Frequency and Cause of Persistent Symptoms in Celiac Disease Patients on a Long-term Gluten-free Diet.

GOALS: To estimate the frequency and cause of nonresponsive celiac disease (CD). BACKGROUND: Treatment of CD is based on life-long adherence to a gluten-free diet (GFD). Some celiac patients experience persistence of symptoms despite a GFD. This condition is defined as nonresponsive CD. STUDY: Celiac patients on a GFD for at least 12 months underwent diet compliance assessment, laboratory tests, breath tests, endoscopic, and histologic evaluations according to the symptoms/signs reported. RESULTS: Seventy of 321 (21.8%) patients had persistent or recurrent symptoms/signs. The cause of symptom persistence was evaluated in 56 of 70 patients. Thirteen of 56 (23%) patients were antiendomysial antibody positive. Among the patients with negative serology, 1 had fibromyalgia, and 3 had evidence that disproved the diagnosis of CD. The remaining 39 patients with negative serology underwent duodenal biopsy sampling, which evidenced histologic alterations in 24 patients. Among the 15 patients with normal histology 3 were lactose intolerant, 9 had irritable bowel syndrome, 2 had gastroesophageal reflux disease, and in 1 patient a cause for the persistent symptom was not identified. In patients with confirmed diagnosis of CD, exposure to dietary gluten was the main cause of persistence of symptoms/signs, and consistently after dietary modification, symptoms resolved in 63% of the patients at later time points during follow-up. CONCLUSION: Nonresponsive CD occurs in nearly one fifth of celiac patients on GFD and its occurrence suggests further investigations to optimize the management of celiac patients.

The IL-12/23/STAT Axis as a Therapeutic Target in Inflammatory Bowel Disease: Mechanisms and Evidence in Man.

BACKGROUND: In inflamed tissues of patients with inflammatory bowel disease (IBD), many immune and non-immune cells produce a vast array of cytokines, which contribute to expand and maintain the pathologic process. Key Message: Interleukin (IL)-12 and IL-23, 2 heterodimeric cytokines sharing the common p40 subunit, are over-produced in IBD and supposed to play a major role in promoting and/or sustaining the pro-inflammatory cytokine response in these disorders. IL-12 targets mostly T cells and innate lymphoid cells and through activation of Stat4 promotes T helper (Th)1 cell polarization, interferon-x03B3; and IL-21 production, while IL-23 activates Stat3 thus amplifying Th17 cell programs. These observations together with the demonstration that IL-12 and IL-23 drive pathogenic responses in animal models of colitis have paved the way for the development of IL-12p40 blockers. Two monoclonal antibodies (ustekinumab and briakinumab) targeting p40 have been tested in Crohn's disease (CD) patients. Blockade of IL-12p40 is beneficial in CD patients resistant to tumor necrosis factor (TNF) antagonists and promotes resolution of psoriatic lesions that develop in IBD patients following anti-TNF therapy. CONCLUSIONS: The available human data support the pathogenic role of IL-12/IL-23 in IBD and suggest that IL-12p40 blockers could help manage some subsets of IBD patients.

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 Crohn's 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.

Successful resolution of pneumonia developed in a patient affected by Crohn's disease, rheumatoid arthritis, myasthenia gravis and recurrent uveitis during concomitant treatment with tumour necrosis factor alpha inhibitors and conventional immunosuppressive drugs.

Tumour necrosis factor alpha inhibitors, both infliximab and adalimumab, have been approved for the treatment of both rheumatoid arthritis and Crohn's disease. A slight increase in the risk of infections in patients receiving immunosuppressants and/or biological agents has been reported. Here, we present the case of a 68-year-old woman affected by Crohn's disease, myasthenia gravis, recurrent uveitis and rheumatoid arthritis who developed pneumonia during concomitant treatment with biological agents and conventional immunosuppressive drugs.

Budesonide: teaching an old dog new tricks for inflammatory bowel disease treatment.

