Methotrexate In Inflammatory Bowel Disease Research Articles

Real-world use of mycophenolate mofetil in inflammatory bowel disease: Results from the ENEIDA registry.

Studies to evaluate the use of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) are limited after the appearance of biological treatments. Our primary objective was to evaluate the effectiveness and safety of MMF in IBD. IBD patients who had received MMF were retrieved from the ENEIDA registry. Clinical activity as per the Harvey-Bradshaw Index (HBI), partial Mayo score (pMS), physician global assessment (PGA) and C-reactive protein (CRP) were reviewed at baseline, at 3 and 6 months, and at final follow-up. Adverse events and causes of treatment discontinuation were documented. A total of 83 patients were included (66 Crohn's disease, 17 ulcerative colitis), 90% of whom had previously received other immunosuppressants. In 61% of patients systemic steroids were used at initiation of MMF, and in 27.3% biological agents were co-administered with MMF. Overall clinical effectiveness was observed in 64.7% of the population. At the end of treatment, 45.6% and 19.1% of subjects showed remission and clinical response, respectively. MMF treatment was maintained for a median of 28.9 months (IQR: 20.4-37.5). Our study suggests, in the largest cohort to date, that MMF may be an effective alternative to thiopurines and methotrexate in IBD.

P357 Monitoring of Thiopurines and Methotrexate in Inflammatory Bowel Disease: Are we Monitoring Too Frequently? A Cross Sectional Study

Abstract Background The use of immunosuppressive medications such as thiopurines and methotrexate (MET) are commonly employed in inflammatory bowel disease (IBD) to control symptoms and maintain remission. The British Society of Gastroenterology recommends three monthly full blood count (FBC) and liver function tests (LFT) to monitor for myelotoxicity and hepatotoxicity after being established on therapy. However, the quality of evidence for this is low. Due to the high burden of blood tests and patients becoming increasingly apprehensive to attend hospital or their general practice surgery in the midst of a pandemic, we aimed to investigate (1) the feasibility to adhere to these recommendations and (2) the frequency of abnormal blood test when recommendations are adhered. Methods We performed a, 12-month cross sectional study from July, 2017 to July, 2018 of patients established on azathioprine (AZA), 6-mercaptopurine (6-MP), or MET. The timeline was split into four windows of three months each. A patient was removed from the study if they reached any one of these six end points: no FBC or LFT checked within a window, new abnormal LFT, white cell count (WCC) less than, 3.5, change in medication, change in dosage, and medication stopped. Results As of, 2019, 4327 patients were under the care of our specialist IBD team with, 1081 on active therapy. We identified, 205 patients who were established on these agents (AZA = 156, 6-MP = 41, MET = 8) within the determined study period. A total number of, 96 patients reached an end point during this period. For our first objective, a patient was deemed to have been monitored if FBC and LFT was checked at least once during a window., 26% (54/212) of patients were removed from the study as they did not fulfil this criteria. Of the remaining, 41 patients who reached an end point, 14 were due to a new abnormal LFT result (AZA = 8, 6-MP = 6, MET = 0) and, 5 due to a WCC less than, 3.5 (AZA = 4, 6-MP = 1, MET =0). Excluding non-adherent patients, our study revealed only, 12% (19/158) of patients had to discontinue therapy due to an abnormal blood test. Conclusion Achieving an adherence of, 74% was possible with a team of dedicated IBD specialist nurses and doctors in a tertiary centre. Whilst there is still much room for improvement, this may be difficult to replicate in smaller centres with more limited resources. Despite the small sample size, our finding of only, 12% of abnormal blood test is consistent with similar studies done by Fournier et.al in, 2010 and Chaparro et.al in, 2013. This would certainly pose the question if we can consider monitoring less frequently.

Potential Role of Methotrexate Polyglutamates in Therapeutic Drug Monitoring for Pediatric Inflammatory Bowel Disease.

