Inhibitors of the Janus Kinases: A New Oral Treatment Option for Ulcerative Colitis.

BACKGROUND: The treatment of ulcerative colitis (UC) is based on conventional therapies (aminosalicylates, corticosteroids, and immunosuppressants) and when these are ineffective, biologic drugs. However, in a substantial portion of patients undergoing treatment with biologic agents there is primary or secondary loss of response. Thus, new therapeutic options are been actively explored; among these, there is interest in the Janus kinase (JAK) inhibitors, small molecules that can be administered orally. METHODS: We carried out an extensive literature search concerning the effects of JAK inhibitors for the treatment of patients with UC. RESULTS: Tofacitinib is the drug more extensively studied in this setting, and it was recently approved in Europe for the treatment of moderate to severe UC. The available data suggest that this drug can be effective in obtaining clinical and endoscopic remission in UC patients unresponsive to other treatments, even in those previously treated with biologic drugs. In addition, the drug was able to improve significantly the quality of life of these patients. There are still few data available for the treatment of UC with other JAK inhibitors. CONCLUSIONS: The JAK inhibitors, in particular tofacitinib, are a new class of orally administered drugs effective for the treatment of UC. However, more studies are needed to ascertain the safety of tofacitinib in the long term and whether other compounds of this class may be equally effective.

Localization of TNF alpha in ileocolonic biopsies of patients with inflammatory bowel disease.

BACKGROUND: Although antitumor necrosis factor alfa (TNFα) agents are widely used to treat patients with inflammatory bowel diseases (IBD) - both Crohn's disease (CD) and ulcerative colitis (UC) - there is still some uncertainty in the cell type expressing TNFα in human ileo-colonic segments. AIMS: We investigated the immunohistochemical (IHC) expression of TNFα in the ileo-colonic segments of patients with both active CD and UC, to establish its anatomic and cellular localization in the inflamed sites. Our aim was to identify patients potentially resistant to anti TNFα agents. PATIENTS AND METHODS: Ileo-colonic slides of complete histological mapping of patients with CD and UC before any treatment was started were obtained, and serial sections assessed for TNFα expression, together with IHC markers for lymphocytes, macrophages, and plasma cells. RESULTS: TNFα was expressed in almost all inflamed segments of IBD patients, albeit with different strength, and was present, in addition to lymphocytes and, to a lesser extent, to macrophages, in plasma cells, where it had a strong positivity, as also demonstrated by colocalization of specific IHC staining. The expression of TNFα was mostly focal in CD patients and more diffuse in UC patients, likely due to the different patterns of inflammation (transmural and mucosal) of the two entities. CONCLUSIONS: In IBD, TNFα is strongly expressed also in plasma cells, and it is easily evidenced by conventional IHC techniques. It remains to be established whether this observation might be useful in future to establish in routine biopsy samples whether patients may be responsive to treatments toward this cytokine.

Enteric glial cells are susceptible to Clostridium difficile toxin B.

Clostridium difficile causes nosocomial/antibiotic-associated diarrhoea and pseudomembranous colitis. The major virulence factors are toxin A and toxin B (TcdB), which inactivate GTPases by monoglucosylation, leading to cytopathic (cytoskeleton alteration, cell rounding) and cytotoxic effects (cell-cycle arrest, apoptosis). C. difficile toxins breaching the intestinal epithelial barrier can act on underlying cells, enterocytes, colonocytes, and enteric neurons, as described in vitro and in vivo, but until now no data have been available on enteric glial cell (EGC) susceptibility. EGCs are crucial for regulating the enteric nervous system, gut homeostasis, the immune and inflammatory responses, and digestive and extradigestive diseases. Therefore, we evaluated the effects of C. difficile TcdB in EGCs. Rat-transformed EGCs were treated with TcdB at 0.1-10 ng/ml for 1.5-48 h, and several parameters were analysed. TcdB induces the following in EGCs: (1) early cell rounding with Rac1 glucosylation; (2) early G2/M cell-cycle arrest by cyclin B1/Cdc2 complex inactivation caused by p27 upregulation, the downregulation of cyclin B1 and Cdc2 phosphorylated at Thr161 and Tyr15; and (3) apoptosis by a caspase-dependent but mitochondria-independent pathway. Most importantly, the stimulation of EGCs with TNF-α plus IFN-γ before, concomitantly or after TcdB treatment strongly increased TcdB-induced apoptosis. Furthermore, EGCs that survived the cytotoxic effect of TcdB did not recover completely and showed not only persistent Rac1 glucosylation, cell-cycle arrest and low apoptosis but also increased production of glial cell-derived neurotrophic factor, suggesting self-rescuing mechanisms. In conclusion, the high susceptibility of EGCs to TcdB in vitro, the increased sensitivity to inflammatory cytokines related to apoptosis and the persistence of altered functions in surviving cells suggest an important in vivo role of EGCs in the pathogenesis of C. difficile infection.

