Luisa Guidi

Advanced Age Is an Independent Risk Factor for Severe Infections and Mortality in Patients Given Anti–Tumor Necrosis Factor Therapy for Inflammatory Bowel Disease

BACKGROUND & AIMS Few data are available on effects of biologic therapies in patients more than 65 years old with inflammatory bowel disease (IBD). We evaluated the risk and benefits of therapy with tumor necrosis factor (TNF) inhibitors in these patients. METHODS We collected data from patients with IBD treated with infliximab (n = 2475) and adalimumab (n = 604) from 2000 to 2009 at 16 tertiary centers. Ninety-five patients (3%) were more than 65 years old (52 men; 37 with ulcerative colitis and 58 with Crohns disease; 78 treated with infliximab and 17 with adalimumab). The control group comprised 190 patients 65 years old or younger who were treated with both biologics and 190 patients older than 65 years who were treated with other drugs. The primary end points were severe infection, cancer, or death. RESULTS Among patients more than 65 years old who received infliximab and adalimumab, 11% developed severe infections, 3% developed neoplasms, and 10% died. No variable was associated with severe infection or death. Among control patients more than 65 years old, 0.5% developed severe infections, 2% developed cancer, and 2% died. Among control patients less than 65 years old, 2.6% developed severe infections, none developed tumors, and 1% died. CONCLUSIONS Patients older than 65 years treated with TNF inhibitors for IBD have a high rate of severe infections and mortality compared with younger patients or patients of the same age that did not receive these therapeutics. The effects of anti-TNF agents in older patients with IBD should be more thoroughly investigated, because these patients have higher mortality related to hospitalization than younger patients.

The Effect of Zinc and Vitamin A Supplementation on Immune Response in an Older Population

OBJECTIVE: To determine if either supplemental vitamin A, zinc, or both increases cell‐mediated immune response in an older population.

-Increased carotid intima-media thickness in patients with inflammatory bowel disease

Background : Patients with inflammatory bowel disease have an increased risk of thrombotic complications; moreover, mesenteric microvascular thrombosis has been hypothesized as a contributing factor in the pathogenesis of inflammatory bowel disease.

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.

Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome

Mutations of forkhead box p3 (FOXP3), the master gene for naturally occurring regulatory T cells (nTregs), are responsible for the impaired function of nTregs, resulting in an autoimmune disease known as the immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. The relevance of other peripheral tolerance mechanisms, such as the presence and function of type 1 regulatory T (Tr1) cells, the major adaptive IL‐10‐producing Treg subset, in patients with IPEX syndrome remains to be clarified. FOXP3mutated Tr1‐polarized cells, differentiated in vitro from CD4+ T cells of four IPEX patients, were enriched in IL‐10+IL‐4−IFN‐γ+ T cells, a cytokine production profile specific for Tr1 cells, and expressed low levels of FOXP3 and high levels of Granzyme‐B. IPEX Tr1 cells were hypoproliferative and suppressive, thus indicating that FOXP3 mutations did not impair their function. Furthermore, we isolated Tr1 cell clones from the peripheral blood of one FOXP3null patient, demonstrating that Tr1 cells are present in vivo and they can be expanded in vitro in the absence of WT FOXP3. Overall, our results (i) show that functional Tr1 cells differentiate independently of FOXP3, (ii) confirm that human Tr1 and nTregs are distinct T‐cell lineages, and (iii) suggest that under favorable conditions Tr1 cells could exert regulatory functions in IPEX 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.