Crohn's disease and ulcerative colitis are chronic relapsing inflammatory bowel diseases with extremely great variability in presentation and clinical course. For many decades, corticosteroids and aminosalicylates have been the mainstay of the treatment for both Crohn's disease and ulcerative colitis, for the induction and maintenance of remission, respectively. The main limiting factors for the repeated use of corticosteroids or the use as a maintenance treatment are the very high prevalence of systemic side effects, together with the possibility of developing dependency on and/or resistance to the drug, which are reported in more than one third of patients with inflammatory bowel disease. In the last decade, a number of corticosteroids with enhanced topical activity and low systemic activity have been developed. Among them, budesonide and beclomethasone dipropionate are the most used for the treatment of the inflammatory bowel diseases. Indeed, budesonide is the drug of choice for the treatment of ileo(-cecal) active Crohn's disease with mild-to-moderate activity, due to controlled ileal release. Budesonide foam and/or enemas are also efficacious in the treatment of left-sided/distal ulcerative colitis. Gastro-resistant, extended release tablets characterized by a multimatrix structure (i.e. MMX-budesonide), have also been developed to allow uniform release along the length of the colon. This paper reviews the mechanism-of-action, safety and efficacy of budesonide in the treatment of inflammatory bowel disease.

Oral beclomethasone: a review of its use in inflammatory bowel disease.

Corticosteroids have represented the mainstay of medical treatment for induction of remission in inflammatory bowel disease. Aim of this paper is to review mechanisms of action, safety and efficacy of beclomethasone dipropionate, a steroid with enhanced topical intestinal activity and low systemic activity, in the treatment of inflammatory bowel disease.

Cytapheresis in inflammatory bowel diseases: current evidence and perspectives.

Ulcerative colitis and Crohn's disease are inflammatory bowel diseases with a chronic relapsing course. Management of both conditions is far from being fully satisfactory. For this reason in the last decade a large number of biological therapies, targeting cytokines involved in intestinal inflammation, has been developed with various results in terms of efficacy, safety and costs. Activated granulocytes and monocytes represent the major sources of pro-inflammatory cytokines in the intestinal mucosa, playing a pivotal role in inducing and maintaining intestinal inflammation. Leukocytapheresis using an adsorptive carrier-based system (Adacolumn) or a removal filter column (Cellsorba) has been proposed as a feasible, safe and effective therapy for ulcerative colitis and Crohn's disease. The objective of this paper is to provide an overview on the current knowledge about mechanisms of action, available clinical data and the possible future perspectives for the use of Adacolumn and Cellsorba in the management of inflammatory bowel diseases.

Tumor necrosis factor-alpha monoclonal antibodies for Crohn's disease: tipping the balance.

Crohn's disease (CD) is a chronic inflammatory disorder which may involve any part of gastrointestinal tract. Chronic inflammation is primarily due to an immunological imbalance between pro- and anti-inflammatory cytokines, and with a defective apoptosis of lamina propria T cells. Amongst the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) seems to play a central role in pathogenesis of CD. Over the last years, increasing knowledge on the pathogenesis of CD together with progresses in bio-technology have led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, most importantly TNF-alpha and its receptors. The aim of this paper is to critically review the rationale and state-of-the art for the use TNF- alpha inhibitors in the treatment of CD.

Medical therapy for Crohn's disease: top-down or step-up?

The emergency of effective biological therapy in the treatment of Crohn's disease (CD) has led to a clinical debate about 'step-up versus top-down strategy'. Step-up refers to the classic therapeutic approach, namely progressive intensification of treatment as disease severity increases. Top-down refers to the early introduction, in all CD patients, of intensive therapies, including biological agents and immunosuppressive drugs, with the aim of avoiding complications and improving quality of life, starting from the assumption that these drugs may interfere with the natural history of the disease. Very recently the Belgian IBD research group together with the Gut Club of North Holland designed 'the Step Up versus Top Down Trial'. Combination of infliximab with immunosuppressives at onset was better than the current standard approach in terms of both induction and maintenance of remission. However, several observations still limit the use of infliximab as first-line treatment in adult CD patients. In particular, the epidemiological observation that over 50% of CD patients have a mild disease over time and will never require aggressive therapies is against the indiscriminate use of top-down strategy. Lack of markers able to identify high-risk patients, discussions about long-term safety and the high costs of infliximab are further factors supporting a more careful approach to the management of CD.

Inflammatory Bowel Disease Phenotype as Risk Factor for Cancer in a Prospective Multicentre Nested Case-Control IG-IBD Study.

