Ustekinumab safety and effectiveness in patients with ulcerative colitis: results from a large real-life study.

BACKGROUND: Ustekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist recently approved for treating ulcerative colitis (UC) but with limited real-world data. Therefore, we evaluated the effectiveness and safety of UST in patients with UC in a real-world setting. RESEARCH DESIGN AND METHODS: This is a multicenter, retrospective, observational cohort study. The primary endpoints were the clinical remission rate (partial Mayo score, PMS, ≤1) and the safety of UST. Other endpoints were corticosteroid-free remission (CSFR) rate, clinical response rate (PMS reduction of at least 2 points), and fecal calprotectin (FC) reduction at week 24. RESULTS: We included 256 consecutive patients with UC (M/F 139/117, median age 52). The clinical remission and clinical response rates at eight weeks were 18.7% (44/235) and 53.2% (125/235), respectively, and 27.6% (42/152) and 61.8% (94/152) at 24 weeks, respectively. At 24 weeks, CSFR was 20.3% (31/152), and FC significantly dropped at week 12 (p = 0.0004) and 24 (p = 0.038). At eight weeks, patients naïve or with one previous biologic treatment showed higher remission (p = 0.002) and clinical >response rates (p = 0.018) than patients previously treated with ≥ 2. Adverse events occurred in six patients (2.3%), whereas four patients (1.6%) underwent colectomy. CONCLUSION: This real-world study shows that UST effectively and safely treats patients with UC.

Switching from VEDOlizumab intravenous to subcutaneous formulation in ulcerative colitis patients in clinical remission: The SVEDO Study, an IG-IBD study.

BACKGROUND: The administration of biological drugs in inflammatory bowel diseases (IBD) is increasingly moving from intravenous to subcutaneous formulations. AIMS: To evaluate the efficacy and safety of vedolizumab subcutaneous administration after switching from intravenous administration in ulcerative colitis (UC) patients in corticosteroid-free clinical remission. METHODS: An observational, multicentre, prospective study was conducted by the Italian Group for the study of IBD (IG-IBD). UC patients in clinical remission (pMAYO < 2) not receiving steroids for > 8 months before the switch, and with at least 6 months of follow-up were included. Switch from intravenous to subcutaneous vedolizumab was defined as successful in patients not experiencing a disease flare (pMAYO ≥ 2) or needing oral steroids or stopping subcutaneous vedolizumab during the 6 months of follow-up after the switch. RESULTS: Overall, 168 patients were included. The switch was a success in 134 patients (79.8%). Vedolizumab retention rate was 88.7% at month six. C-reactive protein and faecal calprotectin values did not change after the switch (p = 0.07 and p = 0.28, respectively). Ten of the 19 patients who stopped subcutaneous formulation switched back to intravenous formulation recapturing clinical remission in 80%. Side effects were observed in 22 patients (13.1%). CONCLUSION: Effectiveness of switching from intravenous to subcutaneous vedolizumab formulation in UC patients in steroid-free clinical remission is confirmed in a real-world setting.

Use of tofacitinib as first or second-line therapy is associated with better outcomes in patients with ulcerative colitis: data from a real-world study.

BACKGROUND: Data regarding the real-world (RW) use of tofacitinib (TOF) in patients with ulcerative colitis (UC) are limited. We aimed to investigate TOF's RW efficacy and safety in Italian UC patients. RESEARCH DESIGN AND METHODS: A retrospective assessment of clinical and endoscopic activity was performed according to the Mayo score. The primary endpoints were to evaluate the effectiveness and safety of TOF. RESULTS: We enrolled 166 patients with a median follow-up of 24 (IQR 8-36) weeks. Clinical remission was achieved in 61/166 (36.7%) and 75/166 (45.2%) patients at 8-week and 24-week follow-ups, respectively. The optimization was requested in 27 (16.3%) patients. Clinical remission was achieved more frequently when TOF was used as a first/second line rather than a third/fourth line treatment (p = 0.007). Mucosal healing was reported in 46% of patients at the median follow-up time. Colectomy occurred in 8 (4.8%) patients. Adverse events occurred in 12 (5.4%) patients and severe in 3 (1.8%). One case of simple Herpes Zoster and one of renal vein thrombosis were recorded. CONCLUSIONS: Our RW data confirm that TOF is effective and safe in UC patients. It performs remarkably better when used as the first/second line of treatment.

Clinical and epidemiological features of ulcerative colitis patients in Sardinia, Italy: Results from a multicenter study.

