Valeria Criscuoli

The Role of CARD15 Mutations and Smoking in the Course of Crohn's Disease in a Mediterranean Area

AIM:To evaluate the role of CARD15 mutations and smoking in the main events of Crohns disease (CD).PATIENTS AND METHODS:A total of 182 patients with CD were included in a prospective study in order to evaluate the role of CARD15 mutations and smoking in the main outcomes of disease course: first operation and surgical recurrence. The following variables were evaluated in a univariable and multivariable analysis: age, sex, site of disease, pattern, smoking habit, extraintestinal manifestations, duration of disease, and CARD15 mutation. The Kaplan–Meier method for survival curves and Cox model for multivariable analysis were, respectively, used.RESULTS:A total of 110 patients were operated on and 32 were reoperated on. The 7-yr cumulative free rate of surgery was 42% (95% CI 34–51%). At multivariate analysis only stricturing and penetrating pattern were predictors of surgery (HR 1.7, 95% CI 1–2.8; HR 3.2, CI 1.8–5.5, respectively). The 7-yr cumulative free rate of reoperation was 75% (95% CI 0.52–0.88). At multivariable analysis in the model with any CARD15 mutation, only smoking habit at diagnosis (HR 3.6, 95% CI 1.4–9.1) was predictive of surgical recurrence. When single mutations were considered in the model smoking (HR 4.2, 95% CI 1.8–10.1) and L1007fs mutation (HR 2.9, 95% CI 1.1–7.3) were predictive of reoperation.CONCLUSIONS:In CD, smoking predicts recurrence after surgery. The role of CARD15 mutations in the clinical course of CD remains undefined.

Incidence of Crohn’s disease and CARD15 mutation in a small township in Sicily

Background: The incidence of Crohn’s disease (CD) has been shown to be lower in Southern than in Northern Europe. Data on the frequency of the NOD2/CARD15 mutations for Mediterranean area are very scant.Aim: To determine the incidence of CD from 1979 to 2002 in a township in Sicily together with the allele frequency of NOD2/CARD15 mutations in patients, family members and controls, and to determine the allele frequency of these mutations in sporadic CD from other areas of Sicily in comparison with a control population.Methods: Casteltermini is a small town close to Agrigento (Sicily) with a population of 9,130 inhabitants. All the diagnoses of inflammatory bowel disease (IBD) made from 1979 to 2002 were obtained through the local health authority. NOD2/CARD15 mutations were studied in 23 out of the 29 patients with CD in Casteltermini, in 60 family members and in 64 controls. NOD2/CARD15 was also studied in 80 sporadic cases of CD disease among Sicilians outside Casteltermini and 118 healthy controls.Results: From 1979 to 2002, 29 patients with CD and 13 patients with ulcerative colitis (UC) were registered. The 6-year mean incidence of CD ranged from 8.0 to 17 new cases for every 100,000 inhabitants, whereas the mean incidence of UC ranged from five new cases to 7.8 for every 100,000 inhabitants. The allele frequencies of NOD2/CARD15 mutations (L1007finsC, G908R, R702W) were 8.7, 4.3 and 8.7%, respectively, in CD cases; 5.0, 4.2 and 3.1% in family members; 1.6, 2.3 and 3.1% in controls. In sporadic Sicilian CD patients outside Casteltermini the allele frequency was 7.5, 8.1, 6.2% whereas in control population it was 3.3, 1.6, 1.6%.Conclusions: A high incidence of CD compared with UC was observed in this small town in Southern Italy. The frequency of NOD2/CARD15 mutations in CD is similar to other Caucasian population studied so far.

Natural history of cytomegalovirus infection in a series of patients diagnosed with moderate-severe ulcerative colitis

AIM To evaluate the natural history of human cytomegalovirus (HCMV) infection in a series of 28 ulcerative colitis patients in whom the search for HCMV was positive. METHODS A series of 85 patients with moderate-severe ulcerative colitis flare-up were evaluated for a HCMV search by performing a haematoxylin and eosin stain, immunohistochemical assay and nested polymerase chain reaction on rectal biopsies. Among 85 screened patients (19 of whom were steroid resistant/dependent), 28 were positive for HCMV; after remission the patients were followed up clinically and histologically. RESULTS Among the 22 patients with complete follow-up, in 8 (36%) patients HCMV-DNA persisted in the intestinal specimens. Among the HCMV positive patients, 4 (50%) experienced at least one moderate-severe flare-up of colitis without evidence of peripheral HCMV. Among the 14 HCMV negative patients, 3 with pouches developed pouchitis and 5 out of 11 (45%) experienced a colitis flare-up. CONCLUSION Our preliminary results suggest that HCMV may remain in the colon after an acute colitis flare-up despite remission; it seems that the virus is not responsible for the disease relapse.

