Impact of a pharmacist-led thiopurine monitoring service in outpatients with inflammatory bowel disease.

BACKGROUND: Thiopurines are effective therapies for inflammatory bowel disease (IBD); however, treatment comes with safety concerns and adverse effects. Knowledge of the impact of pharmacists performing thiopurine monitoring is limited. AIMS: To determine the impact of a pharmacist-led monitoring service in patients with IBD commencing thiopurine therapy managed in the ambulatory care setting. METHODS: Patients commencing thiopurine therapy for IBD pre- and post-introduction of a pharmacist-led monitoring intervention were assessed. Pre-intervention patients received standard of care, while the post-intervention cohort was managed by the pharmacist. Data were acquired via retrospective audit of hospital medical records. The primary end-point was the proportion of patients with documented review for thiopurine adverse effects within the initial 3 weeks. Secondary end-points included achievement of therapeutic drug levels, persistence with thiopurine therapy, IBD-related episodes of care and number of outpatient medical reviews. RESULTS: Pre- and post-intervention cohorts comprised of 37 and 33 patients respectively. Pharmacist intervention increased the proportion of patients with documented monitoring within 3 weeks from 8.1% to 84.8% (P < 0.01). No difference in thiopurine dose optimisation was seen (27% vs 27.3%). Persistence with thiopurine therapy increased from 65.7% to 87.9% (P < 0.03) at 6 months. IBD-related emergency department presentations were not significantly decreased (8.1% vs 3%; P = 0.62). No significant change was observed in hospital admissions (16.2% vs 12.1%; P = 0.74) or outpatient medical reviews. CONCLUSIONS: Pharmacist monitoring of thiopurine therapy initiation in IBD outpatients improves adverse effect monitoring and increases medication persistence.

Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn's disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial.

BACKGROUND: Strictures are the most common structural complication of Crohn's disease. Surgery and endoscopic balloon dilation are the main treatments; drug therapy has been considered contraindicated. Given that most strictures have an inflammatory component, we aimed to find out whether strictures are responsive to drug treatment and whether intensive drug therapy is more effective than standard drug therapy. METHODS: This open-label, single-centre, randomised controlled trial was performed in one specialist inflammatory bowel disease centre in Australia. Patients aged 18 years or older with Crohn's disease were included. Eligible patients had a de novo or postoperative anastomotic intestinal stricture on MRI or ileocolonoscopy, symptoms consistent with chronic or subacute intestinal obstruction (postprandial abdominal pain in the presence of a confirmed stricture), and evidence of active intestinal inflammation. Patients were randomly assigned (2:1) to receive intensive high-dose adalimumab (160 mg adalimumab once per week for 4 weeks followed by 40 mg every 2 weeks, with escalation of dose at 4 months and 8 months if assessment of disease activity indicated active inflammation) plus thiopurine (initial dose of azathioprine 2·5 mg/kg or mercaptopurine 1·5 mg/kg, with dose adjustment based on thiopurine metabolite testing) or standard adalimumab monotherapy (160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks) using stratified fixed block randomisation. Stratification factors were stricture dilation at study baseline colonoscopy and current biologic drug use. The primary endpoint was improvement (decrease) in the 14-day obstructive symptom score at 12 months by one or more points compared with baseline. This trial is registered with ClinicalTrials.gov, NCT03220841, and is completed. FINDINGS: Between Sept 10, 2017, and Sept 6, 2019, 123 patients were screened and 77 randomly assigned to intensive adalimumab plus thiopurine treatment (n=52) or standard adalimumab treatment (n=25). At 12 months, improvement in obstructive symptom score was noted in 41 (79%) of 52 patients in the intensive treatment group and 16 (64%) of 25 in the standard treatment group (odds ratio [OR] 2·10 [95% CI 0·73-6·01]; p=0·17). Treatment failure occurred in five (10%) patients in the intensive treatment group versus seven (28%) in the standard treatment group (OR 0·27 [95% CI 0·08-0·97]; p=0·045); four patients in each group required stricture surgery (0·44 [0·10-1·92]; p=0·27). Crohn's Disease Activity Index was less than 150 in 36 (69%) patients in the intensive treatment group versus 15 (60%) in the standard treatment group (1·50 [0·56-4·05]; p=0·42). MRI at 12 months showed improvement using the stricture MaRIA score (≥25%) in 31 (61%) of 51 versus seven (28%) of 25 patients (3·99 [1·41-11·26]; p=0·0091). MRI complete stricture resolution was seen in ten (20%) versus four (16%) patients (1·28 [0·36 to 4·57]; p=0·70). Intestinal ultrasound at 12 months showed improvement (>25%) in bowel wall thickness in 22 (51%) of 43 versus seven (33%) of 21 patients (2·10 [0·71 to 6·21]; p=0·18). Faecal calprotectin normalised in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Normalisation of CRP was seen in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Eight (15%) patients in the intensive treatment group and four (16%) in the standard treatment group reported serious adverse events. No deaths occurred during the study. INTERPRETATION: Crohn's disease strictures are responsive to drug treatment. Most patients had improved symptoms and stricture morphology. Treat-to-target therapy intensification resulted in less treatment failure, a reduction in stricture-associated inflammation, and greater improvement in stricture morphology, although these differences were not significantly different from standard therapy. FUNDING: Australian National Health and Medical Research Council, Gastroenterological Society of Australia Ferring IBD Clinician Establishment Award, Australasian Gastro Intestinal Research Foundation, AbbVie, and the Spotlight Foundation.