BACKGROUND: There are little data on the epidemiological and clinical features of adult patients with ulcerative colitis (UC) in the different Italian regions, mainly derived from the absence of a national registry. This prevents correct interpretation of the disease burden. AIM: To assess the main clinical and epidemiological features of adult patients diagnosed with UC in Sardinia, Italy. METHODS: We performed a multicenter, observational, cross-sectional study that included adult patients with UC enrolled in seven gastroenterology unit centers in Sardinia. Data were obtained from the patients' medical records and from a questionnaire administered at the inclusion visit. RESULTS: Four hundred and forty-two patients with UC were included. The median age at diagnosis was 39 years (interquartile range 28-48). After a median disease duration of 10 years, 53 patients experienced proximal extension of proctitis or left-sided colitis. Seventy-five patients developed extraintestinal manifestations. Nineteen patients (4.3%) developed cancer: two with colorectal cancer and seventeen with extracolonic cancers. Mesalazine (5-ASA) remains the mainstay of treatment for UC. Overall, 95 patients (21.5%) were treated with one or more biologic agents, whereas 15 patients (3.4%) underwent surgery, mostly colectomy. CONCLUSION: Our results provide important insights into the clinical and epidemiological features of patients with UC, and while waiting for a national Italian registry, present eligible data on the UC population in Sardinia.

Harmful Effects and Potential Benefits of Anti-Tumor Necrosis Factor (TNF)-α on the Liver.

Anti-tumor necrosis factor (TNF)-α agents represent an effective treatment for chronic inflammatory diseases. However, some concerns about their potentially undesirable effects on liver function have been reported. On the other hand, evidence of their therapeutic effects on certain liver diseases is accumulating. Many data showed the safety of anti-TNF-α in patients with chronic hepatitis B and C and in liver transplanted patients even if a strict follow-up and prophylaxis are recommended in well-defined subgroups. On the other side, anti-TNF-α-induced liver injury is not a rare event. However, it is often reversible after anti-TNF-α withdrawal. Anti-TNF-α agents have been tested in advanced stages of severe alcoholic hepatitis and non-alcoholic fatty liver disease. Limited data on the efficacy of anti-TNF-α in patients with autoimmune hepatitis and primary biliary cholangitis are also available. In this review, we explored the hepatic safety concerns in patients receiving anti-TNF-α agents with and without pre-existent hepatic diseases. In addition, the available evidence on their potential benefits in the treatment of specific hepatic diseases is discussed.

Therapeutic Drug Monitoring is More Cost-Effective than a Clinically Based Approach in the Management of Loss of Response to Infliximab in Inflammatory Bowel Disease: An Observational Multicentre Study.

BACKGROUND AND AIMS: Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings. METHODS: Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches. RESULTS: Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied. CONCLUSIONS: In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective.

SICUS and CEUS imaging in Crohn's disease: an update.

Endoscopy remains the main technique in the diagnosis and treatment of Crohn's disease (CD); nevertheless, the recent development of innovative and non-invasive imaging techniques has led to a new tool in the exploration of small bowel in CD patients. This paper reviews the available data on ultrasound imaging used for the evaluation of CD, highlighting the role of small intestine contrast-enhanced ultrasonography with the use of oral and intravenous contrast agents.

What is the best way to manage screening for infections and vaccination of inflammatory bowel disease patients?

The use of biological agents and immunomodulators for inflammatory bowel disease (IBD) is associated with an increased risk of opportunistic infections, in particular of viral or bacterial etiology. Despite the existence of international guidelines, many gastroenterologists have not adopted routine screening and vaccination in those patients with IBD, which are candidate for biologic therapy. Available strategies to screen, diagnose and prevent bacterial and viral infections in patients with IBD prior to start biological therapy are discussed in this review.

Therapeutic drug monitoring of anti-TNF-α agents in inflammatory bowel diseases.

INTRODUCTION: The elaboration of effective and cost-saving algorithms for anti-TNF optimization in patients with inflammatory bowel diseases (IBD) represents one of the biggest challenges over the last few years. Recently, many studies have been focused on the identification of an optimal trough level (TL) for most used anti-TNF agents and on the role of anti-drug antibodies (ADAs), especially in the management of patients who lose response to biological treatments. Therapeutic drug monitoring may potentially help to also prevent lose of clinical benefit overtime and to reduce health-related costs. AREAS COVERED: Current evidence about the correlation between clinical outcomes and anti-TNF TLs, the role of ADAs in the context of safety and loss of response to anti-TNF, the utility of therapeutic drug monitoring in clinical practice. EXPERT OPINION: The data available so far support the utility of TL and ADA measurement for the management of IBD patients with loss of response to anti-TNF but does not currently authorizes a routine application in clinical practice of proactive therapeutic monitoring in patients in clinical remission. However, this remains a promising approach to optimize anti-TNF therapies and possibly to reduce health-related costs, then further prospective studies are strongly expected.

