Dan Greer

Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: A large single centre experience

BACKGROUND Infliximab is licenced for use in Crohns disease (CD). Trial data demonstrate that infliximab is effective for inducing remission of active CD, healing fistulising CD, and preventing relapse once in remission. However, long-term data regarding efficacy, safety, and predictors of response are still emerging. AIM To examine these issues in a large cohort of patients who received infliximab for CD. METHODS A retrospective analysis of prospectively collected data was performed for 210 patients receiving infliximab for luminal or fistulising CD. Response to infliximab induction therapy, and sustained clinical benefit, were assessed by a decrease in Harvey-Bradshaw Index (HBI) of ≥ 2 points. Remission was defined as an HBI ≤ 4. Physicians global assessment was used where HBI could not be obtained. Demographic and disease factors that may predict response to therapy were analysed by Kaplan-Meier plots and univariate and multivariate analyses. RESULTS Overall, 173 (82.4%) patients responded to infliximab induction, with 114 (65.9%) achieving sustained clinical benefit. Almost 40% of the study cohort had an HBI ≤ 4, indicating remission, at last point of follow-up (median 24 months). Concomitant immunosuppression predicted sustained clinical benefit in the first 6 months of therapy (P=0.03). An inflammatory disease phenotype (P=0.04 univariate analysis, P=0.03 Kaplan Meier analysis) and male gender (P=0.03) also predicted sustained clinical benefit. Episodic therapy was associated with an increased likelihood of secondary non-response. Adverse events, including malignancies, were few. CONCLUSION In this single centre study, infliximab was efficacious and well-tolerated in CD.

Mycophenolate mofetil therapy for refractory inflammatory bowel disease

Background: Mycophenolate mofetil (MMF) is an immunomodulatory drug, and its use in inflammatory bowel disease has previously been reported. The aim of this study was to review the Leeds Colitis Clinic experience of the safety and efficacy of MMF in treating patients with refractory Crohns disease (CD) and ulcerative colitis (UC). This is an extension of a previously published study from our center with a longer follow‐up period and approximately twice the number of patients. Methods: A retrospective analysis was performed of the records of all patients treated with MMF for inflammatory bowel disease over a 5‐year period. Results: Of 70 patients identified, 67 had previously been treated with azathioprine unsuccessfully. Seventeen of the 70 patients had been successfully maintained in remission with MMF for an average duration of 33 months. Treatment with MMF was discontinued for 53 patients, 17 because of side effects and 36 because they had not responded to the treatment. Conclusions: In our series, 17 patients (24.3%) had a sustained steroid‐free remission with MMF therapy. Nineteen patients (27%) experienced side effects, of which 17 (24.3% of the total group) had to discontinue therapy. An additional 36 (51.4%) required an escalation in medical therapy or surgery because of failure of the MMF therapy. MMF may have a role in the treatment of refractory inflammatory bowel disease, especially in patients who have previously failed standard therapies such as azathioprine. (Inflamm Bowel Dis 2007)

Costs of care for Crohn's disease following the introduction of infliximab: a single-centre UK experience

Aliment Pharmacol Ther 2010; 32: 1357–1363

Efficacy and tolerability of methotrexate therapy for refractory Crohn’s disease: a large single‐centre experience

Aliment Pharmacol Ther 2012; 35: 284–291

Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn's disease: A single centre experience

BACKGROUND AND AIMS Non-response, loss of response, or intolerance to anti-tumour necrosis factor alpha (anti-TNFα) therapy is well recognised in Crohns disease (CD) patients. Data concerning outcomes following the use of a second anti-TNFα therapy, particularly in patients who do not respond to a first anti-TNFα agent, are still emerging. The aim of this study was to assess response and tolerability to adalimumab following infliximab failure in a single centre cohort of CD patients. METHODS Data were collected prospectively on 44 patients who received adalimumab therapy following infliximab failure. Initial response to adalimumab therapy at 6weeks following induction was defined using a two point decrease in the Harvey-Bradshaw Index, with remission at this point defined using a Harvey Bradshaw index≤4. Sustained clinical benefit at the last point of follow up was determined using a physicians global assessment. Corticosteroid-free sustained clinical benefit was also assessed at this point. RESULTS Thirty-four (77%) patients had initial response to adalimumab therapy, with 28 (64%) having sustained clinical benefit. Corticosteroid-free sustained clinical benefit was achieved in nine (53%) of 17 patients requiring steroids at commencement of adalimumab. Four (44%) of the 9 patients who were primary non-responders to infliximab responded to adalimumab. The majority of CD patients who failed adalimumab therapy required surgery. CONCLUSIONS Second-line anti-TNFα therapy with adalimumab is effective at both inducing remission and maintaining response in CD patients who have failed infliximab, regardless of the reason for infliximab failure.

