Giammarco Mocci

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 Crohns 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.

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.

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.

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.

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 Crohns 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.

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 Crohns 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.

Biological therapies for inflammatory bowel disease: controversies and future options

Over the last few years, advances in understanding the pathogenesis of inflammatory bowel disease, together with progress in biotechnology, have led to the availability of several biological drugs that have dramatically changed the therapeutic approach to these disorders. Indeed, several molecules targeting crucial inflammatory cytokines, blocking T-cell activation/proliferation or the recruitment of inflammatory cells into the inflamed bowel, have been discovered and commercialized. However, the increasing use of biological agents has raised some concerns regarding their short- and long-term safety. This review offers a critical evaluation of the efficacy and safety of biological agents in the management of both Crohn’s disease and ulcerative colitis. In addition, promising therapeutic options are discussed.

Disease patterns in late-onset ulcerative colitis: Results from the IG-IBD “AGED study”

BACKGROUND Late-onset UC represents an important issue for the near future, but its outcomes and relative therapeutic strategies are yet poorly studied. AIM To better define the natural history of late-onset ulcerative colitis. METHODS In a multicenter retrospective study, we investigated the disease presentation and course in the first 3 years in 1091 UC patients divided into 3 age-groups: diagnosis ≥65years, 40-64 years, and <40years. Disease patterns, medical and surgical therapies, and risk factors for disease outcomes were analyzed. RESULTS Chronic active or relapsing disease accounts for 44% of patients with late-onset UC. Across all age-groups, these disease patterns require 3-6 times more steroids than remitting disease, but immunomodulators and, to a lesser extent, biologics are less frequently prescribed in the elderly. Advanced age, concomitant diseases and related therapies were found to be inversely associated with the use of immunomodulators or biologics, but not with surgery. CONCLUSIONS The conclusion that late-onset UC follows a mild course may apply only to a subset of patients. an important percentage of elderly patients present with more aggressive disease. Since steroid use and surgery rates did not differ in this subgroup, lower use of immunosuppressive therapy and biologics may reflect concerns in prescribing these therapies in the elderly.

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.SommarioNell’iter diagnostico e terapeutico della malattia di Crohn l’endoscopia rappresenta la principale metodica strumentale. Tuttavia, la recente introduzione di tecniche di imaging innovative e non invasive ha implementato lo studio dell’intestino nelle malattie infiammatorie croniche intestinali. La seguente revisione raccoglie i dati disponibili in letteratura relativi all’utilizzo dell’ecografia con mezzo di contrasto, sia orale (SICUS) sia endovenoso (CEUS), nella valutazione dei pazienti affetti da malattia di Crohn.