Cytomegalovirus Disappearance After Treatment for Refractory Ulcerative Colitis in 2 Patients Treated with Infliximab and 1 Patient with Leukapheresis

To the Editor: Human cytomegalovirus (HCMV) is a herpesvirus widely spread in the general population. In immunocompetent hosts it rarely causes serious illness but the infection can result in Epstein– Barr virus-like mononucleosis syndrome. In immunologically impaired patients the virus may cause serious multiorgan involvement and complications due to the cytomegalovirus-associated disease. The role of HCMV in patients with inflammatory bowel disease (IBD) is not clearly known. Data from the literature have shown a possible role in exacerbating a colitis flare,1,2 while some authors have reported a role as a bystander and innocent observer.3 Virus interaction with the host’s immune system involves both innate and adaptive immunity. T cells play an important role in controlling viral replication and disease development, but do not eliminate the virus completely; all herpesviruses possess the key property of latency and reactivation.4 The virus is maintained in latency in a non-replicative state in myeloid lineage progenitor cells and it reactivates, in response to inflammatory cytokines and chemokines, when peripheral blood monocytes differentiate into macrophages. The virus produces molecules designed to disrupt or manipulate host inflammatory/ immune responses: interleukin 1 and tumor necrosis factor alpha (TNF) support leukocyte activation and recruitment.5 An important clinical question is what to do when, in severe colitis, there is an indication to use infliximab and HCMV is identified in biopsy specimens or in peripheral blood. Is the presence of HCMV a contraindication to infliximab? We reviewed 3 cases of patients with steroid-dependent moderate-to-severe ulcerative colitis (UC) treated with infliximab and/or leukapheresis for active disease in whom a clinical response with virus disappearance was obtained. Three UC patients were admitted to our department for a severe disease relapse (8 bloody bowel movements per day, abdominal pain and tenderness). Therapy with intravenous steroid (methylprednisolone 1 mg/kg/day) was started, but after 5 days the symptoms were stable. Screening for treatment with infliximab was negative. At sigmoidoscopy, colitis activity was severe. In 1 patient antigenemia pp65 for HCMV detection in peripheral blood was positive, but negative in the other 2. Also, in all patients rectal biopsies (morphologic, immunohistochemical, and polymerase chain reaction [PCR] analysis) were positive for HCMV detection. On the basis of this evidence infliximab treatment was avoided in the first patient, who was treated with leukapheresis (8 sessions, blood volume of 1800 mL in 1 hour). The other 2 patients were treated with 3 infusions (0, 2, and 6 weeks) of infliximab at a dose of 5 mg/kg. All the patients obtained a clinical response with symptoms improvement. At the end on the treatments the endoscopic and histological activity was mild and the morphological and immunohistochemical analysis did not detect HCMV, while PCR proved to be positive. In the first patient antigenemia pp65 for HCMV detection in peripheral blood became negative. Previous data have shown that anti-TNF therapy may cause widespread HCMV infection in refractory Crohn’s disease (CD) through vasculitis, which allows the virus to circulate within the shed endothelial cells.6 An interruption of the replicative sequence may induce an HCMV latent state in infected cells determining immunologic tolerance by the host immune system. Fietze et al7 hypothesized that TNFplays a role in the reversal of HCMV latency and that inhibition of TNFrelease or action may be an alternative strategy for preventing HCMV-associated morbidity in allograft recipients. The replication of HCMV could also increase TNFexpression, allowing it to maintain a steady viral load. According to this evidence, some authors have shown a possible role of TNFin the reactivation of HCMV in septic patients.8 The mechanisms of action of leukapheresis devices have been extensively reviewed and are believed to exert an immunomodulatory and/or antiinflammatory effect on patients with systemic inflammatory disease. Dumont et al9 have shown a substantial reduction in the viral genome load in subjects positive for anti-CMV antibodies and HCMV-DNA, evaluated by qualitative PCR, after leukocyte reduction methods. According to this experience, treatment with anti-TNFantibodies and leukapheresis may be carried out without risk of colitis relapse associated with superimposed colonic HCMV infection. Low TNFactivity after infliximab treatment may interfere both with the viral replication and the inflammation maintenance avoiding colitis, while the decrease in circulating HCMV-infected cells after leukapheresis reduces the risk of colitis flare due to superimposed HCMV action. The improvement of colonic inflammation due to these treatments reduces viral replication, and the detection of HCMV in rectal biopsies only by PCR assay may correspond to a latent and non-pathogenic state of the virus. Although the available evidence arises from anecdotal or experimental observations, this report may be an interesting and useful proposal for further Copyright