Costs of adalimumab versus infliximab as first-line biological therapy for luminal Crohn's disease.

BACKGROUND AND AIMS Randomised controlled trials demonstrate that the anti-tumour necrosis factor-α (anti-TNFα) therapies infliximab and adalimumab are effective in inducing remission and preventing relapse of Crohns disease (CD). As few studies have compared costs and efficacy of these two drugs directly, we examined this issue. METHODS Data were collected for patients receiving either drug as first-line anti-TNFα for CD. Patients were matched as closely as possible on age, gender, weight, height, and date of commencement of therapy. Response to induction therapy was assessed at 12weeks, and sustained clinical benefit at last point of follow-up. Resource data were collected for all patients until study end, with National Health Services reference costs applied to calculate the total cost per patient with adalimumab compared with infliximab. RESULTS Thirty-six patients had been treated with adalimumab as first-line anti-TNFα since 2010. We matched an identical number of infliximab patients. Demographic data were similar between the two groups. Costs were significantly lower with adalimumab (£6692.95 less per patient (95% confidence interval £1816.61-£11569.29)), which was largely driven by the drug costs and drug administration costs associated with infliximab. Twenty-nine (80.6%) patients responded to induction therapy with both drugs, and 22 (61.1%) achieved glucocorticosteroid-free sustained clinical benefit with either drug at last point of follow-up. CONCLUSIONS Costs of infliximab used as first-line anti-TNFα therapy are greater, which may have implications for selection. Clinical outcomes appeared comparable, although power to detect a statistically significant difference would be limited.

Adverse events associated with infliximab therapy in a large single centre UK cohort

Introduction Long term safety data for biologic therapies in Crohns disease (CD) is still emerging. A recent study has suggested that serious adverse events occur in 15% of patients receiving infliximab (IFX) therapy for CD, and more frequently in patients on concomitant immunosuppression. However, the TREAT registry observed no increased risk of adverse events with IFX, compared to other therapies. The authors assessed adverse events in patients who have received IFX therapy for CD at their referral centre. Methods All patients who receive IFX therapy for CD in our referral centre for CD were included on a prospective database. Data stored included sex, age at diagnosis, duration of disease, previous surgical history, smoking history and Montreal classification. Response and remission data are also prospectively recorded. Adverse events to infliximab are documented each time a patient attends for an infusion, or at the following clinic visit. Patients who were not receiving concomitant immunosuppression were premedicated with hydrocortisone at each infusion. Results In total, 3165 IFX infusions were administered to 210 patients (median of 24 (IQR 7–48) months), mean Harvey-Bradshaw index of 9. In total, 59 (28.1%) patients experienced adverse events to IFX. 23 patients had a reaction during the infusion, with 9 discontinuing therapy. 12 patients had hypersensitivity reactions and discontinued IFX. Seven patients discontinued IFX due to psoriatiform rashes. There were 14 (6.7%) opportunistic infections (including seven episodes of Varicella zoster reactivation, and one diagnosis of pulmonary tuberculosis in a Caucasian male who had received 3 years of maintenance therapy and had a normal chest x-ray pre-IFX), 3 infections required permanent discontinuation of IFX. There were 3 malignancies (1.4%) all discontinuing IFX. One was an adenocarcinoma in a peri-anal fistula tract. Examination under anaesthesia (EUA) and biopsy pre-IFX had been non-diagnostic, but EUA was repeated after non-response to IFX. One older diabetic patient developed a fatal spindle-cell tumour, and one patient in remission had an incidental finding of a renal cell carcinoma when disease was being reassessed by imaging prior to withdrawal of IFX. Overall, 34 (16.2%) patients discontinued IFX due to adverse events. 21 (35.6%) patients were receiving concomitant immunomodulator therapy at the time of the adverse event. There was no significant difference in adverse events when comparing episodic versus maintenance therapy (p=0.62). Conclusion IFX is safe and well tolerated with low numbers of adverse events, malignancies and mortality in our large single centre cohort of patients with severe active CD. Careful patient selection, pre-IFX screening and monitoring during therapy can optimise the risk benefit ratio.