Inside cells, the immunomodulator methotrexate (MTX) undergoes the addition of glutamates to form methotrexate polyglutamates (MTX-Glu)—promising biomarkers of systemic exposure and treatment response to MTX in rheumatology. MTX-Glu are underexplored in Inflammatory Bowel Disease (IBD), with no data in pediatrics. In this cross-sectional secondary analysis, we assessed the relationships between MTX-Glu and MTX dose and treatment response in pediatric IBD. Twenty-one children with IBD, receiving maintenance therapy with infliximab (IFX) and MTX, had MTX-Glu1–6 concentrations and IFX troughs/antibodies measured and disease activity assessed for comparison in remission vs. active IBD using non-parametric tests, with associations explored using Spearman’s correlation (ρ) and regression analyses; SASv9.4 (α = 0.05). Total and long-chain MTX-Glu correlated with MTX dose (ρ = 0.51 and 0.56, respectively; p ≤ 0.02). In children with Crohn’s disease (n = 19), short-chain MTX-Glu1–2 were 2.5-fold higher in remission vs. active disease, approaching statistical significance (p = 0.066), with no statistical differences in IFX trough (p = 0.549) between groups. Our study highlights a potential role for long-chain MTX-Glu in the therapeutic drug monitoring of MTX in IBD. It is the first study in pediatric IBD and, although statistical significance was not reached, our findings also suggest that higher short-chain MTX-Glu levels may be associated with IBD treatment response to MTX in children.

Aminosalicylates, thiopurines and methotrexate in inflammatory bowel disease: Is it possible to discontinue the treatment?

The current goals of treatment in inflammatory bowel disease, both Crohn's disease and ulcerative colitis, are to achieve clinical, endoscopic and ideally histological remission and improve the quality of life of these patients. Current therapies are effective in achieving remission in most cases, but there is a lack of clear guidelines on their optimal duration. This review aims to evaluate the current evidence on the withdrawal of therapy with 5-aminosalicylates, thiopurines and methotrexate. We also aim to identify which specific group of patients, while in remission and in the absence of risk factors, may be able to discontinue therapy without a significant risk of relapse.

Update on the Use of Thiopurines and Methotrexate in Inflammatory Bowel Disease.

The increased use of biologic agents over the past two decades has led to a reappraisal of the role of the immunomodulators (thiopurines and methotrexate) in the treatment of inflammatory bowel disease. The purpose of this review is to summarize recent data on the use of thiopurines and methotrexate either as monotherapy or as part of combination therapy with biologic agents. Recent studies have addressed the need for concomitant immunomodulatory therapy in treatment-naïve patients starting anti-TNF-α therapy, the appropriate dose of the immunomodulator in this setting, the minimum duration of combination therapy, and the possible mechanisms by which immunomodulators enhance the effectiveness of anti-TNF-α agents. Little is known about the role of immunomodulators in combination with agents belonging to other classes of biologic therapies. Recent studies have shown that methotrexate is not effective in inducing or maintaining remission in ulcerative colitis. Finally, several studies have broadened our understanding of the infection and malignancy risks of the immunomodulators. Immunomodulators continue to have a place in the treatment of inflammatory bowel disease. However, with the ever-increasing list of biologic agents, properly positioning the immunomodulators within the overall therapeutic scheme is a complicated task. In order to optimize outcomes, each patient requires an individualized approach, which takes into account risks, benefits, cost, alternatives, and patient preferences.

Attenuation of Endoscopic Inflammatory and Stenotic Features in Patients with Co-existing Eosinophilic Esophagitis and Inflammatory Bowel Disease

