Nabeel Khan

Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: A meta-analysis of clinical trials

Background: Crohns disease and ulcerative colitis are chronic debilitating diseases for which there are multiple treatment options. There are limited data on methotrexates efficacy and safety profile. Our aim was to estimate the hepatotoxicity associated with its use in inflammatory bowel diseases (IBDs). Methods: We systematically searched the Medline, Cochrane Library, Web of Science, and EMBASE databases and manually examined references in selected articles for trials that used methotrexate as a treatment for IBDs. Thirteen trials that fulfilled the inclusion and exclusion criteria were included in the meta‐analysis. Information on trial and patient characteristics, use of methotrexate as well as other treatments or placebo, and levels of hepatic aminotransferase enzymes were abstracted by two independent investigators using a standardized form. A random effects model was used to pool the incidence rates of reported abnormalities in hepatic aminotransferases. Results: The pooled incidence rate of abnormal hepatic aminotransferase levels (defined as up to a 2‐fold increase over the upper limit of the normal range) in patients treated with methotrexate for IBD was 1.4 per 100 person‐months, while the rate of hepatotoxicity (defined as greater than a 2‐fold over the upper limit of the normal range) was 0.9 per 100 person‐months. The rate of withdrawal from treatment due to these abnormalities was 0.8 per 100 person‐months. Conclusions: The incidence of methotrexate‐related hepatotoxicity as measured by elevation in transaminases and drug withdrawal secondary to elevated transaminases is relatively low. (Inflamm Bowel Dis 2011;)

Risk of Melanoma and Non-Melanoma Skin Cancer in Ulcerative Colitis Patients Treated With Thiopurines: A Nationwide Retrospective Cohort

OBJECTIVES:There are limited data on the risk of non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC) among thiopurine-treated patients with ulcerative colitis (UC). Our aim was to investigate the risk while on, by cumulative years, and after stopping thiopurine therapy.METHODS:Nationwide data were obtained from the Veterans Affairs (VA) health-care system during 2001–2011. We performed a retrospective cohort study evaluating patients with UC. Cox regression was used to investigate the association between thiopurines use and time to NMSC while adjusting for demographics, ultraviolet radiation exposure, and VA visiting frequency. A matched nested case–control study was conducted to investigate the association between thiopurine use and MSC.RESULTS:We included 14,527 patients with UC in the analysis, with a median follow-up of 8.1 years. A total of 3,346 (23%) patients used thiopurines for a median duration of 1.6 years. We identified 421 NMSC and 45 MSC cases. The adjusted hazard ratios of developing NMSC while on and after stopping thiopurines were 2.1 (P<0.0001) and 0.7 (P=0.07), respectively, as compared with unexposed patients. The incidence rate of NMSC among those who never used thiopurines was 3.7 compared with 5.8, 7.9, 8.3, 7.8, and 13.6 per 1,000 person-years for the 1st, 2nd, 3th, 4th, and 5th year of thiopurine use, respectively. No statistically significant association was observed between thiopurine use and MSC, odds ratio 0.8 (P=0.6).CONCLUSIONS:In this predominantly white male nationwide cohort, there was a twofold increase in the risk of NMSC while on thiopurines. The incidence rate of NMSC significantly increased with subsequent years of cumulative exposure to thiopurines. Stopping thiopurines reduced the risk of NMSC to pre-exposure levels irrespective of the prior exposure duration.

Early corticosteroids requirement after the diagnosis of ulcerative colitis diagnosis can predict a more severe long-term course of the disease - a nationwide study of 1035 patients.

There are limited data regarding clinical outcomes in ulcerative colitis (UC) patients who require early corticosteroids (CS) use.

Long-term mesalamine maintenance in ulcerative colitis: which is more important? Adherence or daily dose.