Predictors of response and loss of response to infliximab therapy for crohn's disease: a large UK single centre experience

Introduction Infliximab (IFX) is licensed for use in Crohns disease (CD) in the UK. Data from randomised controlled trials demonstrate that IFX is more effective than placebo at inducing remission of active CD, healing fistulising CD and preventing relapse once remission is achieved. Factors predicting response to IFX, and sustained clinical benefit are still emerging. The authors analysed which patient characteristics may predict response, and also loss of response, to IFX, from a large prospective database of CD patients. Methods All patients who receive IFX therapy for CD in our referral centre for CD were included on a prospective database. Data stored included sex, age at diagnosis, duration of disease, surgical history, smoking history and Montreal classification. Concomitant therapy, IFX regimen, duration of therapy and number of infusions, Harvey-Bradshaw indices (HBI), were collected prospectively on commencement of IFX. Response to IFX, following induction or during continuing therapy (sustained clinical benefit), was defined as a ≥2 decrease in HBI, or by physicians global assessment (PGA). Results In total, 3165 IFX infusions were delivered to 210 patients over a median of 24 (IQR 7–48) months (median of 12 (IQR 4–22) infusions per patient). In total, 173 (82.4%) patients responded to IFX induction as determined by PGA and HBI scores (mean HBI pre- of 9.0 and 4.3 post-IFX induction). There were 18 (8.6%) patients with primary non-response (NR) to IFX induction (mean HBI of 10.1 pre-IFX and 10.3 post-IFX induction). A further 19 (9.0%) patients discontinued IFX during induction for other reasons including adverse events. At the last point of follow-up, 114 (65.9%) of the 173 responders (54.3% of the original cohort) to induction therapy experienced sustained clinical benefit from IFX, as determined by HBI and/or PGA (mean HBI of 3.9, with 84 (40% of the original cohort) having an HBI≥4, indicating remission). Predictors of response to IFX included male sex (p=0.01 for response to induction and p=0.006 for sustained clinical benefit), luminal disease (p=0.02 for sustained clinical benefit) and scheduled 8 weekly therapy (p=0.03 for sustained clinical benefit). There were 32 (18.5%) with secondary NR, 14 received IFX episodically initially and 18 received IFX as scheduled therapy. Patients were significantly more likely to experience secondary NR if treated episodically at induction (p=0.01). Secondary NR occurred sooner in patients with a stricturing or penetrating phenotype (p=0.007). Conclusion IFX therapy is efficacious for treatment of CD. The authors identify a number of predictors of response to therapy. This data support the proposal of scheduled maintenance therapy for IFX responders as per the new NICE guidance.

OC-037 Epidemiology and resistance patterns of culture-positive spontaneous bacterial peritonitis in Leeds 2006–2008