BACKGROUND AND AIMS: Cancer risk in inflammatory bowel disease [IBD] is still debated. In a prospective, multicentre, nested case-control study, we aimed to characterise incident cases of cancer in IBD. The role of immunomodulators vs clinical characteristics of IBD as risk factors for cancer was also investigated. MATERIALS AND METHODS: From January 2012 to December 2014, each IBD patient with incident cancer was matched with two IBD patients without cancer for: IBD type, gender, and age. Risk factors were assessed by multivariate regression analysis. RESULTS: IBD patients considered numbered 44619: 21953 Crohn's disease [CD], 22666 ulcerative colitis [UC]. Cancer occurred in 174 patients: 99 CD [CD-K], 75 UC [UC-K]. Controls included 198 CD [CD-C], 150 UC [UC-C]. Cancer incidence in IBD was 3.9/1000, higher in CD (4.5/1000 [99/21,953]) than in UC (3.3/1000 [75/22,666]; p = 0.042). Cancers involved: digestive system [36.8%], skin [13.2%], urinary tract [12.1%], lung [8.6%], breast [8%], genital tract [6.9%], thyroid [4.6%], lymphoma [3.5%], others [6.3%]. In CD, penetrating behaviour and combined thiopurines and tumour necrosis factor alpha [TNFα] antagonists were risk factors for cancer overall: odds ratio [OR] (95% confidence interval [CI] 2.33 [1.01-5.47]); 1.97 [1.1-3.5]; and for extracolonic cancers 3.9 [1.56-10.1]; 2.15 [1.17-4.1], respectively. In UC, risk factors were pancolitis and disease-related surgery for cancer overall (OR: 2.52 [1.26-5.1]; 5.09 [1.73-17.1]); disease-related surgery for colorectal cancer [CRC] (OR 3.6 [1.0-12]); and extensive and left-sided vs distal UC for extracolonic cancers (OR: 2.55 [1.15-5.9]; 2.6 [1.04-6.6]), respectively. CONCLUSIONS: In a multicentre study, penetrating CD and extensive UC were risk factors for cancer overall. Cancer incidence was higher in CD than in UC.

Early post-operative endoscopic recurrence in Crohn's disease patients: data from an Italian Group for the study of inflammatory bowel disease (IG-IBD) study on a large prospective multicenter cohort.

INTRODUCTION: The incidence of endoscopic recurrence (ER) in Crohn's disease following curative resection is up to 75% at 1 year. Endoscopy is the most sensitive method to detect the earliest mucosal changes and the severe ER at 1 year seems to predict a clinical relapse. METHODS: The aim of this prospective study was to evaluate the incidence of early ER 6 months after curative resection. Secondary outcome was to evaluate the role of 5-aminosalicylic acid (5-ASA) in the prevention of ER at 6 months. A total of 170 patients were included in the study. They were carried-out from the evaluation of the appearance of ER during a trial performed to assess the role of azathioprine vs. 5-ASA as early treatment of severe ER. All the patients started 5-ASA treatment 2 weeks after surgery. RESULTS: Six months after surgery ER was observed in 105 patients (62%). The endoscopic score was reported as severe in 78.1% of them (82 out of 105). At univariable analysis only ileo-colonic disease influenced the final outcome associating to a lower risk of severe ER (p=0.04; OR 0.52, 95% CI 0.277-0.974). CONCLUSION: In this prospective Italian multicenter IG-IBD study a great proportion of ER occur within 6 months from ileo-colonic resection, with a significant rate of severe ER. Furthermore this study confirms the marginal role of 5-ASA in the prevention of ER. This suggests that post-surgical endoscopic evaluation should be performed at 6 months instead of 1 year to allow an adequate early treatment.

Smad7 antisense oligonucleotide-based therapy for inflammatory bowel diseases.

