G. Rizzuto

Cyclosporine or infliximab as rescue therapy in severe refractory ulcerative colitis: early and long-term data from a retrospective observational study.

INTRODUCTION About 30-40% of patients with acute severe ulcerative colitis (UC) fail to respond to intensive intravenous (iv) corticosteroid treatment. Iv cyclosporine and infliximab are an effective rescue therapy in steroid-refractory UC patients but up to now it is still unclear which is the best therapeutic choice. METHODS We reviewed our series of severe steroid-refractory colitis admitted consecutively since 1994 comparing two historical cohort treated with iv cyclosporine (2 mg/kg) or iv infliximab (5 mg/kg). The main outcome was the colectomy rate at 3 months, 12 months and at the end of the follow-up. RESULTS A total of 65 patients were included: 35 in the cyclosporine group and 30 in the infliximab one. At 3 months the colectomy rate was 28.5% in the cyclosporine group and 17% in the infliximab group (p=0.25), while 48% versus 17% at 12 months (p=0.007, OR 4.7; 95% CI: 1.47-15.16). The 1-2-3 year cumulative colectomy rates were 48%, 54%, 57% in the cyclosporine group, and 17%, 23%, 27% in the infliximab group. At the end of the follow-up the colectomy rate was 60% versus 30% (p=0.04, HR 2.2; 95% CI: 1.11-4.86). High level of C reactive protein (p=0.04), extensive disease (p=0.01) and no azathioprine treatment (p<0.001) were related to the risk of colectomy. CONCLUSION This study, despite being retrospective, indicates that both cyclosporine and infliximab are effective in avoiding a colectomy in steroid-refractory UC patients. During the follow-up the risk of a colectomy is higher in patients treated with cyclosporine than with infliximab.

The PROSIT-BIO Cohort: A Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Infliximab Biosimilar.

Background: Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohns disease. Methods: A prospective, multicenter, cohort study using a structured database. Results: Consecutive patients (313 Crohns disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti–tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 ± 14 infusions of infliximab. The mean follow-up was 4.3 ± 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti–tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05–7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64). Conclusions: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.

Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience

Abstract Objectives: The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. Materials and methods: All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported. Results: Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2–75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn’s disease (p = .04). Conclusions: Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.

Letter: a prospective real life comparison of the efficacy of adalimumab vs. golimumab in moderate to severe ulcerative colitis

SIRS, Effectiveness of subcutaneous anti-tumour necrosis factor (TNF)-a antibodies, adalimumab (ADA) and golimumab (GOL), in the treatment of moderate to severe ulcerative colitis (UC), was shown in two randomised trials. 2 However, to our knowledge, no direct comparison of the two drugs has been published, while network meta-analyses have reported variable results. We agree with the results of the meta-analysis published by Stidham et al., where infliximab (IFX), ADA and GOL were all effective in UC. We report our experience on the efficacy of ADA and GOL in patients with moderate to severe UC. From June 2015 until April 2016, we prospectively evaluated 40 patients: 21 treated with ADA at the induction dosage of 160/80 mg followed by 40 mg every other week, 19 treated with GOL at the induction dosage of 200/ 100 mg followed by 50 or 100 mg, according to body weight, every 4 weeks. Patient characteristics, Mayo score and main results are shown in Table 1. Nineteen patients were na€ıve to anti-TNFa treatment: fourteen and five in the ADA and GOL group, respectively. Twenty-one patients had been previously treated with IFX: eleven discontinued for adverse events, eight for no response or loss of response, and two for previous remission. At 8 weeks, clinical remission was achieved in 15/40 patients (37.5%): 9/19 (47.3%) na€ıve and 6/21 (28.5%)

The real-world effectiveness of vedolizumab on intestinal and articular outcomes in inflammatory bowel diseases