Introduction Spontaneous bacterial peritonitis (SBP) is a life threatening infection of ascitic fluid which occurs primarily in patients with pre-existing ascites in the setting of cirrhosis. Risk factors for developing SBP include: prior episode of SBP, gastrointestinal bleeding, ascitic total protein <1.0 g/dl and Child-Pugh score.1 Causative microorganisms include members of the normal microbial flora of the gastrointestinal tract including Escherichia coli (70%), Klebsiella species (10%), Proteus species (4%), Enterococcus faecalis (4%) and Pseudomonas species (2%).1 The choice of antimicrobial therapy must take into consideration the increasing frequency of hospital acquired infections, such as Clostridium difficile infection. Aim To identify the local epidemiology and resistance patterns of culture-positive SBP. Methods We retrospectively assessed the culture results of all ascitic fluid samples that grew a single organism in Leeds during the 3 years 2006–2008. Patients case notes were assessed to establish a diagnosis of SBP. An ascitic fluid neutrophil count ≥ 250/mm3 in patients with liver disease was used to confirm the diagnosis of SBP.1 2 We excluded culture-negative SBP. Results Single organism positive ascitic cultures were identifed in 42 patients with liver disease and an ascitic fluid neutrophil count ≥250/mm3. Mean age 52.1 years, 32/42 male. Underlying liver disease was ALD 35/42, HCV 3/42, PBC 1/42, NAFLD 1/42, Cryptogenic 1/42 and Post transplant 1/42. At the time of diagnosis of SBP the mean ascitic total white cell count 5.25, mean ascitic neutrophil count 4.08, mean serum Na+ 129.6 mmol/l and mean serum creatinine 147 mmol/l. Overall Child score A 0, B 8/42, C 34/42 and mean MELD score 24.1. The isolated organisms were Escherichia coli 15, Klebsiella spp. 7, other coliforms 10, Gram positive organisms 8 (including Enterococcus 2, Corynebacterium spp. 2). The Gram-negative isolates were resistant to a number of antibiotics: ciprofloxacin 38% (13/34), cefuroxime 29% (10/34), amoxycillin 32% (11/34) and tazocin 17% (6/34). The 30-day mortality was 50%. Conclusion Empirical treatment regimes need to take into account local resistance patterns. Ciprofloxacin has been widely used for treatment and prophylaxis in SBP. Resistance has now become a significant problem.

PWE-038 Adalimumab therapy for infliximab failures in Crohn's disease. A single-centre UK experience

Introduction Adalimumab (ADA) is efficacious in Crohns disease (CD) patients who have lost response to infliximab (IFX).1 However, there are little data detailing the long-term follow-up of IFX failures who are receiving ADA. Our aim was to prospectively analyse long-term outcomes of CD patients treated with ADA as a second line anti-TNF agent in Leeds. Methods CD patient data include demographics, previous IFX regime, reason for IFX discontinuation, disease site, immunomodulator and steroid use, Harvey-Bradshaw indices (HBI), BMI and adverse events. Results Since 2007, 36 CD patients (previously treated with IFX) received ADA in Leeds. 27 females (75%). Mean age 36. 21 had luminal disease (58%), 15 had fistulating disease (42%) 88% of these having perianal fistulae. 16 previously received IFX in a scheduled manner (44%), 11 episodically (31%), with nine switched to scheduled IFX to try and improve response, and nine had three dose induction of IFX only (25%). 22 patients received induction ADA dosing of 80 mg/40 mg (61%), 14 received 160 mg/80 mg (39%). Response was assessed following four injections. 27 patients initially responded (75%) with sustained response in 22 (58%), median follow-up of 12 months. Eight patients were primary non-responders (NR) to ADA, four of whom were primary NR to IFX. One discontinued during ADA induction due to a reaction. Other reasons for discontinuation were: 3 secondary NR, 1 further reaction, 1 patient in remission. The outcomes for patients who discontinued therapy were as follows: 10 patients had surgery (71%), 4 were observed (29%). 20 patients were on steroids prior to ADA therapy (55%), 10 were on steroids at follow-up (28%) with seven patients able to decrease the steroid dose. The mean HBI on commencing ADA was 10.7 and 7.1 after four injections. In 23 responders (four excluded as stoma) the HBI was 10 pre ADA and 5.5 after four injections, with 12 (52%) having HBI of <4 (defined as remission). In primary NR the HBI was 14.2 pre ADA and 12.4 on discontinuation. There were seven reactions attributed to ADA, two requiring cessation of therapy. Three were localised skin reactions at the injection site, and two diffuse skin rashes. There was one opportunistic infection (HSV). Conclusion ADA is a safe and effective therapy in CD patients who have been exposed to IFX. Our data demonstrate a good initial response to ADA and a sustained response out to 12 months of therapy. Steroid sparing was achieved in 50% of patients and few adverse events have been documented. These data confirm the efficacy of ADA use in IFX failures in a single centre UK experience.