Colonic hypereosinophilia in ulcerative colitis may help to predict the failure of steroid therapy.

BACKGROUND: Although glucocorticosteroids (GS) and mesalazine are effective and widely employed to treat moderate-to-severe ulcerative colitis (UC), information regarding the factors responsible for response to such therapy is still scarce. One of these factors is thought to be an increased number of mucosal eosinophils. The aim of our study was to determine whether the presence of hypereosinophilia in colonic mucosa of UC patients might influence the short-term response to l treatment with GS and mesasalazine. METHODS: Clinical, endoscopic, and pathologic data from patients with a recent diagnosis of moderate UC, who had not undergone treatment, were obtained, and the short-term outcome after 1 month of conventional first-line treatment (mesalazine plus GS) was evaluated. RESULTS: There were 53 patients with a median age of 37 years (95% CI 30-47).Overall, at the end of treatment period 16 (30%) patients responded, whereas a response was not observed in the other 37 (70%) patients. Interestingly, all patients of this latter group had colonic mucosal hypereosinophilia. No significant differences were found between the two groups concerning sex and age at diagnosis, but hypereosinophilia was inversely correlated with the duration of the disease (p = 0.054), and significantly correlated to the localization of UC (p = 0.0023). In addition, The Mayo score was significantly higher in patients with hypereosinophilia (median 8; 95% CI 8-9;) when compared to patients without hypereosinophilia (median 7; 95% CI 7-7, p < 0.0001) including the Mayo endoscopic subscore (median 3; 95% CI 2-3 vs median 2; 95% CI 2-2, respectively; p = 0.007). CONCLUSIONS: The presence of colonic mucosal hypereosinophilia may be useful to predict the short-term outcome to conventional first-line therapy in treatment-naïve UC patients. It remains to be seen whether this might be important in modifying the first-line therapy in this subgroup of patients.

Ustekinumab safety and effectiveness in patients with ulcerative colitis: results from a large real-life study.

BACKGROUND: Ustekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist recently approved for treating ulcerative colitis (UC) but with limited real-world data. Therefore, we evaluated the effectiveness and safety of UST in patients with UC in a real-world setting. RESEARCH DESIGN AND METHODS: This is a multicenter, retrospective, observational cohort study. The primary endpoints were the clinical remission rate (partial Mayo score, PMS, ≤1) and the safety of UST. Other endpoints were corticosteroid-free remission (CSFR) rate, clinical response rate (PMS reduction of at least 2 points), and fecal calprotectin (FC) reduction at week 24. RESULTS: We included 256 consecutive patients with UC (M/F 139/117, median age 52). The clinical remission and clinical response rates at eight weeks were 18.7% (44/235) and 53.2% (125/235), respectively, and 27.6% (42/152) and 61.8% (94/152) at 24 weeks, respectively. At 24 weeks, CSFR was 20.3% (31/152), and FC significantly dropped at week 12 (p = 0.0004) and 24 (p = 0.038). At eight weeks, patients naïve or with one previous biologic treatment showed higher remission (p = 0.002) and clinical >response rates (p = 0.018) than patients previously treated with ≥ 2. Adverse events occurred in six patients (2.3%), whereas four patients (1.6%) underwent colectomy. CONCLUSION: This real-world study shows that UST effectively and safely treats patients with UC.

Prevalence and causes of abnormal liver function in patients with coeliac disease.