Management of perianal fistulas in Crohn's disease: an up-to-date review.

Perianal disease is one of the most disabling manifestations of Crohn's disease. A multidisciplinary approach of gastroenterologist, colorectal surgeon and radiologist is necessary for its management. A correct diagnosis, based on endoscopy, magnetic resonance imaging, endoanal ultrasound and examination under anesthesia, is crucial for perianal fistula treatment. Available medical and surgical therapies are discussed in this review, including new local treatment modalities that are under investigation.

Prevention and treatment of venous thromboembolism in patients with IBD: a trail still climbing.

Venous thromboembolism (VTE) represents one of the most common and life-threatening extraintestinal complications of inflammatory bowel disease (IBD). Therefore, the prevention of VTE is essential and foremost involves the assessment of individual patient risk factors for VTE and, consequently, the correction of those risk factors that are modifiable. Mechanical and pharmacological prophylaxis are highly effective at preventing VTE in patients hospitalized for acute disease, and they are recommended by the leading guidelines for hospitalized patients with IBD. Unfortunately, several recent surveys reported that prophylaxis against VTE is still poorly implemented because of concerns about its safety and a lack of awareness of the magnitude of thrombotic risk in patients with IBD. Therefore, further efforts are required to increase the thromboprophylaxis rate in these patients to bridge the gap between the best care and standard care and, consequently, to avoid preventable VTE-associated morbidity and mortality. This review provides insight on the critical points that persist on the prevention and treatment of VTE in patients with IBD.

Faecal calprotectin assay after induction with anti-Tumour Necrosis Factor α agents in inflammatory bowel disease: Prediction of clinical response and mucosal healing at one year.

BACKGROUND: Faecal calprotectin levels correlate with inflammation in inflammatory bowel disease. We evaluated the role of faecal calprotectin after anti-Tumour Necrosis Factor α induction in inflammatory bowel disease patients to predict therapeutic effect at one year. METHODS: Faecal calprotectin levels were measured in stools of 63 patients before and after induction of anti-Tumour Necrosis Factor α therapy. Clinical activity, measured by clinical indices, was assessed before and after biologic treatment. Clinical responders after induction were included in the study and colonoscopy was performed before and after one year of treatment to assess mucosal healing. RESULTS: 63 patients (44 Crohn's disease, 19 ulcerative colitis) were prospectively included (41.2% males, mean age at diagnosis 33 years). A sustained clinical response during the first year was observed in 57% of patients; median faecal calprotectin was 106 µg/g after induction versus 308 µg/g pre-induction (p<0.0001). Post-induction faecal calprotectin was significantly lower in responders versus non-responders (p=0.0002). Post-induction faecal calprotectin had 83% sensitivity and 74% specificity (cut-off ≤ 168 µg/g) for predicting a sustained clinical response at one year (p=0.0001); also, sensitivity was 79% and specificity 57% (cut-off ≤ 121 µg/g) for predicting mucosal healing (p=0.0001). CONCLUSIONS: In inflammatory bowel disease faecal calprotectin assay after anti-Tumour Necrosis Factor α induction can be used as a marker to predict sustained clinical response and mucosal healing at one year.

Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis.

BACKGROUND: Infliximab (IFX) has demonstrated effectiveness for inducing 12-month steroid-free clinical remission in patients with steroid-dependent ulcerative colitis (UC), but long-term data are lacking. The aim of the study was to describe the long-term outcome of IFX treatment in steroid-dependent UC and investigate if predictors of sustained clinical response and colectomy could be identified. METHODS: Consecutive patients with steroid-dependent UC treated with IFX were studied. The coprimary prespecified outcomes were sustained clinical response in patients who achieved clinical remission or response after IFX induction and colectomy-free survival. Secondary analyses were addressed to look for predictors of sustained clinical response and colectomy. RESULTS: After induction, 76% (96/126) of patients achieved clinical benefit. The median duration of follow-up on IFX maintenance therapy was 41.5 months (interquartile range, 26-45). Sixty-four percent (46/96) of patients had sustained clinical response at median follow-up. Colectomy-free survival was 77% at median follow-up. Combination therapy of IFX with thiopurines was an independent predictor of sustained clinical response (P < 0.0001; hazard ratio [HR], 3.98; 95% confidence interval [CI], 1.73-9.14). Independent predictors of colectomy were Mayo endoscopic subscore of 3 at baseline (P = 0.04; HR, 2.77; 95% CI, 1.09-7.05) and high C-reactive protein after induction (P = 0.001; HR, 5.65; 95% CI, 2.03-15.7). Thiopurine naive status (P = 0.025; HR, 0.34; 95% CI, 0.13-0.87) was protective from colectomy. CONCLUSIONS: Long-term IFX treatment is effective in inducing sustained clinical response in patients with steroid-dependent UC. Combination therapy is predictive of sustained clinical response in the long-term. Patients with more severe endoscopic lesions at baseline and high C-reactive protein after induction are at higher risk of colectomy. Conversely, thiopurine naive status is protective from colectomy.