Background:There are limited data about the long-term follow-up of patients with ulcerative colitis (UC) maintained on high versus low doses of mesalamine. We evaluated the best long-term average daily dose that would keep the disease in remission. Methods:Nationwide ulcerative colitis data were obtained from the Veterans Affairs health care system for the period 2001 to 2011. Those who started mesalamine maintenance during this period were included. Average daily dose and the level of adherence were assessed for the period between the first mesalamine dispense and the date of first flare defined as the first filling of 40 mg/day or more of oral prednisone or any dose of intravenous steroids. Patients with ulcerative colitis maintained on an average daily dose 2.4 to 2.8 g/day (low dose) were compared with 4.4 to 4.8 g/day (high dose). Adherence was assessed using continuous single interval medication availability indicator. Results:We included 4452 patients with a median follow-up of 6 years. There was no significant reduction in the risk of flares when comparing high versus low average mesalamine dose among patients with high [hazard ratio = 0.96, P = 0.8)] and medium (hazard ratio = 0.74, P = 0.17) adherence. However, there was a significant reduction in the risk of flares with high dose of mesalamine among patients with low adherence (hazard ratio = 0.28, P = 0.003). Conclusions:Our data show that when starting a patient on mesalamine, there is no difference in the long-term flare risk between low versus high average daily dose as long as the patients have a high to moderate level of adherence.

Safety of anti-TNF therapy in inflammatory bowel disease during pregnancy

Introduction: The highest incidence of inflammatory bowel disease (IBD) is seen between the second and fourth decades of life, which is the most fertile age for women. Increased disease activity has been shown to effect female fertility and pregnancy outcomes, stressing the need for drugs that can safely induce and maintain clinical remission without harming either the mother or fetus. Areas covered: Anti-TNF-α agents have been shown to be effective in both inducing and maintaining remission among IBD patients. This review highlights the results of previous studies conducted on pregnant women who were exposed to anti-TNF-α agents during the course of their pregnancy. The drugs reviewed include infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP) and golimumab (GMB). Of > 200 articles reviewed, 105 were included in the manuscript based on relevance. The keywords used were anti-TNF, infliximab, adalimumab, certolizumab, golimumab, biologics, pregnancy and inflammatory bowel disease. Expert opinion: Anti-TNF agents have been studied extensively during pregnancy from the early case reports to the more recent prospective Pregnancy in IBD and Neonatal Outcomes study. A comprehensive review of the literature has shown that biologics can be safely used during pregnancy. In view of this safety data, it is recommended to maintain therapy during pregnancy.

Long‐term oral mesalazine adherence and the risk of disease flare in ulcerative colitis: nationwide 10‐year retrospective cohort from the veterans affairs healthcare system

Adherence is a major factor in determining disease activity in ulcerative colitis (UC). There are limited data on long‐term nationwide adherence levels among patients with UC.

Methotrexate in ulcerative colitis: a nationwide retrospective cohort from the Veterans Affairs Health Care System.

Background:There are paucity of data regarding the utility of methotrexate (MTX) in the management of ulcerative colitis (UC). The aim of this study was to describe the efficacy of MTX in achieving steroid-free remission. Methods:A retrospective cohort study was conducted using the nationwide Veterans Affairs database to identify steroid-dependent patients with UC using MTX for the period 2001 to 2011. Patients were followed up for 15 months after MTX initiation by tracking their prednisone, MTX, thiopurines, and infliximab dispense. Endpoints were: (1) successful remission, defined as cessation of prednisone filling activity while continuing MTX; (2) failure with continuance, failure to be weaned off steroids while continuing MTX; (3) failure with discontinuance, cessation of MTX while continuing steroids. Results:We included 91 patients with UC with mean age 59 years. The average weekly dose for oral and parenteral MTX was 14 and 25 mg/week, respectively. The average daily dose for prednisone within the oral MTX and parenteral MTX groups was 12 and 25 mg/day, respectively. By the 12th month of follow-up, 37% and 30% of patients on oral and parenteral MTX, respectively, were able to discontinue steroid. There was a nonsignificant trend toward dose reduction of steroids in those who were concomitantly taking oral MTX and steroids. Conclusions:Our study represents the largest cohort of patients with MTX and UC reported to date and suggests that approximately one-third of patients were successfully weaned off steroids with MTX therapy. MTX should be considered in the long-term management of patients with UC on steroids.