BACKGROUND The effectiveness of vedolizumab in real-world practice is under evaluation, while its role in inflammatory bowel disease-associated spondyloarthritis is still unclear. AIMS To report real-world data about the effectiveness of vedolizumab on intestinal and articular symptoms after 10 and 22 weeks of treatment. METHODS Web-based data from the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD) were extracted to perform a prospective multicentre observational study. RESULTS 163 patients (84 with Crohns disease and 79 with ulcerative colitis) were included. At week 10, a steroid-free remission was achieved in 71 patients (43.6%), while at week 22 a steroid-free remission was obtained in 40.8% of patients. A response on articular symptoms was reported after 10 weeks of treatment in 17 out of 43 (39.5%) patients with active spondyloarthritis at baseline, and in 10 out of 22 (45.4%) patients at week 22. The only factor associated with articular response was the coexistence of clinical benefit on intestinal symptoms (at week 10: OR 8.471, p = 0.05; at week 22: OR 5.600, p = 0.08). CONCLUSIONS Vedolizumab showed good effectiveness after 10 and 22 weeks of treatment. A subset of patients reported improvement also on articular symptoms, probably as a consequence of the concomitant control of gut inflammation.

P387 The addition of an immunosuppressant is an effective optimization strategy after loss of response to anti-TNF-alpha monotherapy in patients with inflammatory bowel disease: a two-year experience

Crohn’s disease (CD), and that 6-thioguanine nucleotide (TGN) levels ≥125 pmol/8×108 RBC positively influence IFX pharmacokinetics. We aim to assess clinical outcomes after induction and during maintenance in CD patients treated with IFX and a thiopurine with respect to TGN and IFX levels. Methods: CD patients commenced on IFX between 2010–15 with or without concomitant thiopurines were retrospectively identified. “Response” to induction (CRP <5mg/L and absence of activity on physician global assessment) or “non response” (lack of clinical improvement during induction or flare requiring CD therapy adjustment or surgery during first 6 months) were assessed at week 14. Maintenance outcomes were assessed in 6-month semesters and classed as “response”, “flare” or “failure” (IFX cessation due to active disease or intolerance). TGN and IFX trough levels were recorded during induction and maintenance. Results: Of 89 patients (49 male, mean age 35y, range 18–61), combination therapy (n=73) had a higher response than IFX monotherapy (n=16) on induction (78% vs 50%, p=0.02). Median TGN was similar between responders and non-responders (314 vs 254, p=0.12), with TGN ≥125 patients more likely to respond (76% vs 47%, p=0.018). On multivariable analysis, TGN ≥125 was associated with response (OR 5.7; 95% CI: 1.6–20.1; p=0.006). Mean time to IFX failure was 26 months for monotherapy vs 53 months for combination therapy (p=0.55); a significant difference was observed when re-stratified by TGN ≥125, p=0.043 (Fig. 1).

Splenic tuberculosis in a patient with Crohn's disease on infliximab: Case report