Venous thromboembolism in patients with inflammatory bowel disease: focus on prevention and treatment.

Inflammatory bowel disease (IBD) patients have an increased risk of venous thromboembolism (VTE), which represents a significant cause of morbidity and mortality. The most common sites of VTE in IBD patients are the deep veins of the legs and pulmonary system, followed by the portal and mesenteric veins. However, other sites may also be involved, such as the cerebrovascular and retinal veins. The aetiology of VTE is multifactorial, including both inherited and acquired risk factors that, when simultaneously present, multiply the risk to the patient. VTE prevention involves correcting modifiable risk factors, such as disease activity, vitamin deficiency, dehydration and prolonged immobilisation. The role of mechanical and pharmacological prophylaxis against VTE using anticoagulants is also crucial. However, although guidelines recommend thromboprophylaxis for IBD patients, this method is still poorly implemented because of concerns about its safety and a lack of awareness of the magnitude of thrombotic risk in these patients. Further efforts are required to increase the rate of pharmacological prevention of VTE in IBD patients to avoid preventable morbidity and mortality.

FOXP3⁺ T regulatory cell modifications in inflammatory bowel disease patients treated with anti-TNFα agents.

Treg modulation has been hypothesized as one of the mechanisms by which antitumor necrosis factor α (TNFα) agents exert their action in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, data in IBD are still conflicting. We evaluated CD4⁺CD25⁺FOXP3⁺ (Tregs) by flow cytometry in peripheral blood from 32 adult IBD patient before (T0) and after the induction of anti-TNFα therapy (T1). Eight healthy controls (HCs) were included. We also evaluated the number of FOXP3⁺ cells in the lamina propria (LP) in biopsies taken in a subset of patients and controls. Treg frequencies were significantly increased in peripheral blood from our patients after anti-TNFα therapy compared to T0. T1 but not T0 levels were higher than HC. The increase was detectable only in clinical responders to the treatment. A negative correlation was found among delta Treg levels and the age of patients or disease duration and with the activity score of Crohn's disease (CD). No significant differences were found in LP FOXP3⁺ cells. Our data suggest the possibility that in IBD patients the treatment with anti-TNFα may affect Treg percentages and that Treg modifications may correlate with clinical response, but differently in early versus late disease.

Prevention of postoperative recurrence with azathioprine or infliximab in patients with Crohn's disease: an open-label pilot study.

BACKGROUND AND AIMS: Patients with Crohn's disease (CD) often require surgery over their clinical course. However, endoscopic and clinical recurrence of disease appear respectively in up to 80% and 30% of patients after one year. Thus, a prophylactic treatment is needed to reduce the possibility of recurrence. Both azathioprine and infliximab have been demonstrated to be effective, but head to head studies have not been performed so far. Aim of this open-label prospective study was to analyse endoscopic, histological and clinical recurrence after one year of treatment with azathioprine or infliximab as postoperative therapies in CD patients with "high risk" of recurrence. METHODS: Consecutive CD patients who underwent curative ileocolonic resection were randomized (1:1) to receive infliximab (standard induction and maintenance schedule) or azathioprine (2.5 mg/kg/day) for 1 year. Co-primary endpoints were endoscopic, histological and clinical recurrence after 12 months of therapy. RESULTS: Twenty-two consecutive CD patients (15 male; median age 32 years, IQR 22-38) were enrolled after curative ileocolonic resection. Eleven patients were treated with infliximab and 11 received azathioprine. Among patients treated with azathioprine, 4/10 (40%) had endoscopic recurrence compared to 1/11 (9%) in the infliximab group (p=0.14). Eight out of 10 (80%) among those who received azathioprine had severe histological activity, whereas 2/11 (18%) in the infliximab group presented histological recurrence (p=0.008). No significant clinical differences were found between the two groups. CONCLUSIONS: Infliximab was more effective than azathioprine in reducing histological, but not endoscopic and clinical recurrence after curative ileocolonic resection in "high risk" CD patients.