Mesalazine for the treatment of inflammatory bowel disease

Introduction: Ulcerative colitis (UC) and Crohns disease (CD) represent a chronic inflammatory condition of the bowel that often require lifelong medical therapy for the induction and maintenance of the remission. Mesalazine therapies are available both as oral delayed-release and sustained-release formulation, topical formulations and as prodrug. Areas covered: Available literature regarding mesalazine is extensively reviewed in this article, covering its mechanism of action, pharmaceutics and pharmacokinetics, clinical efficacy, safety and tolerability in different settings. Expert opinion: Mesalazine has a well-established role in the management of UC. It is the treatment of choice in active and inactive mild-to-moderate UC combining oral and topical drug. No clear role of mesalazine in prevention of colon cancer has been demonstrated because of the contradictory results coming from case–control and prospective studies. The role of mesalazine in the management of CD is less clear; some studies suggest a potential efficacy of 5-ASA in preventing relapse of CD after surgical resection but more convincing results are needed.

The Role of Portal Vein Thrombosis in the Clinical Course of Inflammatory Bowel Diseases: Report on Three Cases and Review of the Literature

Inflammatory bowel diseases are associated with an increased risk of vascular complications. The most important are arterial and venous thromboembolisms, which are considered as specific extraintestinal manifestations of inflammatory bowel diseases. Among venous thromboembolism events, portal vein thrombosis has been described in inflammatory bowel diseases. We report three cases of portal vein thrombosis occurring in patients with active inflammatory bowel disease. In two of them, hepatic abscess was present. Furthermore, we performed a systematic review based on the clinical literature published on this topic.

Budesonide MMX and mesalamine to induce remission in patients with ulcerative colitis.

Dear Sir: We read with interest about the randomized, controlled trial (RCT) by Sandborn et al,1 which deserve some comments concerning the methodology and the interpretation of the results. First, the authors compared the efficacy of Budesonide MMX (9 and 6 mg/d) with mesalamine 2.4 g/d or placebo to induce remission in patients with active mild to moderate ulcerative colitis (UC). When a new drug must be evaluated versus an old treatment, the main rule is to choose the most appropriate dosage of the comparison drug. In 1987, Schroeder et al2 showed hat oral 5-aminosalicylic acid therapy in a dosage of .8 g/d was an effective therapy to induce remission in ctive UC. Two successive metaanalyses of the all RCTs f mesalamine confirmed that 3 g/d are needed to chieve the best result.3,4 Therefore, the comparison in this trial was not appropriate. Second, the clinical and combined remission (clinical and endoscopic) data observed in this study with mesalamine tablets (34% and 12%, respectively) are at variance with those of published RCTs. Leifeld et al,5 in a ooled analysis of 4 RCTs of 3 g/d of mesalamine, howed that tablets were able to obtain a clinical reission in 71% and endoscopic remission in 48% of atients. In the discussion, the authors state that mealamine 2.4 g/d is not more effective than placebo, hen this statement seems debatable according to the nalysis previously quoted.5 Considering that mesalamine is an effective drug in mild-to-moderate, active UC, before introducing budesonide MMx as a standard treatment for mild to moderate UC, it is advisable to design a trial which compare budesonide MMX with an effective dose of mesalamine.