Introduction: Eosinophilic esophagitis (EoE) has become an increasingly well-described disease entity characterized by symptoms of esophageal dysfunction and eosinophil-predominant inflammation of esophageal mucosa. EoE has been associated with atopic and autoimmune diseases. This study compares clinical and endoscopically identified esophageal manifestations of patients with EoE and inflammatory bowel disease (IBD) concomitantly to patients with EoE alone. Methods: Data from 22 patients with concomitant EoE and IBD (64% with Crohn's disease) and 50 control patients with EoE alone between 1993 and 2014 was retrospectively evaluated. Clinical charts of patients between ages 18-80 years old were identified using ICD-9 codes (EoE: 530.13; CD: 555.9, 555.1, 555.2, 555.0; UC: ICD-9 556.9, 557.0, 556.5, 556.3, 556.6) by our Enterprise Data Warehouse (EDW). EoE controls were tested to not be statistifically significantly different from patients with concomitant EoE and IBD in gender, race, or age. Demographic and disease-specific characteristics, endoscopic findings using a validated instrument (EoE Endoscopic Reference Score), histopathology, and treatment in patients with concomitant IBD and EoE were examined. Bivariate analysis with the chi-square test was used to look for statistical significance between the two groups.Table 1: Demographics and Disease-specific Characteristics of Concomitant EoE and IBD Compared to EoE AloneResults: Patients with concomitant EoE and IBD compared to EoE alone were found to have significantly less strictures (9% vs 58%, p=0.0001), furrows (64% vs 92%, p-0.003) and exudates (18% vs 56%, p=0.003) on endoscopy (Table and Figure 1). Of the 22 patients with concomitant EoE and IBD, 11 patients (50%) were treated with immunomodulators including anti-TNF agents, 6-MP, azathioprine and methotrexate for IBD, and 0/11 of these patients had strictures. Patients with EoE and IBD compared to EoE alone were also found to present less frequently with dysphagia as an initial symptom (68% vs 88%, p=0.04).Figure 1Conclusion: Patients with concomitant EoE and IBD demonstrated significantly lower prevalence of endoscopically identified inflammatory (furrows, exudate) and remodeling (stricture) features compared to EoE patients alone. The decreased activity of EoE in patients with concomitant EoE and IBD may be related to immunomodulator therapy used to treat IBD or earlier diagnosis of EoE owing to healthcare utilization amongst IBD patients.

Safety profile of methotrexate in inflammatory bowel disease

ABSTRACTIntroduction: Methotrexate, which was initially developed in 1948 for the treatment of leukemia, is known to be an immunomodulatory and anti-inflammatory drug. It has been widely used for over 60 years as both a low and high-dose therapy in chronic inflammatory diseases. The aim of this review was to analyze and summarize the available data specifically on the safety of this drug in the management of inflammatory bowel diseases.Areas covered: A structured search of articles was conducted using the PubMed database up to April 2016. All articles in English with isolated or combined keywords were included according to their relevance to the aims of this study.Expert opinion: Numerous of studies have established the efficacy of parenteral methotrexate in the management of steroid-dependent and steroid-resistant Crohn’s disease, either for inducing or maintaining remission. However, its efficacy in ulcerative colitis has not been properly investigated. Additionally, methotrexate has been shown to reduce the effect of immunization with anti-TNF agents when combined. The drug has potential advantages over thiopurines such as its weekly administration, a possible shorter time of action, low cost, decreased risk for malignancy and overall a comparable safety profile.

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease.

Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.

Use of methotrexate in inflammatory bowel disease in 2014: A User's Guide.

Methotrexate has been used an immunomodulator in many autoimmune diseases, including inflammatory bowel disease. However, many physicians are unfamiliar or uncomfortable with its use in the management of inflammatory bowel disease. We summarize the data for use of methotrexate in common clinical scenarios: (1) steroid dependant Crohn's disease (CD); (2) maintenance of remission in steroid free CD; (3) azathioprine failures in CD; (4) in combination therapy with Anti-TNF agents in CD; (5) decreasing antibody formation to Anti-TNF therapy in CD; (6) management of fistulizing disease in CD; and (7) as well as induction and maintenance of remission in ulcerative colitis. An easy to use algorithm is provided for the busy clinician to access and safely prescribe methotrexate for their inflammatory bowel disease patients.

OC-018 Limited long Term Tolerance of Methotrexate For Inflammatory Bowel Disease: 11 Years Experience from a Single Centre