The aetiology of both Crohn's disease and ulcerative colitis, the major forms of inflammatory bowel diseases in human beings, remains unknown. However, compelling evidence suggests that the associated pathological process in inflammatory bowel disease is driven by an excessive immune response directed against normal components of the bacterial microflora and marked by defects in counter-regulatory mechanisms, such as those involving transforming growth factor-ß1. Indeed, a diminished activity of transforming growth factor-ß1, as indicated by a reduced phosphorylation of Smad3, a signalling molecule associated with the activated transforming growth factor-ß receptor, is evident in the inflamed gut of inflammatory bowel disease patients and this alteration is due to high Smad7, an intracellular inhibitor of Smad3 phosphorylation. Consistently, silencing of Smad7 with a specific antisense oligonucleotide restores transforming growth factor-ß1/Smad3 signalling, thereby leading to inhibition of inflammatory cytokine production and attenuation of experimental colitis in mice. These findings together with the demonstration that Smad7 antisense oligonucleotide is safe and well-tolerated in patients with Crohn's disease indicate that Smad7 antisense oligonucleotide-based pharmaceutical compounds could enter the therapeutic armamentarium of these disorders. In this article we review the available data supporting the pathogenic role of Smad7 in the gut and discuss why Smad7 antisense therapy could help dampen the mucosal inflammation in inflammatory bowel disease.

Guillain-Barrè syndrome after treatment with human anti-tumor necrosis factorα (adalimumab) in a Crohn's disease patient: case report and literature review.

Anti-tumor necrosis factor alpha antibodies have been used with increasing frequency despite the number of reported adverse effects. Further new information is still emerging. Here we report the case of a 71-years-old patient affected by Crohn's disease and HCV-positive who developed Guillain-Barrè syndrome after four injections of fully human anti-tumor necrosis factor alpha antibodies (adalimumab). Indication for the treatment was severe clinical recurrence of Crohn's disease following intestinal resection. Guillain-Barrè syndrome was treated by intravenous immunoglobulins, and methylprednisolone and plasmapheresis were started with a progressive partial resolution of neurological symptoms. To date, Crohn's disease was maintained in clinical remission with low dose steroid therapy.

Cancer in Crohn's Disease patients treated with infliximab: a long-term multicenter matched pair study.

BACKGROUND: The long-term risk of neoplasia in Crohn's disease (CD) patients treated with infliximab is undefined. The aim was to assess, in a multicenter, matched-pair study, whether infliximab use in CD is associated with an increased frequency of neoplasia in the long term. METHODS: A multicenter, long-term, matched-pair study was conducted in 12 referral inflammatory bowel disease (IBD) centers. An initial cohort of 808 CD patients, including 404 infliximab-treated (CD-IFX) and 404 matched CD controls never treated with infliximab (CD-C) studied from 1999 to 2004, was followed up for an additional 4 years (2004-2008). Cases and controls were matched for: sex, age (±5 years), CD site, follow-up (±5 years), immunosuppressant use, and CD duration (±5 years). From 1999 to 2008 the frequency and characteristics of neoplasia were compared between CD-IFX and CD-C. RESULTS: In 2008, 591 patients (304 CD-IFX, 287 CD-C) were in follow-up. Matched couples included 442 patients: 221 CD-IFX and 221 CD-C (median follow-up, months: 72, range 48-114 versus 75, range 44-114). From 1999 to 2008 the frequency of neoplasia among the 591 patients did not differ between CD-IFX (12/304; 3.94%) and CD-C (12/287; 4.19%; P = 0.95). A comparable frequency of neoplasia was also observed between the 221 matched couples (CD-IFX: 8/221; 3.61% versus CD-C: 9/221; 4.07%; P = 1). No specific histotype of cancer appeared associated with infliximab use. CONCLUSIONS: The frequency of neoplasia was comparable in an adult population of CD patients treated or not with infliximab, matched for clinical variables and followed up for a median of 6 years.

Narrow-band imaging endoscopy to assess mucosal angiogenesis in inflammatory bowel disease: a pilot study.

AIM: To investigate whether narrow band imaging (NBI) is a useful tool for the in vivo detection of angiogenesis in inflammatory bowel disease (IBD) patients. METHODS: Conventional and NBI colonoscopy was performed in 14 patients with colonic inflammation (8 ulcerative colitis and 6 Crohn's disease). Biopsy samples were taken and CD31 expression was assayed immunohistochemically; microvascular density was assessed by vessel count. RESULTS: In areas that were endoscopically normal but positive on NBI, there was a significant (P < 0.05) increase in angiogenesis (12 +/- 1 vessels/field vs 18 +/- 2 vessels/field) compared with areas negative on NBI. In addition, in areas that were inflamed on white light endoscopy and positive on NBI, there was a significant (P < 0.01) increase in vessel density (24 +/- 7 vessels/field) compared with NBI-negative areas. CONCLUSION: NBI may allow in vivo imaging of intestinal angiogenesis in IBD patients.