To the Editor: An increased risk of reactivation of latent tuberculosis (TB) during therapy with tumor necrosis factor alpha (TNFa)-antagonists was first reported in 2001. Therefore, screening for the presence of latent Mycobacterium tuberculosis infection by purified protein derivative test (PPD) and chest x-ray is now routinely performed before starting treatment with anti-TNFa. Nevertheless, cases of TB, especially extrapulmonary, are still reported during anti-TNFa treatment. This may be related to the limited sensitivity of the PPD skin test in patients who are already immunosuppressed as the result of previous treatment. This has led to the development of more accurate tests. We report a case of a patient with Crohn’s disease (CD) treated with infliximab who, in spite of negative screening tests, developed fever and splenic focal lesions that were initially interpreted as lymphoma leading to splenectomy. Splenic TB was diagnosed on the resected specimen. A 34-year-old man with ileocolonic CD was admitted to the Gastroenterology and Hepatology Unit in June 2008. In 2002, because of recurrent abdominal pain, he underwent a follow-up colonoscopy that showed a stenosis of the ileocecal valve and was treated with a course of oral prednisone. The patient was asymptomatic from 2004 to 2006. In May 2007 he experienced a new relapse complicated by an abdominal abscess. He received total parenteral nutrition associated with intravenous steroids and underwent an ileocecal resection with ileocolonic anastomosis. An early clinical and endoscopic anastomotic relapse, complicated by enteromuscular fistula and abscess in the right iliac fossa, occurred 6 months after the operation. The patient was treated with antibiotics and steroids, obtaining resolution of the abscess. Since the fistula remained active, in April 2008 he started induction therapy with infliximab (Remicade, Schering-Plough, Milan, Italy) 5 mg/kg at weeks 0, 2, 6. Screening with the PPD test, chest x-ray, and hepatitis virus C and B markers was negative. No infusion reaction or delayed hypersensitivity-like reaction was observed. After the third infliximab infusion the fistula closed and the patient was in clinical remission and was able to stop steroids. In June 2008 he presented to our clinic with high fever (up to 39 C) that had developed 2 weeks after the last infliximab infusion. There was no history of prior infection, foreign travel, or infectious contacts. A physical examination revealed tachycardia and splenomegaly. He had no intestinal symptoms and magnetic resonance imaging (MRI) confirmed fistula closure. Laboratory tests showed an elevated erythrocyte sedimentation rate (90 mm/h) and C-Reactive Protein (7 mg/dL; normal <1). Ultrasonography (US) revealed multiple hypoechoic splenic focal lesions. There was no evidence of abdominal abscess. Chest x-ray as well as serologic tests for Brucella, Salmonella, human immunodeficiency virus (HIV), and cytomegalovirus and blood and urine cultures were negative. Polymerase chain reaction (PCR) for mycobacteria on blood and urine samples was negative. Abdominal MRI confirmed an enlarged spleen (14 cm) and multiple focal lesions that were isointense lesions (<1 cm) on T1and T2-weighted images and, on dynamic contrastenhanced images, hypointense with peripheral enhancement (Fig. 1). Image findings suggested lymphoma but a bone marrow biopsy was negative. A chest computed tomography (CT) revealed paratracheal, hilar, pretracheal, and subcarinal lymphnodes (diameter 1.5–2.5 cm), confirmed on positron emission tomography (PET) scan. The PET scan did not show abnormal uptake of the radioisotope in the spleen. Fever disappeared after a 7-day course of empiric treatment with piperacilline-tazobactam (4 g/day), ceftazidime (4 g/day), metronidazole (1.5 g/day), and fluconazole (100 mg/day) and the patient was initially discharged, but follow-up CT 2 months later showed persistent splenic hypodense lesions and mediastinal lymphnodes. We decided to perform a splenectomy. On the resected organ diffuse caseating granulomas were shown but Ziehl–Neelsen staining was negative. PCR on splenic tissue revealed, however, the presence of mycobacteria. The QuantiFeron-TB, an in vitro whole-blood assay for the detection of IFN-c production in response to M. tuberculosis-specific antigens, was positive: IFN-c level 8.84 IU/ml (normal <0.35). The patient was placed on a regimen of isoniazid (300 mg/day), rifampicin (600 mg/day), ethambutol (1200 mg/day), and pyrazinamide (1000 mg/day) associated with B6 vitamin supplementation. Patients treated with infliximab are at increased risk for infectious complications. In a report by Keane et al involving 70 cases of TB occurring during infliximab therapy in 147,000 patients, extrapulmonary and disseminated TB was observed in 57% and 24% of patients; these rates are considerably higher than those observed in the general population. Apart from the extent of infection, the clinical presentation of TB occurring during treatment with TNF antagonists can be unusual and constitute a diagnostic dilemma. The patient in this report had ileocolic CD and infliximab was used for fistulizing disease refractory to conventional CopyrightVC 2009 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20998 Published online 9 July 2009 in Wiley InterScience (www.interscience.wiley.com).

Mycophenolate mofetil is a valid option in patients with inflammatory bowel disease resistant to TNF-α inhibitors and conventional immunosuppressants

BACKGROUND Few studies investigated the role of mycophenolate mofetil in inflammatory bowel disease, and none of them had specifically focused on patients with previous multiple intolerances and/or nonresponses to conventional immunosuppressants and biologics. AIMS To evaluate clinical benefit and tolerability profile of mycophenolate mofetil in patients with inflammatory bowel disease and limited treatment options. METHODS All consecutive patients with previous multiple intolerances and/or nonresponses to immunosuppressants and biologics who started an off-label treatment with mycophenolate mofetil from January 2014 to February 2016 were entered in a prospectively maintained database. RESULTS Twenty-four patients were included. Four weeks after initiation of mycophenolate mofetil therapy, a steroid-free remission was achieved in 4 patients (16.7%), while a clinical response in 13 (54.1%). At the end of follow-up, 12 patients (50.0%) remained on mycophenolate mofetil. Six achieved and maintained steroid-free remission throughout the study period (25.0%), and a further 6 patients (25.0%) achieved a clinical response with complete discontinuation of steroids. Twelve patients (50.0%) were considered as treatment failure, and five of them underwent surgery. CONCLUSIONS This is the first experience reporting a clinical benefit and tolerability of mycophenolate mofetil in patients with inflammatory bowel disease and multiple previous failures to other immunosuppressants and/or biologics.