Toxic megacolon and human Cytomegalovirus in a series of severe ulcerative colitis patients

BACKGROUND Human Cytomegalovirus (HCMV) infection has been reported to be a cause of refractory ulcerative colitis (UC). Toxic megacolon (TM) is a rare but severe complication of an acute attack of UC. OBJECTIVES Aim of this study is to evaluate in a case-control study the association between HCMV and TM. STUDY DESIGN All patients who were admitted at Medicine Department of V. Cervello Hospital in Palermo (tertiary referral center) for a severe UC flare-up complicated by the onset of TM (diameter of the transverse colon>6 cm) between January 1990 and November 2011 were identified through the electronic database. A total of 24 consecutive patients (16 male/8 female) with TM were identified. Each case of TM were individually matched by sex, age, extent of the underlying disease to 24 severe UC controls who did not develop TM. A further non matched control population of 48 severe UC was included. Haematoxilin and eosin stain, immunohistochemical procedure and nested polymerase chain reaction were performed to detect HCMV genes and proteins on rectal biopsies or surgical specimens. Pp65 antigenemia was performed in order to diagnose any possible systemic infection. HCMV frequency was compared between patients with and without TM during follow-up, using Fishers Exact test. RESULTS AND CONCLUSIONS HCMV was detected in histological specimens of 11 patients (46%) with TM compared to 2 (9%) severe UC matched controls (P = 0.0078) and 7 (14%) unmatched controls (p = 0,003). In severe colitis the presence of HCMV is more frequently associated with TM.

Oral valganciclovir for colonic dilatation in ulcerative colitis associated with human cytomegalovirus infection

To the Editor: Toxic megacolon is a rare complication of severe ulcerative colitis (UC) exacerbation defined as a clinical syndrome accompanied by radiographic evidence of colonic dilatation that in most cases must be treated aggressively with surgical intervention; human cytomegalovirus (HCMV) infection is a potential cause mainly in immunocompromised or critically ill patients. We describe a case of initial colonic dilatation on acute UC with superimposed HCMV infection successfully treated with oral valganciclovir. A 69-year-old woman patient affected by distal UC since 1999 was hospitalized on April 2009 for a severe disease flare-up. She had 10 bloody bowel movements per day, abdominal pain with tenderness and fever (38.7 C), with a blood pressure of 110/ 70 mmHg and a pulse rate of 80 beats/ min. The laboratory studies were normal except for an erythrocyte sedimentation rate of 78, mm/hr, a hypoalbuminemia of 2.4 g/dL, and a kaliemia of 3.4 mEq/L; blood and stools cultures showed no infection. In the past she was treated with infliximab (4 infusions from September to December 2007) and she was currently treated with azathioprine for steroid dependence. Therapy with steroid intravenous (methylprednisolone 1 mg/kg/die) and parenteral nutrition was started. After 4 days the symptoms were stable with development of colonic dilatation at plain abdomen x-ray (Fig. 1) and CT scan. Proctoscopy without air insufflation showed multiple large and bloody ulcers, lesion in the rectum with severe endoscopical activity; rectal biopsies revealed HCMV nuclear inclusions in epithelial and lamina propria cells with perivascular infiltrate suggestive for vascular damage at haematoxylin and eosin stain. The pp65-antigenemia on peripheral leukocytes was performed showing a positivity of 8 fluorescent nuclei/2 10 leukocytes; a serologic determination of IgM antiHCMV was negative. Treatment with oral valganciclovir, maintaining the same steroid treatment, was started (450 mg bid) for 14 days, obtaining a rapid clinical response with complete clinical remission after 7 days of treatment; afterward the steroids were gradually reduced. A daily planned plain abdomen x-ray was carried out showing a progressive improvement of the colonic dilatation. A pp65-antigenemia assay was repeated after 10 days of treatment with a negative result. To our knowledge, this is the first case of initial colon dilatation in UC complicated by HCMV infection successfully treated with oral valganciclovir. Valganciclovir is an orally administered prodrug of the standard anti-HCMV drug ganciclovir, well tolerated and efficacious in the treatment of HCMV retinitis in patients with AIDS and as prophylaxis against HCMV infection in solid organ transplant high-risk patients. It provides greater systemic ganciclovir exposure than oral ganciclovir, thus reducing the risk of viral resistance when used for prophylaxis in high-risk solid organ transplant recipients, with better

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.