A Single Educational Intervention Improves Pregnancy-Related Knowledge and Emotional Health Among Women With IBD Who Are Pregnant or Wish to Conceive.

BACKGROUND: There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD. METHODS: This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn's and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction. RESULTS: One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients' pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn's and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent. CONCLUSIONS: Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.

Risk of COVID 19 in patients with inflammatory bowel diseases compared to a control population.

BACKGROUND: It is unclear whether patients with inflammatory bowel disease (IBD) are at increased risk of COVID-19. OBJECTIVES: This observational study compared the prevalence of COVID-19 symptoms, diagnosis and hospitalization in IBD patients with a control population with non-inflammatory bowel disorders. METHODS: This multicentre study, included 2733 outpatients (1397 IBD patients and 1336 controls), from eight major gastrointestinal centres in Lombardy, Italy. Patients were invited to complete a web-based questionnaire regarding demographic, historical and clinical features over the previous 6 weeks. The prevalence of COVID-19 symptoms, diagnosis and hospitalization for COVID-19 was assessed. RESULTS: 1810 patients (64%) responded to the questionnaire (941 IBD patients and 869 controls). IBD patients were significantly younger and of male sex than controls. NSAID use and smoking were more frequent in controls. IBD patients were more likely treated with vitamin-D and vaccinated for influenza. Highly probable COVID-19 on the basis of symptoms and signs was less frequent in the IBD group (3.8% vs 6.3%; OR:0.45, 95%CI:0.28-0.75). IBD patients had a lower rate of nasopharyngeal swab-PCR confirmed diagnosis (0.2% vs 1.2%; OR:0.14, 95%CI:0.03-0.67). There was no difference in hospitalization between the groups (0.1% vs 0.6%; OR:0.14, 95%CI:0.02-1.17). CONCLUSION: IBD patients do not have an increased risk of COVID-19 specific symptoms or more severe disease compared with a control group of gastroenterology patients.

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure.

BACKGROUND: The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown. AIMS: To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance METHODS: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable. RESULTS: We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: -0.33 to -0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow-up testing. CONCLUSIONS: During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.

Comparison of Adalimumab Serum Drug Levels When Delivered by Pen Versus Syringe in Patients With Inflammatory Bowel Disease. An International, Multicentre Cohort Analysis.

BACKGROUND: Adalimumab is administered via a pre-filled syringe or spring-loaded pen. In a previous study in Crohn's disease, higher drug levels were observed in syringe users. The aim of this study was to evaluate the impact of delivery device on adalimumab drug levels in patients with Crohn's disease. METHODS: Consecutive Crohn's disease patients treated with maintenance adalimumab [40 mg fortnightly] were recruited from five centres. The first recorded drug level with matched clinical and biochemical markers of disease activity was compared between pen and syringe users. RESULTS: Of 218 patients, 64% used pen, with a median faecal calprotectin 110 µg/g and serum C-reactive protein 4 mg/L. In comparison to pen, syringe users had higher albumin [39 vs 42 g/L; p = 0.016], lower Harvey-Bradshaw Index [2 vs 1; p = 0.017], and higher rates of concomitant immunomodulation [54% vs 71%; p = 0.014]. Drug levels were equivalent between pen and syringe users [median 5.3 vs 5.2 µg/ml; p = 0.584], even after controlling for disease activity and immunomodulation. Syringe users at Alfred Health had higher drug levels than pen [6.1 vs 4.5 µg/ml; p = 0.039]; a greater proportion achieved therapeutic levels [75% vs 44%; p = 0.045]. A higher proportion of pen users from Saint-Étienne had therapeutic levels [79% vs 42%; p = 0.027], yet no significant difference in drug levels [7.9 vs 4.5 µg/ml; p = 0.119]. CONCLUSIONS: Delivery device does not appear to significantly affect adalimumab drug levels. Given differences between study sites, studies evaluating administration education and technique are warranted.

Immunomodulator use does not prevent first loss of response to anti-tumour necrosis factor alpha therapy in inflammatory bowel disease: long-term outcomes in a real-world cohort.