Letter: switching from one to another anti-tumour necrosis factor alpha agent, and the risks of an overlap of exposure.

SIRS, We read with interest the recent meta-analysis by Gisbert and colleagues which investigated the efficacy and safety of a second anti-TNF agent after primary/secondary failure or intolerance to a first drug. We believe that the reported rates of serious adverse events (AE) related to the administration of a second anti-TNF in patients with Crohn’s disease (CD) were truly representative of clinical practice. Although these events are relatively infrequent, they can be serious (serious AEs: 0–21%; discontinuation rate due to AEs: up to 20% of patients). We think that the time interval between the administration of two different biological drugs is crucial. In this regard, we would like to report the case of a 23-year-old man with a history of steroid-dependent CD, intolerance to thiopurines and under treatment with anti-TNF therapy, who presented to our out-patient clinic with confluent, painful vesicles on the palm of the right hand (Figure 1). He had switched, following loss of response, from adalimumab to infliximab with a gap of 15 days between the last adalimumab injection and the first infusion of infliximab; the rash, which was diagnosed as cutaneous herpes zoster, appeared 3 days later. The patient was promptly treated with oral valganciclovir. The rash initially spread to the ipsilateral arm and forearm, but regressed rapidly after the completion of a 10-day course of anti-viral therapy. A second infusion of infliximab was given 3 weeks after the first one, without further complications. According to the German and the British Society of Rheumatology Biologics registers, infectious skin complications are second only to respiratory infections in biologics-exposed patients, occurring in 1.5% of patients. 3 Reactivation of Varicella-zoster virus always requires close clinical monitoring because of the potential severe sequelae due not only to neurocutaneous manifestations but also to disseminated disease. In this case, the proximity of the AE with the first infusion of infliximab, and its initial worsening despite adequate anti-viral therapy, suggests to us that the time frame between the last injection of adalimumab and the first dose of infliximab was too short, with a consequent overlap of exposure between the two anti-TNF agents contributing to the protracted herpes zoster infection.

A propensity score-matched comparison of infliximab and adalimumab in TNF-α inhibitors naïve and non-naïve patients with Crohn’s disease: real-life data from the Sicilian Network for Inflammatory Bowel Disease (SN-IBD)

Background and Aims There is an unmet need to better understand the effectiveness of different biologics in inflammatory bowel diseases. We aimed at performing a multicentre, real-life comparison of the effectiveness of infliximab [IFX] and adalimumab [ADA] in Crohns disease [CD]. Methods Data of consecutive patients with CD treated with IFX and ADA from January 2013 to May 2017 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease. We used propensity score-matching accounting for the main baseline characteristics in TNF-α inhibitor-naïve and non-naïve patients. Results A total of 632 patients [735 total treatments] were included. Among naïve patients, a clinical benefit [the sum of steroid-free remission plus clinical response] was achieved in 81.8% patients treated with ADA and in 77.6% patients treated with IFX (adjusted odds ratio [OR]: 1.23, 95% CI 0.63-2-44, p = 0.547] at 12 weeks; after 1 year, a clinical benefit was achieved in 69.2% of patients treated with ADA and in 64.5% patients treated with IFX [adjusted OR: 1.10, 95% CI 0.61-1.96, p = 0.766]. Among non-naïve patients, a clinical benefit was achieved in 61.7% of patients treated with ADA and in 68.1% of patients treated with IFX [adjusted OR: 0.72, 95% CI 0.21-2.44, p = 0.600] at 12 weeks; after 1 year, a clinical benefit was achieved in 48.9% of patients treated with ADA and in 40.4% patients treated with IFX [adjusted OR: 1.23, 95% CI 0.54-2.86, p = 0.620]. Conclusions In this propensity score-matched comparison of ADA and IFX in CD, both drugs showed high rates of clinical benefit, without significant differences between them.