Infliximab in steroid-dependent ulcerative colitis: effectiveness and predictors of clinical and endoscopic remission.

BACKGROUND: Up to 20% of patients with ulcerative colitis (UC) become steroid-dependent during their course. Thiopurines are recommended in steroid-dependent UC, but their efficacy is debated. Data exploring the use of infliximab in these patients are scarce. Aims of this study were to evaluate the effectiveness of infliximab in steroid-dependent UC and identify predictors of steroid-free remission, mucosal healing (MH), and colectomy. METHODS: Steroid-dependent UC patients were enrolled and intentionally treated with infliximab. The prospectively designed analyses evaluated (1) steroid-free clinical remission at 6 and 12 months, (2) steroid-free clinical remission and MH at 12 months, and (3) colectomy within 12 months. RESULTS: One hundred and twenty-six active steroid-dependent UC patients were studied. Of the 126 patients, 36 patients were retrospectively included and 90 patients prospectively enrolled. Steroid-free remission was 53% and 47% at 6 and 12 months, respectively. Predictors of steroid-free remission at 6 and 12 months were thiopurine-naive status (hazard ratio [HR], 2.5 and HR, 2.8, respectively) and combination therapy (HR, 2.1 and HR, 2.2, respectively). At 12 months, 32% were in steroid-free remission and MH. Thiopurine-naive status predicted steroid-free remission and MH (odds ratio, 3.6). C-reactive protein drop to normal after infliximab induction was predictive of steroid-free remission at 6 (HR, 5.9) and 12 months (HR, 4.6) and steroid-free remission and MH at 12 months (odds ratio, 6.0). Twelve patients underwent colectomy after a median of 4.7 months. Steroid sparing significantly reduced the risk of colectomy within 12 months (HR, 0.14). CONCLUSIONS: Infliximab seems effective in steroid-dependent UC. Thiopurine-naive status and combination therapy significantly increase the rate of steroid-free remission up to 12 months.

Comparison of Quantiferon-TB Gold versus tuberculin skin test for tuberculosis screening in inflammatory bowel disease patients.

BACKGROUND & AIM: Screening for latent tuberculosis (LTB) is recommended before starting anti-TNF-alpha therapy. We compared the performance of Quantiferon-TB Gold (QFT-G) with the tuberculin skin test (TST) for the screening of LTB in a population of inflammatory bowel disease (IBD) patients who were candidates for anti-TNF-α therapy. METHODS: Ninety-two IBD patients who were candidates for anti-TNF-α therapy were tested with QTF-G and TST. Concomitant therapy and laboratory parameters were recorded. RESULTS: One subject was vaccinated with Bacille Calmette Guèrin (BCG), 76% of patients were on immunosuppressive therapy (IST), and all patients had a negative TB history and negative chest X-ray. Agreement between the two tests was observed in 89.2% of patients (79.4% +/+, 9.8% -/-), QFT-G+/TST- was observed in 4.4% (4) patients, and QFT-G-/TST+ was observed in 5.5%, one of which was previously vaccinated. All disagreements were observed in patients on IST (14.3% in this group). The agreement analysis showed moderate strength among the patients (k=0.508), while the agreement was only fair in the subgroup of patients on IST (k=0.388). CONCLUSION: Given the high risk of LTB reactivation in patients subjected to anti-TNF-α therapy, our results suggest that in our population, with low TB rate and very low BCG vaccination rate, both tests could be employed.

Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease.

The clinical introduction of tumour necrosis factor (TNF) inhibitors has deeply changed the treatment of inflammatory bowel diseases (IBD). It has demonstrated impressive efficacy as compared to alternative treatments, allowing for the chance to achieve near-remission and long-term improvement in function and quality of life and to alter the natural history of Crohn's disease (CD) and ulcerative colitis (UC). As a consequence of longer follow-up periods the number of side effects which may be attributed to treatment with biologics is growing significantly. Cutaneous reactions are among the most common adverse reactions. These complications include injection site reactions, cutaneous infections, immune-mediated complications such as psoriasis and lupus-like syndrome and rarely skin cancers. We review the recent literature and draw attention to dermatological side effects of anti-TNF therapy of inflammatory bowel disease.