BACKGROUND & AIMS: Coeliac disease patients frequently display mild elevation of liver enzymes and this abnormality usually normalizes after gluten-free diet. To investigate the cause and prevalence of altered liver function tests in coeliac patients, basally and after 1 year of gluten-free diet. PATIENTS AND METHODS: Data from 245 untreated CD patients (196 women and 49 men, age range 15-80 years) were retrospectively analysed and the liver function tests before and after diet, as well as associated liver pathologies, were assessed. RESULTS: Overall, 43/245 (17.5%) patients had elevated values of one or both aminotransferases; the elevation was mild (<5 times the upper reference limit) in 41 (95%) and marked (>10 times the upper reference limit) in the remaining 2 (5%) patients. After 1 year of gluten-free diet, aminotransferase levels normalized in all but four patients with HCV infection or primary biliary cirrhosis. CONCLUSIONS: In coeliac patients, hypertransaminaseaemia at diagnosis and the lack of normalization of liver enzymes after 12 months of diet suggest coexisting liver disease. In such instance, further evaluation is recommended to exclude the liver disease. Early recognition and treatment of coeliac disease in patients affected by liver disease are important to improve the liver function and prevent complications.

The role of colonic mast cells and myenteric plexitis in patients with diverticular disease.

BACKGROUND: Gut mast cells represent an important cell population involved in intestinal homeostasis and inflammatory processes. However, their possible role has not to date been investigated in colonic diverticular disease. AIMS: This study aims to evaluate colonic mast cells in patients undergoing surgery for diverticular disease. METHODS: Surgical resection samples from 27 patients undergoing surgery for diverticular disease (12 emergency procedures for severe disease and 15 elective procedures) were evaluated. The number of mast cells was assessed in the various layers by means of a specific antibody (tryptase) and compared with those evaluated in ten controls. In patients with mast cells degranulation, double immunohistochemistry, also assessing nerve fibres, was carried out. In addition, the presence of myenteric plexitis was sought. RESULTS: Compared with controls, the number of mast cells in diverticular patients was significantly increased, both as an overall figure and in the various layers of the large bowel. In patients in whom mast cells degranulation was present, these were always closed to nerve fibres. No differences were found between the two subgroups of patients with respect to the number and distribution of mast cells; however, all patients undergoing emergency surgery (but none of those undergoing elective procedures) had myenteric plexitis, represented by lymphocytic infiltration in 67 % and eosinophilic infiltration in 33 % of cases. CONCLUSIONS: Patients with diverticular disease display an increase of mast cells in the large bowel. The presence of myenteric plexitis in those with complicated, severe disease, suggest that this could represent a histopathologic marker of more aggressive disease.

Residual Lung Abnormalities in Survivors of Severe or Critical COVID-19 at One-Year Follow-Up Computed Tomography: A Narrative Review Comparing the European and East Asian Experiences.

The literature reports that there was a significant difference in the medical impact of the coronavirus disease (COVID-19) pandemic between European and East Asian countries; specifically, the mortality rate of COVID-19 in Europe was significantly higher than that in East Asia. Considering such a difference, our narrative review aimed to compare the prevalence and characteristics of residual lung abnormalities at one-year follow-up computed tomography (CT) after severe or critical COVID-19 in survivors of European and East Asian countries. A literature search was performed to identify articles focusing on the prevalence and characteristics of CT lung abnormalities in survivors of severe or critical COVID-19. Database analysis identified 16 research articles, 9 from Europe and 7 from East Asia (all from China). Our analysis found a higher prevalence of CT lung abnormalities in European than in Chinese studies (82% vs. 52%). While the most prevalent lung abnormalities in Chinese studies were ground-glass opacities (35%), the most prevalent lung abnormalities in European studies were linear (59%) and reticular opacities (55%), followed by bronchiectasis (46%). Although our findings required confirmation, the higher prevalence and severity of lung abnormalities in European than in Chinese survivors of COVID-19 may reflect a greater architectural distortion due to a more severe lung damage.

Real-world efficacy and safety of vedolizumab in managing ulcerative colitis versus Crohn's disease: results from an Italian multicenter study.