BACKGROUND: Recent prospective studies suggest combination therapy with immunomodulators improves efficacy, but long-term data is limited. AIM: To assess whether anti-tumour necrosis factor alpha (anti-TNF) monotherapy was associated with earlier loss of response (LOR) than combination therapy in a real-world cohort with long-term follow up. METHODS: A retrospective audit was conducted of inflammatory bowel disease patients receiving anti-TNF therapy in a tertiary centre and specialist private practices. All patients with accurate data for anti-TNF commencement and adequate correspondence to determine end-points were included. Outcomes measured included time to first LOR, causes and biochemical parameters. RESULTS: Two hundred and twenty-four patients were identified; 139 (62.1%) on combination therapy and 85 (37.9%) on monotherapy. Forty-five percent of patients had LOR during follow up until a maximum of 8.5 years; 59.4% on combination therapy and 40.6% on monotherapy (P = 0.533). The median time to LOR was not different between groups; 1069 days for combination therapy and 1489 days for monotherapy (P = 0.533). There was no difference in time to LOR between patients treated with different combination regimens or different anti-TNF agents. CONCLUSION: In this large cohort of patients in a real-world setting, patients treated with anti-TNF monotherapy had similar rates of LOR as patients on anti-TNF combination therapy, at both short- and long-term follow up.

Safety and Efficacy of Teduglutide (Gattex) in Patients With Crohn's Disease and Need for Parenteral Support Due to Short Bowel Syndrome-associated Intestinal Failure.

BACKGROUND: Teduglutide is a GLP-2 analogue indicated for treatment of adults with short bowel syndrome (SBS). Because of the rarity of SBS, real-world safety or efficacy data are not available in patients with Crohn's disease (CD) and SBS treated with teduglutide. AIM: To evaluate teduglutide's safety and efficacy in CD patients with SBS. METHODS: We conducted a retrospective cohort study at 3 tertiary centers in the United States between 2012 and 2014. Demographic, clinical, and therapeutic data were retrieved from medical record systems. RESULTS: Thirteen CD patients were included, 8 (62%) of whom were on concomitant immunosuppression. Median duration of teduglutide therapy was 365 days [interquartile range (IQR), 122 to 482 d] and 9/13 patients (69%) remain on therapy. At teduglutide initiation, 69% were on parenteral nutrition. At conclusion of follow-up, 1 patient was on parenteral nutrition. All patients were on intravenous fluids (IVF) before teduglutide; median IVF were 9000 mL/wk (IQR, 7000 to 14,000 mL/wk). IVF requirements decreased by a median of 3100 mL/wk (IQR, 2400 to 8400 mL/wk). Six patients (46%) ceased IVF. Adverse events attributed to teduglutide were obstructive symptoms (n=1), pancreatitis (n=1), asymptomatic lipase and amylase elevation (n=1), nausea (n=1), and abdominal pain (n=1). Catheter-related sepsis occurred in 4 patients. CONCLUSIONS: This is the first report evaluating the safety and efficacy of teduglutide in a cohort of CD patients with SBS requiring parenteral support. More of half the cohort was on concomitant immunosuppression. Teduglutide seemed to be safe and the majority of patients were weaned off parenteral support.

Cancer Recurrence Following Immune-Suppressive Therapies in Patients With Immune-Mediated Diseases: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Physicians frequently encounter patients with immune-mediated diseases and a history of malignancy. There are limited data on the safety of immunosuppressive therapy for these patients. Published studies have been small with few events, precluding robust estimates of risk. METHODS: We searched Medline, EMBASE, and conference proceedings for terms related to immune-mediated disease, immune-suppressive therapy, and cancer recurrence from inception to April 2015. We included 16 studies (9 of patients with rheumatoid arthritis, 8 of patients with inflammatory bowel disease, and 1 of patients with psoriasis) and stratified studies by type of immune-suppressive therapy (monoclonal antibodies to tumor necrosis factor [anti-TNF], conventional immune-modulatory agents, or no immune suppression). A random-effects meta-analysis was performed to calculate the pooled incidence rates as well as risk differences between the various treatments. RESULTS: Our analysis included 11,702 persons contributing 31,258 person-years (p-y) of follow-up evaluation after a prior diagnosis of cancer. Rates of cancer recurrence were similar among individuals receiving anti-TNF therapy (33.8 per 1000 p-y), immune-modulator therapy (36.2 per 1000 p-y), or no immunosuppression (37.5 per 1000 p-y), but were numerically higher among patients receiving combination immune suppression (54.5 per 1000 p-y) (P > .1 for all). Subgroup analysis of new and recurrent cancers separately, type of immune-modulator therapy, or immune-mediated disease showed similar results, with no increase in risk. We found similar pooled incidence values for new or primary cancers when immunosuppression was initiated within 6 years (33.6 per 1000 p-y for immune-modulatory agents and 43.7 per 1000 p-y for anti-TNF agents) vs more than 6 years after the index cancer (32.9 per 1000 p-y for immune-modulatory agents, P = .86; and 21.0 per 1000 p-y for anti-TNF agents, P = .43). CONCLUSIONS: In a meta-analysis of 16 studies, we observed similar rates of cancer recurrence among individuals with prior cancer who received no immunosuppression, anti-TNF therapy, immune-modulator therapy, or combination treatments. Prospective studies are needed to ascertain optimal intervals for re-initiation of immune-suppressive therapies for individuals with specific cancers.

Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort.

BACKGROUND: Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients. METHODS: Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey-Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey-Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey-Bradshaw index ≤4, simple clinical colitis activity index ≤2 and physician assessment of response and remission. RESULTS: Our study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%. CONCLUSIONS: VDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.

A randomized controlled study of trimethoprim-sulfamethoxazole versus norfloxacin for the prevention of infection in cirrhotic patients.

OBJECTIVE: To prospectively compare norfloxacin (N) with trimethoprim-sulfamethoxazole (T-S) in preventing infection in cirrhotic patients. METHODS: Cirrhotic patients at high risk of spontaneous bacterial peritonitis (SBP) were recruited and assigned N (400 mg daily) or T-S (160/800 mg daily). Patients were followed up for 12 months. The primary end-point was the incidence of infection. Secondary end-points included the incidence of SBP, bacteremia, extraperitoneal infection requiring antibiotic treatment, liver transplantation, death, side effects and rate of resistance to N or T-S. RESULTS: A total of 80 patients with a mean age of 53.0 ± 9.3 years were prescribed N (n = 40) or T-S (n = 40). Child-Pugh status, model for end-stage liver disease and risk factors for SBP were similar between the groups. There were 10 episodes of infections in the N group and 9 in the T-S group (P = 0.79). Two patients each in the N and T-S group developed SBP (P = 0.60). There was a difference in the rate of transplantation favoring N (P = 0.03) but not death. The number of adverse events for N (n = 7) and T-S (n = 10) were similar (P = 0.59), with T-S being associated with an increased risk of developing a definite or probable adverse event compared to N (22.5% vs 0%, P = 0.01). CONCLUSIONS: This study failed to demonstrate a difference between N and T-S groups in their effects on preventing infection in patients with liver cirrhosis. T-S can be considered an alternative first-line therapy for infection prophylaxis.

Risk stratification of upper GI bleeding with an esophageal capsule.

BACKGROUND: Analysis of upper GI bleeding (UGIB) presentations to our institutions suggests that many patients admitted for endoscopic investigation could be managed safely as outpatients. OBJECTIVE: To learn whether an esophageal capsule could identify a low-risk group of patients with UGIB who could safely wait for elective EGD. DESIGN: Diagnostic, nonrandomized, single-blind (investigator) study. SETTING: Three tertiary-care referral centers. PATIENTS: Eighty-three consecutive adult patients referred for management of UGIB. INTERVENTION: A capsule endoscopy (CE) was performed before EGD for the investigation and management of UGIB. MAIN OUTCOME MEASUREMENTS: Detection rates of UGIB source and identification of a low-risk group of patients who would have been suitable for outpatient EGD based on CE findings. RESULTS: In total, 62 of 83 patients (75%) had a cause for bleeding identified. Findings were concordant across both modalities in 34 patients (55%). Twenty-one patients (38%) with positive EGD results had negative CE results, 7 of whom were due to lack of duodenal visualization alone. However, 7 of 28 patients (25%) with normal EGD results had positive CE results. The subgroup of patients with duodenal visualization on CE, 23 of 25 (92%), were concordant with EGD for low-risk lesions that would have been suitable for outpatient management. LIMITATIONS: Low duodenal visualization rates with CE and low concordance between EGD and CE. CONCLUSION: Although CE is not currently ready to be used as a triage tool, when duodenal visualization was achieved CE correlated well with EGD findings and identified 92% of patients who may have been managed as outpatients.

Late onset Pneumocystis pneumonia in patients receiving rituximab for humoral renal transplant rejection.

Rituximab has been used increasingly in the treatment of antibody-mediated rejection (AbMR) in solid organ transplantation despite the absence of clinical trials demonstrating efficacy. A contributor to the growing use of rituximab is an apparent lack of morbidity; and there are no reports of specific opportunistic infections associated with its use in renal transplant recipients. Two cases of Pneumocystis pneumonia (PCP) occurring nearly 3 years after administration of rituximab for refractory AbMR are reported herein. These cases emphasize the need for ongoing vigilant observation in patients who have received rituximab, and highlight the importance of clinical trials to establish the role of rituximab in prevention and treatment of AbMR.