<h3>Introduction</h3> Methotrexate (MTX) is used as an immunosuppressive treatment in inflammatory bowel disease (IBD). The aim of the study was to evaluate the long-term tolerability of MTX in adults with IBD from a large, single, tertiary referral centre. <h3>Methods</h3> IBD patients who had received MTX at a single centre between 2000 – 2011 were identified from the IBD service database and clinical records reviewed. <h3>Results</h3> 137 patients received MTX (Crohn’s Disease 105 (77%); ulcerative colitis (UC) 32 (23%)); mean age 44 (range 18–77). The median duration of MTX treatment was 13 months (range 1–127) with an initial dose of 25mg/week (range 10–25 mg) in 127/137 (93%) with 94% commencing MTX intramuscularly. The proportion who continued MTX for ≥ 3, 5, 10 years were 24% (33/137), 10% (14/137) and 1.5% (2/137) respectively. 89/137 (65%) discontinued MTX during the 11 year follow-up. The cessation rate due to lack of effectiveness was 17/137 (12%) by the end of the 2^nd year of MTX, after which there were no further discontinuations for this reason. 77/137 (57%) reported ≥ 1 side-effect (SE) attributed to MTX, which was the commonest reason for discontinuing MTX (61/89; 69%). SEs leading to MTX cessation were most frequent during induction (defined as 0–3months): 22/61 (36%); followed by 3–12 months following initiation of MTX: 16/61 (26%). Specific SEs resulting in cessation during the 1st year of MTX were due to ≥ 1 of the following; 15 (40%) gastrointestinal (GI), 12 (32%) neurological (NS), 5 (13%) nonspecific malaise, 5 (13%) abnormal hepatic aminotransferase levels (2-fold increase up to or over the upper limit of normal), 2 (5%) hair loss, 5 other (1 each of sore throat, rash, infection, low platelets, injection site reaction). The incidence of discontinuation due to SEs in successive MTX years fell from commencement of MTX: 10/61 (16%) in the 2^nd year, 5/61 (8%) in the 3^rd year, 3/61 (5%) in the 4^th year and 5 (8%) in total between the 5^th-10^th years. The most frequent SEs attributed to late discontinuation ( &gt; 1year) were GI and NS. Over 11 years there were 12/137 (9%) reported cases of presumed MTX induced abnormal hepatic aminotransferase levels, of which 8 (67%) resulted in MTX cessation with biochemical resolution. Hepatotoxicity occurred during induction in 7/12 cases (58%) and was stopped in 5 of these (71%). In 5 patients with late abnormal hepatic aminotransferase levels, the median time to detection was 36 months (range 10–100months). MTX was discontinued in 3 of these. <h3>Conclusion</h3> In the largest single-centre experience to date, MTX in IBD is limited by high withdrawal rates with a 28% discontinuation rate due to SEs within the 1st year. Late hepatoxicity highlights the need for long term monitoring in maintenance therapy. <h3>Disclosure of Interest</h3> None Declared

Changes in Liver Biochemistry During Methotrexate Use for Inflammatory Bowel Disease

We aimed to characterize the spectrum of liver enzyme test (LET) abnormalities that occur while using methotrexate for inflammatory bowel disease (IBD). A retrospective review was undertaken of subjects using methotrexate for IBD at a single center. The clinical and epidemiological parameters, and hepatotoxicity risk factors, were recorded. Subjects were excluded if cumulative methotrexate doses could not be ascertained, if they had a diagnosis of rheumatoid arthritis or psoriasis, or if baseline and follow-up LETs were not available. Also noted were the cumulative methotrexate dose during the peak LET increase, severity of LET increase, and whether normalization occurred. Eighty-seven subjects were included (Crohn's disease, n=67; UC, n=17; indeterminate colitis n=3). The mean therapy duration was 81 weeks (3- to 364-week range), and the cumulative average dose was 1,813 mg (25-8,255-mg range). Thirty-seven (43%) subjects received a cumulative dose >1,500 mg. Sixty-seven (77%) had normal LETs, and in 51 (76%) LETs remained normal throughout methotrexate therapy. In the 16 (24%) who developed LET abnormalities, seven (44%) had underlying risk factor(s) for liver disease. Normalization (without dose reduction) occurred in 14 (88%) while continuing methotrexate. Of 20 subjects with abnormal LETs at baseline, nine (45%) subsequently normalized while continuing methotrexate, whereas nine (45%) worsened. Seventeen liver biopsies were performed in 11 and were classified as Roenigk's grade I in 15 (88%) subjects. Roenigk IIIb or IV was not seen. Methotrexate is commonly associated with LET abnormalities, but these frequently normalize while still on therapy, and in only 5% will drug discontinuation be necessary. Liver biopsies rarely have substantive abnormalities.

The pharmacogenetics of methotrexate in inflammatory bowel disease

Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD. We studied 102 IBD patients treated with MTX, and 202 patients with Crohn's disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy. No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P < 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response. Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs.