BACKGROUND: Vedolizumab (VDZ) can be used to treat refractory ulcerative colitis (UC) and Crohn's disease (CD). We assessed whether there are differences in treating UC vs CD with VDZ. RESEARCH DESIGN AND METHODS: Mayo score in UC and the Harvey-Bradshaw Index (HBI) in CD scored the clinical activity. Achievement and maintenance of clinical remission during the follow-up, and safety were the primary endpoints. RESULTS: 729 patients (475 with UC and 254 with CD), median follow-up of 18 (IQR 6-36) months, were enrolled. Clinical remission at the 6th month of treatment was achieved in 488 (66.9%) patients (74.4% in CD vs 62.9% in UC, p<0.002) while, during the follow-up, no difference was found (81.5% in the UC group and 81.5% pts in the CD group; p=0.537). The clinical remission at the 6th month of treatment (p=0.001) and being naïve to biologics (p<0.0001) were significantly associated with prolonged clinical remission. The clinical response was significantly higher in UC (90.1%) vs CD (84.3%) (p=0.023), and surgery occurred more frequently in CD (1.9% in UC vs 5.1% in CD, p=0.016). CONCLUSION: We found differences when using VDZ in UC vs CD in real life. These parameters can help the physician predict this drug's longterm efficacy.

Increase of colonic mast cells in obstructed defecation and their relationship with enteric glia.

BACKGROUND: Mast cells are involved in visceral hypersensitivity and motor activity of the gastrointestinal tract. However, there is almost no information concerning mast cells in constipated patients. AIMS: The purpose of this study was to investigate mast cells distribution in all colonic layers in controls and severely constipated patients with obstructed defecation. METHODS: Full-thickness specimens from colons of patients undergoing surgery for obstructed defecation due to refractoriness to other therapeutic interventions (n = 11), compared to controls, were obtained and the number of mast cells (evaluated by specific monoclonal antibodies) were counted in the whole viscus and in the various colonic segments (cecum, ascending, transverse, descending, and sigmoid). RESULTS: Compared to controls, constipated patients had significantly higher numbers of mast cells, both as an overall number and in single colonic segments. This increase was especially evident in the mucosa and submucosa. Mast cells were homogeneously represented in the various segment of the large bowel, in both controls and patients. Degranulated mast cells were found to be close to enteric glial cells and glial filaments. CONCLUSIONS: Colonic mast cells are increased in obstructed defecation patients. This might represent a vicariating mechanism to the impaired colonic propulsive activity of these patients.

Update on ozanimod for ulcerative colitis.

Treating moderate to severe ulcerative colitis (UC) has been enriched by the increasing number of drugs available for this disease. However, failure of conventional therapies, an incomplete response, or loss of response to biologics is experienced in many UC patients. Thus, there is still a growing need for new drugs in the therapeutic arsenal for UC. Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator which has been recently approved for UC therapy. In this review, we focus on the mechanism of action of ozanimod hydrochloride in preclinical studies of intestinal inflammation as well as its clinical effectiveness and safety in moderate to severe UC patients. In this population, ozanimod was shown to be significantly more effective than placebo to induce clinical remission. Additionally, in terms of clinical response, corticosteroid-free remission, endoscopic improvement and mucosal healing, ozanimod performed significantly better than placebo in this population. No significant safety concerns about ozanimod emerged from clinical trials in UC.

Non-IBD colitides: clinically useful histopathological clues.

Apart from inflammatory bowel diseases (IBD), there are several other form of colitis that may resemble macroscopically IBD, entering the differential diagnosis. These forms are represented by infectious colitis, ischemic colitis, pseudomembranous colitis, colitis related to diverticular disease, colitis related to mucosal prolapse, drug colitis, allergic colitis, and microscopic colitis. However, to distinguish between these forms is not always easy, and it frequently requires a strict interrelationship between the pathologist and the gastroenterologist. Here we discuss the more frequent forms of non- inflammatory bowel diseases colitides, trying to give useful hints for helping the clinician to better understand the extent to which the pathologist is called to give a definitive response in the differential diagnosis of these entities.