Prevalence and Predictors of Low Bone Mineral Density in Males With Ulcerative Colitis

CONTEXT Low bone mineral density (BMD) is common in patients with inflammatory bowel diseases. OBJECTIVE The objective of the study was to assess the prevalence and the predictors of low BMD (osteoporosis or osteopenia) and fragility fractures among men with ulcerative colitis. DESIGN This was a retrospective database analysis. SETTING The study was conducted at a nationwide Veterans Affairs health care system. PATIENTS Male ulcerative colitis patients who were followed up in the Veterans Affairs system between 2001 and 2011 were identified using the International Classification of Diseases, ninth revision (ICD-9). MAIN OUTCOME MEASURES We identified patients with low BMD and fragility fractures using ICD-9 codes. Steroid exposure was assessed using pharmacy data. A multivariate analysis was used to identify the independent effect of systemic steroids on the risk of low BMD and fragility fractures. RESULTS We identified 34 665 patients. Among them, 31% used steroids. The prevalence of low BMD was 15.8% and 7.1% among those who used and did not use steroids, respectively (P < .001). Prevalence of fragility fractures was 7.9%, 4.4%, and 1.1% for those with osteoporosis and osteopenia and those without low BMD, respectively (P < .001). Steroid exposure showed a dose-response pattern, patients who had cumulative prednisone exposure of greater than 11 136 mg (10th decile) were more likely to develop low BMD (odds ratio 8.9, P < .001) and fragility fractures (odds ratio 1.8, P < .001) as compared with non-steroid users after controlling for other possible predictors. CONCLUSION In this nationwide cohort, the prevalence of low BMD was higher than what was reported for the general male population. There was a strong correlation between the cumulative steroid use and the risk of low BMD. Both steroids and low BMD were independent risk factors for fragility fractures.

Corticosteroid use and complications in a US inflammatory bowel disease cohort

Background and Aims Corticosteroids are effective for the short-term treatment of inflammatory bowel disease (IBD). Long-term use, however, is associated with significant adverse effects. To define the: (1) frequency and duration of corticosteroid use, (2) frequency of escalation to corticosteroid-sparing therapy, (3) rate of complications related to corticosteroid use, (4) rate of appropriate bone density measurements (dual energy X-ray absorptiometry [DEXA] scans), and (5) factors associated with escalation and DEXA scans. Methods Retrospective review of Veterans Health Administration (VHA) data from 2002–2010. Results Of the 30,456 Veterans with IBD, 32% required at least one course of corticosteroids during the study time period, and 17% of the steroid users had a prolonged course. Among these patients, only 26.2% underwent escalation of therapy. Patients visiting a gastroenterology (GI) physician were significantly more likely to receive corticosteroid-sparing medications. Factors associated with corticosteroid-sparing medications included younger age (OR = 0.96 per year,95%CI:0.95, 0.97), male gender (OR = 2.00,95%CI:1.16,3.46), GI visit during the corticosteroid evaluation period (OR = 8.01,95%CI:5.85,10.95) and the use of continuous corticosteroids vs. intermittent corticosteroids (OR = 2.28,95%CI:1.33,3.90). Rates of complications per 1000 person-years after IBD diagnosis were higher among corticosteroid users (venous thromboembolism [VTE] 9.0%; fragility fracture 2.6%; Infections 54.3) than non-corticosteroid users (VTE 4.9%; fragility fracture 1.9%; Infections 26.9). DEXA scan utilization rates among corticosteroid users were only 7.8%. Conclusions Prolonged corticosteroid therapy for the treatment of IBD is common and is associated with significant harm to patients. Patients with prolonged use of corticosteroids for IBD should be referred to gastroenterology early and universal efforts to improve the delivery of high quality care should be undertaken.

Safety of herpes zoster vaccination among inflammatory bowel disease patients being treated with anti-TNF medications

The risk of herpes zoster (HZ) is elevated in inflammatory bowel disease (IBD) patients treated with anti‐TNF medications. While it is optimal to give herpes zoster vaccine prior to initiation of therapy clinical circumstances may not always allow this.