormal liver function tests (19%), minor infections (15%), hyperkalemia (13%), and gingival swelling (4%).
CONCLUSIONS:  In our initial experience, limited duration CsA therapy was frequently associated with adverse events although the majority of these were minor and responded to dose adjustment. Although not all severe adverse events can be clearly attributed to CsA use alone, its high incidence suggests that vigorous monitoring by experienced clinicians at tertiary care centers may be required.     

The use of questionnaires in pediatric inflammatory bowel disease

Inflammatory bowel disease is a chronic illness with symptoms including abdominal pain, weight loss, chronic diarrhea, hematochezia, and growth failure. It affects both children and adults. The goal of management is to induce and maintain clinical remission and to reduce psychosocial and quality of life issues caused by the disease. Various questionnaires have been developed to help physicians and investigators gain information regarding healthrelated quality of life, treatment satisfaction, disease activity, and disease-specific knowledge. The purpose of this review is to discuss the questionnaires available to clinicians treating children and adolescents with inflammatory bowel disease.     

Emerging use of artificial intelligence in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a complex, immune-mediated gastrointestinal disorder with ill-defined etiology, multifaceted diagnostic criteria, and unpredictable treatment response. Innovations in IBD diagnostics, including developments in genomic sequencing and molecular analytics, have generated tremendous interest in leveraging these large data platforms into clinically meaningful tools. Artificial intelligence, through machine learning facilitates the interpretation of large arrays of data, and may provide insight to improving IBD outcomes. While potential applications of machine learning models are vast, further research is needed to generate standardized models that can be adapted to target IBD populations.