Dermatological Manifestations in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) may be associated with extra-intestinal manifestations. Among these, mucocutaneous manifestations are relatively frequent, often difficult to diagnose and treat, and may complicate the course of the underlying disease. In the present review, a summary of the most relevant literature on the dermatologic manifestations occurring in patients with inflammatory bowel diseases has been reviewed. The following dermatological manifestations associated with IBDs have been identified: (i) specific manifestations with the same histological features of the underlying IBD (occurring only in Crohn's disease); (ii) cutaneous disorders associated with IBDs (such as aphthous stomatitis, erythema nodosum, psoriasis, epidermolysis bullosa acquisita); (iii) reactive mucocutaneous manifestations of IBDs (such as pyoderma gangrenosum, Sweet's syndrome, bowel-associated dermatosis-arthritis syndrome, aseptic abscess ulcers, pyodermatitis-pyostomatitis vegetans, etc.); (iv) mucocutaneous conditions secondary to treatment (including injection site reactions, infusion reactions, paradoxical reactions, eczematous and psoriasis-like reactions, cutaneous infections, and cutaneous malignancies); (v) manifestations due to nutritional malabsorption (such as stomatitis, glossitis, angular cheilitis, pellagra, scurvy, purpura, acrodermatitis enteropathica, phrynoderma, seborrheic-type dermatitis, hair and nail abnormalities). An accurate dermatological examination is essential in all IBD patients, especially in candidates to biologic therapies, in whom drug-induced cutaneous reactions may assume marked clinical relevance.

A simplified method for anal ultrasonography: preliminary report.

BACKGROUND: Anal endosonography (AES) is able to reliably visualize and identify anal sphincter abnormalities. However, dedicated probes are quite expensive. AIM: We describe a simple and less costly method to perform AES in a unit that already has echoendoscopes available by inserting the endoscope through a disposable anoscope filled with standard ultrasound gel. PATIENTS: Subjects without anal abnormalities and patients with anal disease (abscesses, fistulas) were evaluated. RESULTS: Good-quality images were obtained in both controls and patients, with optimal visualization of the anatomic structures and pathologic features. The latter (abscesses, fistulas) were always confirmed by magnetic resonance imaging. CONCLUSIONS: This simple and less costly method allows to perform good-quality AES in units having echoendoscopes availability, without the need of a more expensive dedicated probe.

Novel oral-targeted therapies for mucosal healing in ulcerative colitis.

Ulcerative colitis (UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing (MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.

Enteric glial cells and their role in gastrointestinal motor abnormalities: introducing the neuro-gliopathies.

The role of enteric glial cells has somewhat changed from that of mere mechanical support elements, gluing together the various components of the enteric nervous system, to that of active participants in the complex interrelationships of the gut motor and inflammatory events. Due to their multiple functions, spanning from supporting elements in the myenteric plexuses to neurotransmitters, to neuronal homeostasis, to antigen presenting cells, this cell population has probably more intriguing abilities than previously thought. Recently, some evidence has been accumulating that shows how these cells may be involved in the pathophysiological aspects of some diseases. This review will deal with the properties of the enteric glial cells more strictly related to gastrointestinal motor function and the human pathological conditions in which these cells may play a role, suggesting the possibility of enteric neuro-gliopathies.

Usefulness of Different Pathological Scores to Assess Healing of the Mucosa in Inflammatory Bowel Diseases: A Real Life Study.

The concept of remission for patients with inflammatory bowel diseases has recently evolved, and should also include histological healing of the mucosa, difficult to evaluate since there is no agreement on pathological scores and those available are quite complex to use in the daily routine. We evaluated the possible usefulness of a simplified pathological score to assess histological healing of the mucosa in inflammatory bowel diseases patients compared with four commonly proposed pathological scores. Slides from 24 patients (12 Crohn's disease, 12 ulcerative colitis, age range 24-62 years), pre- and post-treatment with biological agents and displaying endoscopic remission were assessed by two pathologists. Pre- and post-treatment results and the time employed to calculate the various scores were obtained. All scores were useful to document highly significant post-treatment decreases of histological activity. However, the simplified score needed significant less time to be calculated for each slide, had high inter-rater agreement, and avoided subjectivity from the pathologists. The simplified score is easy to calculate and seems apt to document histological healing of the mucosa, in a manner similar to the more complex scores. It remains to be established whether this score could simplify the daily routinary practice in this context.