The Bioavailability of Oral Methotrexate in Children with Inflammatory Bowel Disease

Methotrexate is used to treat patients with inflammatory bowel disease. Although no available pharmacologic data support the assumption that the bioavailability of methotrexate is diminished in patients with inflammatory bowel disease, most such patients receive methotrexate parenterally. The oral bioavailability of methotrexate was determined in 11 pediatric patients being treated with methotrexate for inflammatory bowel disease. Serial plasma methotrexate concentrations were determined after equal subcutaneous and oral doses of methotrexate. The mean bioavailability of methotrexate in patients with inflammatory bowel disease was 84% +/- 38%. Interpatient variability in drug exposure was similar after oral and subcutaneous administration. The bioavailability of methotrexate in patients with inflammatory bowel disease is no different from that observed in other disease states. Subcutaneous administration of methotrexate does not appear to decrease the interpatient variability in drug exposure. There is no sound pharmacologic basis for favoring administration of methotrexate via the subcutaneous route for patients with inflammatory bowel disease.

Experience with the use of low-dose methotrexate for inflammatory bowel disease.

Thiopurine drugs (azathioprine and 6-mercaptopurine) are well established in the treatment of patients with inflammatory bowel disease. However, some patients are intolerant or resistant to thiopurine drugs and their management remains a challenge. Several studies have suggested methotrexate is effective for the induction and maintenance of remission in Crohn's disease. This study was conducted because the overall data on clinical efficacy of methotrexate in inflammatory bowel disease remain limited and there are no data regarding fistulating Crohn's disease or concomitant use of methotrexate with thiopurine drugs in inflammatory bowel disease. This study was a retrospective review of medical notes. Clinical response was defined as sustained withdrawal of oral steroids or fistula improvement. New episodes of steroid therapy, infliximab or surgery during the first 6 months were considered as failure to achieve clinical response. Seventy-two patients were studied (66 Crohn's disease and six ulcerative colitis). The mean dose of methotrexate used was 18.2 mg/week. Clinical response was achieved in 22 of 54 patients (40.7%) who completed 6 months of methotrexate treatment. For patients with Crohn's disease, fistula improvement was achieved in eight of 18 (44.4%) patients compared with 11 of 30 (36.7%) receiving methotrexate for steroid withdrawal. Clinical response was achieved in six of 15 patients (40%) treated with methotrexate and azathioprine at the same time compared with 16 of 39 patients (41%) treated with methotrexate alone. Methotrexate is reasonably effective in clinical practice as a steroid sparing agent in inflammatory bowel disease. The efficacy in fistulating Crohn's disease justifies its use as an immunomodulator in these patients. Combined azathioprine and methotrexate treatment appears to offer no advantage over methotrexate alone.

Low dose methotrexate in inflammatory bowel disease: current status and future directions.

Despite many recent advances, some notable limitations exist in the medical management of patients with inflammatory bowel disease. Glucocorticoids suppress active inflammation very effectively, but their long term use is associated with high rates of relapse and unacceptable toxicity. 6-Mercaptopurine and its prodrug azathioprine are effective in inducing and maintaining remission; however, a significant number of patients are resistant or intolerant to thiopurines. Low dose methotrexate, an anti-inflammatory drug, is a well established medication for rheumatoid arthritis and psoriasis. After an initial report in 1989, several clinical trials and analyses of clinical notes have examined the role of methotrexate in patients with ulcerative colitis and Crohn's disease. This review was conducted to summarize the current knowledge about the underlying basic anti-inflammatory mechanisms of methotrexate as well as the pharmacology and toxicology of this drug with particular emphasis on inflammatory bowel disease. It also critically evaluates all existing trials not only in the induction of remission but also in maintenance therapy. We conclude that low dose methotrexate is an effective and safe treatment in glucocorticoid-dependent and thiopurine intolerant patients with Crohn's disease but not ulcerative colitis. It remains to be seen whether low dose methotrexate may also be useful in long term maintenance therapy in patients with inflammatory bowel disease.

Intestinal lumen and tissue pharmacokinetics of methotrexate in inflammatory bowel disease: Subcutaneous methotrexate achieves pharmacologically active concentrations in the rectum

Intestinal lumen and tissue pharmacokinetics of methotrexate in inflammatory bowel disease: Subcutaneous methotrexate achieves pharmacologically active concentrations in the rectum