Ileal Crohn Disease: Mural Microvascularity Quantified with Contrast-enhanced US Correlates with Disease Activity

PURPOSE To quantitatively assess microvascular activation in the thickened ileal walls of patients with Crohn disease (CD) by using contrast-enhanced ultrasonography (US) and evaluate its correlation with widely used indexes of CD activity. MATERIALS AND METHODS This prospective study was approved by the ethics committee, and written informed consent was obtained from all patients. The authors examined 54 consecutively enrolled patients (mean age, 35.29 years; age range, 18-69 years; 39 men, 15 women) with endoscopically confirmed CD of the terminal ileum. Ileal wall segments thicker than 3 mm were examined with low-mechanical-index contrast-enhanced US and a second-generation US contrast agent. The authors analyzed software-plotted time-enhancement intensity curves to determine the maximum peak intensity (MPI) and wash-in slope coefficient (β) and evaluated their correlation with (a) the composite index of CD activity (CICDA), (b) the CD activity index (CDAI), and (c) the simplified endoscopic score for CD (SES-CD, evaluated in 37 patients) for the terminal ileum. Statistical analysis was performed with the Mann-Whitney test, Spearman rank test, and receiver operating characteristic (ROC) analysis. RESULTS MPI and β coefficients were significantly increased in the 36 patients with a CICDA indicative of active disease (P<.0001 for both), the 33 patients with a CDAI of at least 150 (P<.032 and P<.0074, respectively), and the 26 patients with an SES-CD of at least 1 (P<.0001 and P<.002, respectively). ROC analysis revealed accurate identification (compared with CICDA) of active CD with an MPI threshold of 24 video intensity (VI) (sensitivity, 97%; specificity, 83%) and a β coefficient of 4.5 VI/sec (sensitivity, 86%; specificity, 83%). CONCLUSION Contrast-enhanced US of the ileal wall is a promising method for objective, reproducible assessment of disease activity in patients with ileal CD.

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.

Enteroclysis CT and PEG-CT in patients with previous small-bowel surgical resection for Crohn’s disease: CT findings and correlation with endoscopy

The aim of this study was to evaluate the accuracy of multidetector CT in patients with Crohn’s disease (CD) relapse after ileocolic resection compared with endoscopy. Thirty-four patients were studied by endoscopy and multidetector CT, after oral administration of polyethylene glycol solution (n = 21) or after administration of methylcellulose via nasojejunal tube (n = 13). In CT examinations we evaluated the presence of mural thickening, target sign, perienteric stranding, comb sign, fibrofatty proliferation and complications. Endoscopic results were classified in accordance with Rutgeerts score (from 0 to 4). The statistical evaluations were carried out by using Fisher’s exact text and χ2 testing (p < 0.05, statistically significant difference). Sensitivity, specificity and accuracy of the CT were 96.9%, 100% and 97%, respectively. We found a statistically significant correlation between an endoscopic score of 4 and the CT signs of target sign, perienteric stranding, comb sign and fibrofatty proliferation, and between scores 1 and 2 and mucosal hyperdensity without or with mural thickening, respectively (p < 0.05). Moreover, only CT identified the presence of jejunal and proximal ileum disease in two and three patients, respectively, and fistulas in three patients. CT is a reliable method in the diagnosis of CD relapse and shows agreement with the approved endoscopic Rutgeerts score.

Impairment of lymphocyte activities in depressed aged subjects

Lymphocyte activities were determined in a population of 26 institutionalized aged subjects, selected as healthy according to the SENIEUR protocol and previously reported to display immunological and endocrinological abnormalities correlated with depressive disorders. The lymphocyte mitotic response to PHA, which was reduced in aged as compared to adult subjects, was found to be significantly lower and negatively correlated with the depression score in the elderly subjects. In supernatants of PHA-stimulated lymphocyte culture from aged subjects, IL-2, IL-4 and gamma-IFN levels were very low and more severely affected in the depressed aged group. Each cytokine production was negatively correlated with age and depression score. NK activity was lower in the aged and it could be augmented by the addition of IL-2 or alpha-IFN, even though to a lesser extent than in the adult subjects. The nondepressed aged displayed higher levels of IL-2 inducible NK activity than the depressed aged subjects. IL-2 and alpha-IFN stimulated NK activities were negatively correlated with depression score. The present work indicates that the psychological status could affect lymphocyte reactivity in the aged. Given the relatively high frequency of affective disorders in these subjects, the psychological status should be considered in studies of immune senescence.