Carla Felice

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.

Review article: selective histone deacetylase isoforms as potential therapeutic targets in inflammatory bowel diseases

A link between histone deacetylases (HDACs) and intestinal inflammation has been established. HDAC inhibitors that target gut‐selective inflammatory pathways represent a potential new therapeutic strategy in patients with refractory inflammatory bowel diseases (IBD).

Vascular Involvement in Inflammatory Bowel Disease: Pathogenesis and Clinical Aspects

Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), are chronic inflammatory conditions, characterized by a microvascular and also macrovascular involvement. Chronically inflamed intestinal microvessels of IBD patients have demonstrated significant alterations in their physiology and function compared with vessels from healthy and uninvolved IBD intestine. Recently, some studies have revealed that the poor mucosal healing, refractory inflammatory ulcerations and damage in the IBD intestine could depend on microvascular dysfunction, resulting in diminished vasodilatory capacity and tissue hypoperfusion in the IBD gut. Furthermore, several data show that the activation of intestinal endothelium plays a critical role in the pathogenesis and/or in perpetuating and amplifying the inflammatory process in IBD and, consequently, it is now emerging as a potential use of anticoagulant or coagulation-related drugs in treating IBD. IBD is also associated with an increased risk of macrovascular venous and arterial thrombosis. Thrombotic events occur prevalently as deep vein thrombosis and pulmonary embolism. They happen at an earlier age than in non-IBD patients. Prothrombotic risk factors in IBD patients could be distinguished as acquired, such as active inflammation, immobility, surgery, steroid therapy, and use of central venous catheters, and inherited. Furthermore, it has been found that IBD, per se, is an independent risk factor for thrombosis. The prevention of thromboembolic events in IBD patients includes the elimination of removable risk factors and, if thrombosis occurs, a pharmacological therapy similar to that used for thromboembolic events occurring in the general population.

Use of Infliximab in Particular Clinical Settings: Management Based on Current Evidence

With the increasingly widespread use of the anti-tumor necrosis factor-α agent infliximab for the treatment of Crohns disease and ulcerative colitis, there have been some concerns raised about the potential consequences of such therapy in particular clinical settings. In this review, we report the current strategies for optimizing treatment outcomes and minimizing the risks of some of the most serious events attributable to infliximab therapy. In particular, an up-to-date overview is provided on how to treat patients with inflammatory bowel disease using infliximab therapy, with regard to the diagnosis and management of latent tuberculosis infection and the risk of reactivation of hepatitis B and C infections. Furthermore, based on the available evidence, we evaluate the possibility of using infliximab during pregnancy. Finally, we evaluate whether patients with malignancies or pre-neoplastic lesions could be candidates for infliximab therapy. Overall, this review will provide physicians who use infliximab for the treatment of inflammatory bowel disease with several practical recommendations for the management of some complex situations that may occur in daily clinical practice.

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.

Italian Expert Panel on the management of patients with coexisting spondyloarthritis and inflammatory bowel disease

Spondyloarthritis (SpA) is a group of diseases with similar clinical, radiologic and serologic features, including SpA associated with inflammatory bowel disease (IBD-associated SpA). Several studies have estimated the occurrence of SpA in IBD patients as ranging from 17% to 39%, confirming that SpA is the most frequent extra-intestinal manifestation in patients with IBD. In this paper, the expert panel presents some red flags to guide clinicians - both rheumatologists and gastroenterologists - to make a correct diagnosis of IBD-associated SpA in clinical practice. IBD-associated SpA classification, clinical presentation and diagnostic work-up are also presented. From the therapeutic point of view, only separate recommendations/guidelines are currently available for the treatment of Crohns disease, ulcerative colitis and for both axial and peripheral SpA. However, when IBD and SpA coexist, the therapeutic strategy should be modulated to take into account the variable manifestations of IBD in terms of intestinal and extra-intestinal features, and the clinical manifestations of SpA, with particular attention to peripheral enthesitis, dactylitis and anterior uveitis. To our knowledge, this is the first attempt to define therapeutic algorithms for the integrated management of different IBD-associated SpA clinical scenarios.

Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents☆

BACKGROUND The prevalence rates of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with inflammatory bowel disease (IBD) have been reported to be higher than rates of infection among the general population. Although several cases of HBV infection reactivation in IBD patients treated with anti-TNF-α agents have been described, no evidence exists that anti-TNF-α therapy exacerbates the course of HCV. The aims of this study were to assess the prevalence of HBV and HCV and the rate of HBV vaccination in a population of IBD patients; and to investigate the long-term effects of anti-TNF-α therapy in the subgroup with HBV or HCV infections. METHODS 301 patients were studied. Prior to the initiation of anti-TNF-α therapy, serum samples were tested for HBsAg and anti-HBc, anti-HBs and anti-HCV antibodies. During the follow-up, HBsAg and anti-HBc positive patients underwent periodic blood testing for viral markers, HBV-DNA and liver function; anti-HCV positive patients were assessed for liver function and HCV-RNA. RESULTS One patient was HBsAg positive (0.3%), and 22 (7.3%) tested positive for anti-HBc. Seventy-two patients (23.9%) had been vaccinated for HBV. Four patients tested positive for anti-HCV (1.3%). During anti-TNF-α therapy, none of the patients experienced HBV or HCV reactivation. CONCLUSIONS HBV and HCV infection rates were similar to infection rates among the general population. Less than one quarter of the patients had been vaccinated against HBV. Anti-TNF-α agents appear to be safe for patients with HBV infection; more data are needed for patients with HCV infection.

Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-α agents: Effects of combined therapy with immunosuppressants

BACKGROUND AND AIMS Our first objective was to evaluate the immune response to the adjuvanted 2009 A/H1N1 pandemic (pH1N1) vaccine in inflammatory bowel disease (IBD) patients treated with anti-TNF-α alone or combined with immunosuppressants (IS). Second and third aims were the safety of pH1N1 vaccine and the effects on IBD clinical activity. METHODS 36 patients with Crohns disease (CD) and 26 with ulcerative colitis (UC) and thirty-one healthy control (HC) subjects were enrolled. 47 patients were on anti TNF-α maintenance monotherapy and 15 on anti TNF-α combined with IS. Sera were collected at baseline (T0) and 4 weeks after the vaccination (T1) for antibody determination by hemagglutination inhibition (HAI). Disease activity was monitored at T0 and T1. RESULTS Seroprotective titers (≥1:40) in patients were comparable to HC. Seroconvertion rate (≥4 fold increase in HAI titer) was lower than HC in IBD patients (p=0.009), either on anti TNF-α monotherapy (p=0.034) or combined with IS (p=0.011). Geometric mean titer (GMT) of antibodies at T1 was significantly lower in patients on combined therapy versus those on monotherapy (p=0.0017) and versus HC (p=0.011). The factor increase of GMT at T1 versus T0 was significantly lower in IBD patients versus HC (p=0.042), and in those on combined immunosuppression, both versus monotherapy (p=0.0048) and HC (p=0.0015). None of the patients experienced a disease flare. CONCLUSION Our study has shown a suboptimal response to pH1N1 vaccine in IBD patients on therapy with anti TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.

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

Perianal disease is one of the most disabling manifestations of Crohns 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.

Role of HMGB1 as a suitable biomarker of subclinical intestinal inflammation and mucosal healing in patients with inflammatory bowel disease.

Background:Noninvasive biomarkers of high- and low-grade intestinal inflammation and of mucosal healing (MH) in patients with inflammatory bowel disease are currently lacking. We have recently shown that fecal high mobility group box 1 (HMGB1) protein is a novel biomarker of gut inflammation. We aimed at investigating in a mouse model if HMGB1 was able to foresee both a clinically evident and a subclinical gut inflammation and if its normalization indicated MH. We also aimed at confirming the results in patients with Crohns disease (CD) and ulcerative colitis. Methods:C57BL6/J mice were treated with increasing doses of dextran sodium sulphate to induce colitis of different severity degrees; 28 with CD, 23 with ulcerative colitis, and 17 controls were also enrolled. Fecal HMGB1 was analyzed by enzyme-linked immunosorbent assay and immunoblotting. Results:Fecal HMGB1 increased by 5-, 11-, 18-, and 24-folds with dextran sodium sulphate doses of 0.25%, 0.50%, 1%, and 4%, respectively, showing that the protein detected a high-grade and a subclinical inflammation. After a recovery time of 4-week posttreatment, HMGB1 returned to control levels, paralleling MH. In patients, fecal HMGB1 significantly correlated with endoscopic indexes (Simple Endoscopic Score for Crohns Disease [SES-CD], endoscopic Mayo subscore), but not with the disease activity indexes (Crohns disease Activity Index, partial Mayo score). Conclusions:Fecal HMGB1 is a robust noninvasive biomarker of clinically overt and subclinical gut inflammation; it can also be a surrogate marker of MH. We suggest the use of fecal HMGB1 to monitor the disease course and assess therapy outcomes in inflammatory bowel disease.